Preparation of the N G -acylated imidazolylpropylguanidines 4.63-4.83

synthesis and structure-activity relationships at the histamine receptor subtypes

4.3.3 Summary and conclusion

4.4.1.12 Preparation of the N G -acylated imidazolylpropylguanidines 4.63-4.83

General procedure

The pertinent Boc/trityl-protected N^G-acylated imidazolylpropylguanidine was stirred for 5 h in a mixture of TFA (5.0 mL) and DCM (20 mL). After removing the solvent in vacuo, the crude product was purified by preparative HPLC. All compounds were dried by lyophilization and obtained as trifluoroacetates.

N¹-[2-(1H-Imidazol-4-yl)ethyl]-N²-(3-phenylbutanoyl)guanidine (4.63)

The title compound was prepared from 4.42 (220 mg, 0.41 mmol) according to the general procedure. Purification by preparative HPLC (MeCN/0.1 % TFA (aq.): 22.5/72.5) yielded a colorless semisolid compound (80 mg, 37 %). ¹H-NMR (300 MHz, D₂O, trifluoroacetate): δ [ppm] = 1.19 (d, 3H, ³J = 7.0 Hz, PhCH₃CH), 2.59 (dd, 1H, ²J = 14.8 Hz, ³J = 9.2 Hz, PhCH3CH-CH2), 2.69 (dd, 1H, ²J = 14.8 Hz, ³J = 6.3 Hz, PhCH3CH-CH2), 2.93 (t, 2H, ³J = 6.6 Hz, Im-4-CH₂), 3.03 – 3.21 (m, 1H, PhCH₃CH), 3.47 (t, 2H, ³J = 6.6 Hz, Im-4-CH₂-CH₂), 7.10 – 7.32 (m, 6H, Ph-H + Im-5-H), 8.50 (d, 1H, ⁴J = 1.4 Hz, Im-2-H). ¹³C-NMR (75 MHz, D2O, trifluoroacetate): δ [ppm] = 21.18 (+, PhCH₃CH), 22.80 (-, Im-4-CH₂), 36.61 (+, PhCH₃CH), 39.85 (-, Im-4-CH2-CH2), 45.06 (-, PhCH3CH-CH2), 116.63 (+, Im-C-5), 126.88 (+, 2 Ph-C), 126.99 (+, Ph-C-4), 128.89 (+, 2 Ph-C), 129.38 (C_quat, Im-C-4), 133.56 (+, Im-C-2), 144.84 (Cquat, Ph-C-1), 152.97 (Cquat, C=N), 176.02 (Cquat, C=O). IR (cm^-1) = 3144, 3034, 2847, 1662,

Structure-activity relationships of N^G-acylated imidazolylalkylguanidines 151

1630, 1177, 1131. HRMS (EI-MS) calcd. for C16H21N5O [M^+•] 299.1746; found 299.1744.

C₁₆H₂₁N₅O · 2 TFA (527.42).

N¹-[2-(1H-Imidazol-4-yl)ethyl]-N²-[3-(thiophen-2-yl)butanoyl]guanidine (4.64)

The title compound was prepared from 4.43 (240 mg, 0.44 mmol) according to the general procedure. Purification by preparative HPLC (MeCN/0.1 % TFA (aq.): 25/75) yielded a colorless semisolid compound (62 mg, 27 %). ¹H-NMR (300 MHz, D₂O, trifluoroacetate): δ [ppm] = 1.26 (d, 3H, ³J = 7.0 Hz, ThioCH3CH), 2.60 (dd, 1H, ²J = 15.0 Hz, ³J = 9.0 Hz, ThioCH₃CH-CH₂), 2.72 (dd, 1H, ²J = 15.0 Hz, ³J = 6.2 Hz, ThioCH₃CH-CH₂), 2.95 (t, 2H, ³J = 6.6 Hz, Im-4-CH2), 3.40 – 3.56 (m, 3H, Im-4-CH2-CH2 + ThioCH3CH), 6.81 (ddd, 1H, ³J = 3.5 Hz, ⁴J = 1.2 Hz, ⁴J = 0.7 Hz, Thio-3-H), 6.88 (dd, 1H, ³J = 5.0 Hz, ³J = 3.5 Hz, Thio-4-H), 7.14 – 7.20 (m, 2H, Thio-5-H + Im-5-H), 8.51 (d, 1H, ⁴J = 1.4 Hz, Im-2-H). ¹³C-NMR (75 MHz, D₂O, trifluoroacetate): δ [ppm] = 22.12 (+, ThioCHCH₃), 22.82 (-, Im-4-CH₂), 31.95 (+, ThioCH₃CH), 39.92 (-, Im-4-CH₂-CH₂), 46.06 (-, ThioCH₃CH-CH₂), 116.69 (+, Im-C-5), 123.67, 123.90 (+, Thio-C-3,4), 127.15 (+, Thio-C-5), 129.40 (C_quat, 4), 133.61 (+, Im-C-2), 148.70 (C_quat, Thio-C-2), 153.02 (C_quat, C=N), 175.52 (C_quat, C=O). IR (cm^-1) = 3139, 3023, 2852, 1662, 1626, 1182, 1126. HRMS (EI-MS) calcd. for C14H19N5OS [M^+•] 305.1310; found 305.1312. C₁₄H₁₉N₅OS · 2 TFA (533.44).

N¹-(3,3-Diphenylpropanoyl)-N²-[2-(1H-imidazol-4-yl)ethyl]guanidine (4.65)

The title compound was prepared from 4.44 (350 mg, 0.58 mmol) according to the general procedure. Purification by preparative HPLC (MeCN/0.1 % TFA (aq.): 35/65) yielded a white solid (80 mg, 23 %); mp 69 – 72 °C. ¹H-NMR (300 MHz, D₂O, trifluoroacetate): δ [ppm] = 2.90 (t, 2H, ³J = 6.6 Hz, Im-4-CH2), 3.16 (d, 2H, ³J = 8.2 Hz, Ph2CH-CH2), 3.45 (t, 2H, ³J = 6.6 Hz, Im-4-CH₂-CH₂), 4.42 (t, 1H, ³J = 8.2 Hz, Ph₂CH), 7.10 (d, 1H, ⁴J = 1.3 Hz, Im-5-H), 7.13 – 7.31 (m, 10H, Ph-H), 8.47 (d, 1H, ⁴J = 1.3 Hz, Im-2-H). ¹³C-NMR (75 MHz, D2O, trifluoroacetate): δ [ppm] = 22.78 (-, Im-4-CH₂), 39.88 (-, Im-4-CH₂-CH₂), 42.25 (-, Ph₂ CH-CH₂), 46.52 (+, Ph₂CH), 116.59 (+, Im-C-5), 127.16 (+, 2 Ph-C-4), 127.40 (+, 4 Ph-C), 129.04 (+, 4 Ph-C), 129.35 (Cquat, Im-C-4), 133.53 (+, Im-C-2), 142.82 (Cquat, 2 Ph-C-1), 152.93 (C_quat, C=N), 175.22 (C_quat, C=O). IR (cm^-1) = 3141, 2989, 2900, 1667, 1594, 1190, 1131.

HRMS (EI-MS) calcd. for C₂₁H₂₃N₅O [M^+•] 361.1903; found 310.1905. C₂₁H₂₃N₅O · 2 TFA (589.49).

N¹-[4-(1H-Imidazol-4-yl)butyl]-N²-(3-phenylbutanoyl)guanidine (4.66)

The title compound was prepared from 4.45 (330 mg, 0.58 mmol) according to the general procedure. Purification by preparative HPLC (MeCN/0.1 % TFA (aq.): 27.5/72.5) yielded a colorless semisolid compound (160 mg, 50 %). ¹H-NMR (300 MHz, D₂O, trifluoroacetate): δ

[ppm] = 1.22 (d, 3H, ³J = 7.0 Hz, PhCH3CH), 1.47 – 1.65 (m, 4H, Im-4-CH2-CH2-CH2),2.57 – 2.67 (m, 3H, Im-4-CH₂ + PhCH₃CH-CH₂), 2.73 (dd, 1H, ²J = 14.7 Hz, ³J = 6.3 Hz, PhCH₃ CH-CH2), 3.11 – 3.26 (m, 3H, Im-4-(CH2)3-CH2 + PhCH3CH), 7.10 (d, 1H, ⁴J = 1.4 Hz, Im-5-H), 7.13 – 7.32 (m, 5H, Ph-H), 8.25 (d, 1H, ⁴J = 1.4 Hz, Im-2-H). ¹³C-NMR (75 MHz, D₂O, trifluoroacetate): δ [ppm] = 21.19 (+, PhCH3CH), 23.33, 24.81, 26.46 (-, Im-4-CH2-CH2-CH2), 36.71 (+, PhCH₃CH), 40.94 (-, Im-4-(CH₂)₃-CH₂), 45.17 (-, PhCH₃CH-CH₂), 115.27 (+, Im-C-5), 126.93 (+, 2 Ph-C), 127.02 (+, Ph-C-4), 128.94 (+, 2 Ph-C), 132.78 (+, Im-C-2), 133.42 (C_quat, Im-C-4), 144.92 (C_quat, Ph-C-1), 152.72 (C_quat, C=N), 176.06 (C_quat, C=O). IR (cm^-1) = 3140, 2969, 2868, 1662, 1627, 1178, 1130. HRMS (EI-MS) calcd. for C₁₈H₂₅N₅O [M^+•] 327.2059; found 327.2059. C₁₈H₂₅N₅O · 2 TFA (555.47).

N¹-[4-(1H-Imidazol-4-yl)butyl]-N²-[3-(thiophen-2-yl)butanoyl]guanidine (4.67)

The title compound was prepared from 4.46 (270 mg, 0.47 mmol) according to the general procedure. Purification by preparative HPLC (MeCN/0.1 % TFA (aq.): 27.5/72.5) yielded a colorless semisolid compound (150 mg, 57 %). Prep. HPLC (MeCN/0.1 % TFA (aq.):

27.5/72.5). ¹H-NMR (300 MHz, D₂O, trifluoroacetate): δ [ppm] = 1.27 (d, 3H, ³J = 7.0 Hz, ThioCH3CH), 1.46 – 1.64 (m, 4H, Im-4-CH2-CH2-CH2), 2.55 – 2.67 (m, 3H, Im-4-CH2 + ThioCH₃CH-CH₂), 2.72 (dd, 1H, ²J = 14.9 Hz, ³J = 6.2 Hz, ThioCH₃CH-CH₂), 3.18 (t, 2H, ³J = 6.2 Hz, Im-4-(CH2)3-CH2), 3.42 – 3.56 (m, 1H, ThioCH3CH), 6.82 (ddd, 1H, ³J = 3.5 Hz, ⁴J = 1.3 Hz, ⁴J = 0.6 Hz, Thio-3-H), 6.85 (dd, 1H, ³J = 5.0 Hz, ³J = 3.5 Hz, Thio-4-H), 7.10 (d, 1H,

4J = 1.4 Hz, Im-5-H), 7.15 (dd, 1H, ³J = 5.0 Hz, ⁴J = 1.3 Hz, Thio-5-H), 8.43 (d, 1H, ⁴J = 1.4 Hz, Im-2-H). ¹³C-NMR (75 MHz, D₂O, trifluoroacetate): δ [ppm] = 22.13 (+, ThioCH₃CH), 23.30, 24.81, 26.43 (-, Im-4-CH2-CH2-CH2), 32.00 (+, ThioCH3CH), 40.94 (-, Im-4-(CH2)3 -CH₂), 46.08 (-, ThioCH₃CH-CH₂), 115.24 (+, Im-C-5), 123.67, 123.88 (+, Thio-C-3,4), 127.13 (+, Thio-C-5), 132.73 (+, Im-C-2), 133.38 (C_quat, Im-C-4), 148.73 (C_quat, Thio-C-2), 152.70 (C_quat, C=N), 175.50 (C_quat, C=O). IR (cm^-1) = 3133, 2989, 2900, 1662, 1627, 1178, 1129.

HRMS (EI-MS) calcd. for C16H23N5OS [M^+•] 333.1623; found 333.1618. C16H23N5OS · 2 TFA (561.50).

N¹-(3,3-Diphenylpropanoyl)-N²-[4-(1H-imidazol-4-yl)butyl]guanidine (4.68)

The title compound was prepared from 4.47 (220 mg, 0.35 mmol) according to the general procedure. Purification by preparative HPLC (MeCN/0.1 % TFA (aq.): 35/65) yielded a white solid (96 mg, 44 %); mp 78 – 82 °C. ¹H-NMR (300 MHz, D2O, trifluoroacetate): δ [ppm] = 1.48 – 1.64 (m, 4H, Im-4-CH₂-CH₂-CH₂),2.64 (t, 2H, ³J = 6.8 Hz, Im-4-CH₂), 3.15 – 3.26 (m, 4H, Im-4-(CH2)3-CH2 + Ph2CHCH2), 4.50 (t, 1H, ³J = 6.8 Hz, Ph2CH), 7.10 (d, 1H, ⁴J = 1.4 Hz, Im-5-H), 7.15 – 7.34 (m, 10H, Ph-H), 8.47 (d, 1H, ⁴J = 1.4 Hz, Im-2-H). ¹³C-NMR (75 MHz, D2O, trifluoroacetate): δ [ppm] = 23.34, 24.81, 26.44 (-, Im-4-CH2-CH2-CH2), 41.01 (-,

Im-4-Structure-activity relationships of N^G-acylated imidazolylalkylguanidines 153

(CH2)3-CH2), 42.38 (-, Ph2CH-CH2), 46.66 (+, Ph2CH), 115.28 (+, Im-C-5), 127.22 (+, 2 Ph-C-4), 127.57 (+, 4 Ph-C), 129.11 (+, 4 Ph-C), 132.79 (+, Im-C-2), 133.42 (C_quat, Im-C-4), 142.95 (Cquat, Ph-C-1), 152.71 (Cquat, C=N), 175.30 (Cquat, C=O). IR (cm^-1) = 3027, 2866, 1665, 1601, 1181, 1128. HRMS (EI-MS) calcd. for C₂₃H₂₇N₅O [M^+•] 389.2216; found 389.2220. C₂₃H₂₇N₅O

· 2 TFA (617.54).

N¹-[4-(1H-Imidazol-4-yl)butyl]-N²-[3-phenyl-3-(thiazol-2-yl)propanoyl]guanidine (4.69) The title compound was prepared from 4.48 (210 mg, 0.33 mmol) according to the general procedure. Purification by preparative HPLC (MeCN/0.1 % TFA (aq.): 25/75) yielded a pale yellow semisolid compound (170 mg, 70 %). ¹H-NMR (300 MHz, D2O, trifluoroacetate): δ [ppm] = 1.41 – 1.62 (m, 4H, Im-4-CH₂-CH₂-CH₂),2.59 (t, 2H, ³J = 6.8 Hz, Im-4-CH₂), 3.15 (t, 2H, ³J = 6.3 Hz, Im-4-(CH₂)₃-CH₂), 3.31 (dd, 1H, ²J = 16.6 Hz, ³J = 8.1 Hz, PhThiazCH-CH₂), 3.46 (dd, 1H, ²J = 16.6 Hz, ³J = 7.3 Hz, PhThiazCH-CH₂), 5.04 (dd, 1H, ³J = 8.1 Hz, ³J = 7.3 Hz, PhThiazCH), 7.04 (d, 1H, ⁴J = 1.4 Hz, Im-5-H), 7.21 – 7.35 (m, 5H, Ph-H), 7.65 (d, 1H, ³J

= 3.7 Hz, Thiaz-5-H), 7.79 (d, 1H, ³J = 3.7 Hz, Thiaz-4-H), 8.41 (d, 1H, ⁴J = 1.4 Hz, Im-2-H).

13C-NMR (75 MHz, D₂O, trifluoroacetate): δ [ppm] = 23.26, 24.77, 26.37 (-, Im-4-CH₂-CH₂ -CH2), 41.00 (-, Im-4-(CH2)3-CH2), 41.50 (-, PhThiazCHCH2), 42.95 (+, PhThiazCH), 115.19 (+, Im-C-5), 122.41 (+, Thiaz-C-5), 127.85 (+, 2 C), 127.85 (+, C-4), 128.73 (+, 2 Ph-C), 132.69 (+, Im-C-2), 133.32 (Cquat, Im-C-4), 137.14 (+, Thiaz-C-4), 138.11 (Cquat, Ph-C-1), 152.51 (C_quat, C=N), 172.92, 175.30 (C_quat, Thiaz-C-2 + C=O). IR (cm^-1) = 3133, 2989, 2901, 1663, 1627, 1131. HRMS (EI-MS) calcd. for C20H24N6OS [M^+•] 396.1735; found 396.1732.

C₂₀H₂₄N₆OS · 3 TFA (738.58).

N¹-[3-(1H-Imidazol-4-yl)-2-methylpropyl]-N²-(3-phenylbutanoyl)guanidine (4.70)

The title compound was prepared from 4.49 (250 mg, 0.44 mmol) according to the general procedure. Purification by preparative HPLC (MeCN/0.1 % TFA (aq.): 30/70) yielded a colorless semisolid compound (106 mg, 43 %). ¹H-NMR (300 MHz, CD₃OD, trifluoroacetate):

δ [ppm] = 0.98 (d, 3H, ³J = 6.7 Hz, Im-4-CH₂-CH-CH₃), 1.32 (d, 3H, ³J = 7.0 Hz, PhCH₃CH), 2.09 – 2.26 (m, 1H, Im-4-CH2-CH), 2.59 (dd, 1H, ²J = 15.0 Hz, ³J = 8.7 Hz, Im-4-CH2), 2.74 (dd, 1H, ²J = 15.2 Hz, ³J = 7.4 Hz, PhCH₃CH-CH₂), 2.81 (dd, 1H, ²J = 15.2 Hz, ³J = 7.7 Hz, PhCH3CH-CH2), 2.86 (ddd, 1H, ²J = 15.0 Hz, ³J = 8.7 Hz, ⁴J = 1.7 Hz, Im-4-CH2), 3.14 – 3.39 (m, 3H, Im-4-CH₂-CH-CH₂ + PhCH₃CH), 7.11 – 7.32 (m, 5H, Ph-H), 7.37 (d, 1H, ⁴J = 1.3 Hz, Im-5-H), 8.79 (d, 1H, ⁴J = 1.3 Hz, Im-2-H). ¹³C-NMR (75 MHz, CD3OD, trifluoroacetate): δ [ppm] = 17.23 (+, Im-4-CH₂-CHCH₃), 22.32 (+, PhCH₃CH), 29.83 (-, Im-4-CH₂), 33.76 (+, Im-4-CH2-CH), 37.75 (+, PhCH3CH), 46.17 (-, PhCH3CH-CH2), 47.57 (-, Im-4-CH2-CH-CH2), 117.97 (+, Im-C-5), 127.72 (+, Ph-C-4), 127.97 (+, 2 Ph-C), 129.68 (+, 2 Ph-C), 133.13 (C_quat, Im-C-4), 134.99 (+, Im-C-2), 146.42 (Cquat, Ph-C-1), 155.45 (Cquat, C=N), 176.23 (Cquat, C=O).

IR (cm^-1) = 3139, 2972, 2901, 1663, 1627, 1174, 1136. HRMS (LSI-MS) calcd. for C18H26N5O [M + H]⁺ 328.2132; found 328.2137. C₁₈H₂₆N₅O · 2 TFA (555.47).

N¹-[3-(1H-Imidazol-4-yl)-2-methylpropyl]-N²-[3-(thiophen-2-yl)butanoyl]guanidine (4.71) The title compound was prepared from 4.50 (250 mg, 0.43 mmol) according to the general procedure. Purification by preparative HPLC (MeCN/0.1 % TFA (aq.): 27.5/72.5) yielded a colorless semisolid compound (90 mg, 37 %). ¹H-NMR (300 MHz, CD₃OD, trifluoroacetate): δ [ppm] = 0.99 (d, 3H, ³J = 6.7 Hz, Im-4-CH2-CH-CH3), 1.40 (d, 3H, ³J = 7.0 Hz, ThioCH3CH), 2.09 – 2.30 (m, 1H, Im-4-CH₂-CH), 2.61 (dd, 1H, ²J = 15.0 Hz, ³J = 8.7 Hz, Im-4-CH₂), 2.77 (dd, 1H, ²J = 15.4 Hz, ³J = 7.2 Hz, ThioCH3CH-CH2),2.84 (dd, 1H, ²J = 15.4 Hz, ³J = 7.5 Hz, ThioCH₃CH-CH₂), 2.88 (dd, 1H, ²J = 15.0 Hz, ³J = 5.3 Hz, Im-4-CH₂), 3.17 – 3.31 (m, 2H, Im-4-CH₂-CH-CH₂), 3.57 – 3.71 (m, 1H, ThioCH₃CH), 6.87 – 6.93 (m, 2H, Thio-3,4-H), 7.19 (dd, 1H, ³J = 4.1 Hz, ⁴J = 2.2 Hz, Thio-5-H), 7.37 (s, 1H, Im-5-H), 8.79 (d, 1H, ⁴J = 1.3 Hz, Im-2-H). ¹³C-NMR (75 MHz, CD₃OD, trifluoroacetate): δ [ppm] = 17.25 (+, Im-4-CH₂-CH-CH₃), 23.22 (+, ThioCH₃CH), 29.85 (-, Im-4-CH₂), 33.00 (+, ThioCH₃CH), 33.78 (+, Im-4-CH₂-CH), 47.09 (-, ThioCH-CH₂), 47.63 (-, Im-4-CH₂-CH-CH₂), 117.98 (+, Im-C-5), 124.24, 124.48 (+, Thio-C-3,4), 127.77 (+, Thio-C-5), 133.13 (Cquat, Im-C-4), 134.99 (+, Im-C-2), 149.96 (Cquat, Thio-C-2), 155.46 (C_quat, C=N), 175.73 (C_quat, C=O). IR (cm^-1) = 3133, 2970, 2901, 1662, 1627, 1184, 1127. HRMS (EI-MS) calcd. for C16H24N5OS [M + H]⁺ 334.1696; found 334.1692.

C₁₆H₂₃N₅OS · 2 TFA (561.50).

N¹-(3,3-Diphenylpropanoyl)-N²-[3-(1H-imidazol-4-yl)-2-methylpropyl]guanidine (4.72) The title compound was prepared from 4.51 (210 mg, 0.33 mmol) according to the general procedure. Purification by preparative HPLC (MeCN/0.1 % TFA (aq.): 35/65) yielded a white solid (100 mg, 49 %); mp 54 – 57 °C. ¹H-NMR (600 MHz, D₂O, trifluoroacetate, COSY): δ [ppm] = 0.81 (d, 3H, ³J = 6.7 Hz, Im-4-CH2-CH-CH3), 2.00 – 2.11 (m, 1H, Im-4-CH2-CH), 2.48 (dd, 1H, ²J = 15.2 Hz, ³J = 8.4 Hz, Im-4-CH₂), 2.63 (dd, 1H, ²J = 15.2 Hz, ³J = 5.8 Hz, Im-4-CH₂), 3.07 (dd, 1H, ²J = 13.9 Hz, ³J = 6.8 Hz, Im-4-CH₂-CH-CH₂), 3.11 (dd, 1H, ²J = 13.9 Hz,

3J = 7.0 Hz, Im-4-CH2-CH-CH2), 3.20 (d, 2H, ³J = 8.2 Hz, Ph2CH-CH2), 4.47 (t, 1H, ³J = 8.2 Hz, Ph₂CH), 7.10 (s, 1H, Im-5-H), 7.15 – 7.30 (m, 10H, Ph-H), 8.36 (s, 1H, Im-2-H). ¹³C-NMR (150 MHz, D2O, trifluoroacetate, HSQC, HMBC): δ [ppm] = 16.02 (+, Im-4-CH2-CH-CH3), 28.25 (-, Im-4-CH₂), 31.86 (+, Im-4-CH₂-CH), 42.29 (-, Ph₂CH-CH₂), 46.31 (-, Im-4-CH₂ -CH-CH2), 46.56 (+, Ph2CH), 116.26 (+, Im-C-5), 127.18 (+, 2 Ph-C-4), 127.50 (+, 4 Ph-C), 129.06 (+, 4 Ph-C), 131.13 (C_quat, Im-C-4), 133.02 (+, Im-C-2), 142.86 (C_quat, 2 Ph-C-1), 152.90 (Cquat, C=N), 175.29 (Cquat, C=O). IR (cm^-1) = 3182, 3033, 2858, 1663, 1629, 1188, 1130.

HRMS (LSI-MS) calcd. for C₂₃H₂₈N₅O [M + H]⁺ 390.2288; found 390.2285. C₂₃H₂₇N₅O · 2 TFA (617.54).

Structure-activity relationships of N^G-acylated imidazolylalkylguanidines 155

N¹-[3-(1H-Imidazol-4-yl)-2-methylpropyl]-N² -[3-phenyl-3-(thiazol-2-yl)propanoyl]-guanidine (4.73)

The title compound was prepared from 4.52 (220 mg, 0.34 mmol) according to the general procedure. Purification by preparative HPLC (MeCN/0.1 % TFA (aq.): 35/65) yielded a pale yellow semisolid (79 mg, 31 %). ¹H-NMR (600 MHz, CD3OD, trifluoroacetate): δ [ppm] = 1.00 (d, 3H, ³J = 6.7 Hz, Im-4-CH₂-CH-CH₃), 2.16 – 2.25 (m, 1H, Im-4-CH₂-CH), 2.62 (dd, 1H, ²J = 15.1 Hz, ³J = 8.8 Hz, Im-4-CH2), 2.89 (ddd, 1H, ²J = 15.1 Hz, ³J = 5.4 Hz, ⁴J = 2.8 Hz, Im-4-CH₂), 3.19 – 3.30 (m, 3H, Im-4-CH₂-CH-CH₂ + PhThiazCH-CH₂), 3.61 (dd, 1H, ²J = 16.4 Hz,

3J = 8.4 Hz, PhThiazCH-CH₂), 4.99 (dd, 1H, ³J = 8.4 Hz, ³J = 6.7 Hz, PhThiazCH), 7.27 – 7.38 (m, 5H, Ph-H), 7.39 (s, 1H, Im-5-H), 7.48 (d, 1H, ³J = 3.3 Hz, Thiaz-5-H), 7.71 (d, 1H, ³J

= 3.3 Hz, Thiaz-4-H), 8.81 (d, 1H, ⁴J = 1.0 Hz, Im-2-H). ¹³C-NMR (150 MHz, CD₃OD, trifluoroacetate, HSQC): δ [ppm] = 17.18 (+, Im-4-CH₂-CH-CH₃), 29.80 (-, Im-4-CH₂), 33.74 (+, Im-4-CH₂-CH), 43.55 (-, PhThiazCHCH₂), 45.94 (+, PhThiazCH), 47.58 (-, Im-4-CH₂ -CH-CH2), 117.94 (+, Im-C-5), 121.20 (+, Thiaz-C-5), 128.91 (+ , Ph-C-4), 129.05 (+, 2 Ph-C), 130.09 (+, 2 Ph-C), 133.09 (C_quat, Im-C-4), 134.98 (+, Im-C-2), 142.31 (C_quat, Ph-C-1), 142.83 (+, Thiaz-C-4), 155.32 (Cquat, C=N), 174.29, 174.93 (Cquat, C=O + Thiaz-C-2). IR (cm^-1) = 3131, 3030, 2853, 1663, 1627, 1170, 1130. HRMS (EI-MS) calcd. for C₂₀H₂₄N₆OS [M^+•] 396.1732; found 396.1731. C20H24N6OS · 3 TFA (738.58).

N¹-[3-(5-Methyl-1H-imidazol-4-yl)propyl]-N²-(3-phenylbutanoyl)guanidine (4.74)

The title compound was prepared from 4.53 (340 mg, 0.43 mmol) according to the general procedure. Purification by preparative HPLC (MeCN/0.1 % TFA (aq.): 30/70) yielded a colorless semisolid compound (147 mg, 62 %). ¹H-NMR (300 MHz, D2O, trifluoroacetate): δ [ppm] = 1.20 (d, 3H, ³J = 7.0 Hz, PhCH₃CH), 1.76 – 1.88 (m, 2H, Im-4-CH₂-CH₂),2.09 (s, 3H, Im-5-CH₃), 2.58 (t, 2H, ³J = 7.4 Hz, Im-4-CH₂), 2.62 (dd, 1H, ²J = 15.0 Hz, ³J = 9.2 Hz, PhCH₃CH-CH₂), 2.62 (dd, 1H, ²J = 15.0 Hz, ³J = 6.4 Hz, PhCH₃CH-CH₂), 3.09 – 3.26 (m, 3H, Im-4-(CH₂)₂-CH₂+ PhCH₃CH), 7.12 – 7.33 (m, 5H, Ph-H), 8.25 (s, 1H, Im-2-H). ¹³C-NMR (75 MHz, CD3OD, trifluoroacetate): δ [ppm] = 8.78 (+, Im-5-CH3), 21.55 (-, Im-4-CH2), 22.37 (+, PhCH₃CH), 28.22 (-, Im-4-CH₂-CH₂), 37.69 (+, PhCH₃CH), 41.65 (-, Im-4-(CH₂)₂-CH₂), 46.10 (-, PhCH3CH-CH2), 126.85 (Cquat, Im-C-5), 127.73 (+, Ph-C-4), 127.97 (+, 2 Ph-C), 129.03 (C_quat, Im-C-4), 129.68 (+, 2 Ph-C), 133.32 (+, Im-C-2), 146.45 (C_quat, Ph-C-1), 155.26 (C_quat, C=N), 176.09 (Cquat, C=O). IR (cm^-1) = 3027, 2901, 1663, 1603, 1178, 1127. HRMS (EI-MS) calcd. for C₁₈H₂₅N₅O [M^+•] 327.2059; found 327.2052. C₁₈H₂₅N₅O · 2 TFA (555.47).

N¹-[3-(5-Methyl-1H-imidazol-4-yl)propyl]-N²-[3-(thiophen-2-yl)butanoyl]guanidine (4.75) The title compound was prepared from 4.54 (470 mg, 0.70 mmol) according to the general procedure. Purification by preparative HPLC (MeCN/0.1 % TFA (aq.): 27.5/72.5) yielded a

colorless semisolid compound (220 mg, 56 %). ¹H-NMR (300 MHz, D2O, trifluoroacetate): δ [ppm] = 1.29 (d, 3H, ³J = 7.0 Hz, ThioCH₃CH), 1.79 – 1.94 (m, 2H, Im-4-CH₂-CH₂), 2.12 (s, 3H, Im-5-CH3), 2.62 (t, 2H, ³J = 7.4 Hz, Im-4-CH2), 2.65 (dd, 1H, ²J = 15.0 Hz, ³J = 9.0 Hz, ThioCH₃CH-CH₂), 2.75 (dd, 1H, ²J = 15.0 Hz, ³J = 6.2 Hz, ThioCH₃CH-CH₂), 3.20 (t, 2H, ³J = 6.7 Hz, Im-4-(CH2)2-CH2), 3.45 – 3.60 (m, 1H, ThioCH3CH), 6.86 (ddd, 1H, ³J = 3.5 Hz, ⁴J = 1.3 Hz, ⁴J = 0.7 Hz, Thio-3-H), 6.90 (dd, 1H, ³J = 5.0 Hz, ³J = 3.5 Hz, Thio-4-H), 7.20 (dd, 1H,

3J = 5.0 Hz, ⁴J = 1.3 Hz, Thio-5-H), 8.28 (s, 1H, Im-2-H). ¹³C-NMR (75 MHz, D2O, trifluoroacetate): δ [ppm] = 7.94 (+, Im-5-CH₃), 20.01 (-, Im-4-CH₂), 22.25 (+, ThioCHCH₃), 26.26 (-, Im-4-CH₂-CH₂), 31.93 (+, ThioCH₃CH), 40.44 (-, Im-4-(CH₂)₂-CH₂), 45.98 (-, ThioCH₃CH-CH₂), 123.69, 123.93 (+, Thio-C-3,4), 125.44 (C_quat, Im-C-5), 127.04 (+, Thio-C-5), 127.20 (C_quat, Im-C-4), 131.37 (+, Im-C-2), 148.80 (C_quat, Thio-C-2), 152.83 (C_quat, C=N), 175.50 (C_quat, C=O). IR (cm^-1) = 3036, 2876, 1662, 1177, 1128. HRMS (EI-MS) calcd. for C₁₆H₂₃N₅OS [M^+•] 333.1623; found 333.1621. C₁₆H₂₃N₅OS · 2 TFA (561.50).

N¹-(3,3-Diphenylpropanoyl)-N²-[3-(5-methyl-1H-imidazol-4-yl)propyl]guanidine (4.76) The title compound was prepared from 4.55 (260 mg, 0.36 mmol) according to the general procedure. Purification by preparative HPLC (MeCN/0.1 % TFA (aq.): 35/65) yielded a white solid (120 mg, 54 %); mp 54 – 57 °C. ¹H-NMR (300 MHz, D₂O, trifluoroacetate): δ [ppm] = 1.74 – 1.89 (m, 2H, Im-4-CH2-CH2), 2.06 (s, 3H, Im-5-CH3), 2.57 (t, 2H, ³J = 7.4 Hz, Im-4-CH₂), 3.12 – 3.25 (m, 4H, Im-4-(CH₂)₂-CH₂ + Ph₂CH-CH₂), 4.47 (t, 1H, ³J = 8.2 Hz, Ph₂CH), 7.12 – 7.32 (m, 10H, Ph-H), 8.18 (s, 1H, Im-2-H). ¹³C-NMR (75 MHz, CD3OD, trifluoroacetate): δ [ppm] = 8.78 (+, Im-5-CH₃), 21.52 (-, Im-4-CH₂), 28.16 (-, Im-4-CH₂-CH₂), 41.65 (-, Im-4-(CH2)2-CH2), 43.80 (-, Ph2CH-CH2), 48.06 (+, Ph2CH), 126.85 (Cquat, Im-C-5), 127.83 (+, 2 Ph-C-4), 128.83 (+, 4 Ph-C), 128.99 (C_quat, Im-C-4), 129.73 (+, 4 Ph-C), 133.31 (+, Im-C-2), 144.53 (C_quat, 2 Ph-C-1), 155.17 (C_quat, C=N), 175.53 (C_quat, C=O). IR (cm^-1) = 3031, 2909, 1664, 1599, 1180, 1129. HRMS (EI-MS) calcd. for C₂₃H₂₇N₅O [M^+•] 389.2216;

found 389.2216. C23H27N5O · 2 TFA (617.54).

N¹-[3-(5-Methyl-1H-imidazol-4-yl)propyl]-N² -[3-phenyl-3-(thiazol-2-yl)propanoyl]-guanidine (4.77)

The title compound was prepared from 4.56 (390 mg, 0.53 mmol) according to the general procedure. Purification by preparative HPLC (MeCN/0.1 % TFA (aq.): 27.5/72.5) yielded a white solid (150 mg, 38 %); mp 58 – 61. ¹H-NMR (600 MHz, D2O, trifluoroacetate, COSY): δ [ppm] = 1.78 – 1.88 (m, 2H, Im-4-CH₂-CH₂), 2.08 (s, 3H, Im-5-CH₃), 2.59 (t, 2H, ³J = 7.3 Hz, Im-4-CH2), 3.18 (t, 2H, ³J = 6.5 Hz, Im-4-(CH2)2-CH2), 3.23 (dd, 1H, ²J = 16.3 Hz, ³J = 8.0 Hz, PhThiazCH-CH₂), 3.41 (dd, 1H, ²J = 16.3 Hz, ³J = 7.7 Hz, PhThiazCH-CH₂), 4.90 (dd, 1H, ³J

= 8.0 Hz, ³J = 7.7 Hz, PhThiazCH), 7.20 – 7.35 (m, 5H, Ph-H), 7.40 (d, 1H, ³J = 3.3 Hz,

Structure-activity relationships of N^G-acylated imidazolylalkylguanidines 157

Thiaz-5-H), 7.61 (d, 1H, ³J = 3.3 Hz, Thiaz-4-H), 8.25 (s, 1H, Im-2-H). ¹³C-NMR (150 MHz, D₂O, trifluoroacetate, HSQC, HMBC): δ [ppm] = 7.90 (+, Im-5-CH₃), 19.95 (-, Im-4-CH₂), 26.20 (-, Im-4-CH2-CH2), 40.40 (-, Im-4-(CH2)2-CH2), 42.06 (-, PhThiazCH-CH2), 44.17 (+, PhThiazCH), 120.61 (+, Thiaz-C-5), 125.41 (C_quat, Im-C-5), 127.04 (C_quat, Im-C-4), 127.75 (+, 2 Ph-C), 128.09 (+, Ph-C-4), 129.28 (+, 2 Ph-C), 131.37 (+, Im-C-2), 140.29 (Cquat, Ph-C-1), 141.64 (+, Thiaz-C-4), 152.99 (C_quat, C=N), 173.17 (C_quat, Thiaz-C-2), 174.24 (C_quat, C=O). IR (cm^-1) = 2989, 2901, 1668, 1652, 1179, 1129. HRMS (LSI-MS) calcd. for C20H25N6OS [M + H]⁺ 397.1805; found 397.1803. C₂₀H₂₄N₆OS · 3 TFA (738.58).

N¹-[2-(5-Methyl-1H-imidazol-4-yl)ethyl]-N²-(3-phenylbutanoyl)guanidine (4.78)

The title compound was prepared from 4.57 (360 mg, 0.65 mmol) according to the general procedure. Purification by preparative HPLC (MeCN/0.1 % TFA (aq.): 25/75) yielded a white solid (150 mg, 43 %). ¹H-NMR (300 MHz, CD₃OD, trifluoroacetate): δ [ppm] = 1.30 (d, 3H, ³J

= 7.0 Hz, PhCH₃CH), 2.23 (s, 3H, Im-5-CH₃), 2.73 (dd, 1H, ²J = 15.3 Hz, ³J = 7.4 Hz, PhCH₃CH-CH₂), 2.79 (dd, 1H, ²J = 15.3 Hz, ³J = 7.8 Hz, PhCH₃CH-CH₂), 2.98 (t, 2H, ³J = 6.6 Hz, Im-4-CH₂), 3.22 – 3.36 (m, 1H, PhCH₃CH), 3.56 (t, 2H, ³J = 6.6 Hz, Im-4-CH₂-CH₂), 7.14 – 7.32 (m, 5H, Ph-H), 8.72 (s, 1H, Im-2-H). ¹³C-NMR (75 MHz, CD3OD, trifluoroacetate): δ [ppm] = 8.82 (+, Im-5-CH₃), 22.43 (+, PhCH₃CH), 23.45 (-, Im-4-CH₂), 37.67 (+, PhCH₃CH), 41.23 (-, Im-4-CH2-CH2), 46.03 (-, PhCH3CH-CH2), 126.32 (Cquat, Im-C-5), 127.75 (+, Ph-C-4), 127.97 (+, 2 Ph-C), 128.32 (C_quat, Im-C-4), 129.69 (+, 2 Ph-C), 133.80 (+, Im-C-2), 146.40 (Cquat, Ph-C-1), 155.30 (Cquat, C=N), 176.11 (Cquat, C=O). IR (cm^-1) = 3036, 2876, 1670, 1602, 1179, 1128. HRMS (EI-MS) calcd. for C₁₇H₂₃N₅O [M^+•] 313.1903; found 310.1899. C₁₇H₂₃N₅O

· 2 TFA (541.44).

N¹-[2-(5-Methyl-1H-imidazol-4-yl)ethyl]-N²-[3-(thiophen-2-yl)butanoyl]guanidine (4.79) The title compound was prepared from 4.58 (200 mg, 0.36 mmol) according to the general procedure. Purification by preparative HPLC (MeCN/0.1 % TFA (aq.): 25/75) yielded a colorless semisolid compound (51 mg, 26 %). ¹H-NMR (300 MHz, CD₃OD, trifluoroacetate): δ [ppm] = 1.38 (d, 3H, ³J = 7.0 Hz, ThioCH3CH), 2.26 (s, 3H, Im-5-CH3), 2.76 (dd, 1H, ²J = 15.6 Hz, ³J = 7.1 Hz, ThioCH₃CH-CH₂), 2.82 (dd, 1H, ²J = 15.6 Hz, ³J = 7.6 Hz, ThioCH₃CH-CH₂), 3.00 (t, 2H, ³J = 6.6 Hz, Im-4-CH2), 3.58 (t, 2H, ³J = 6.6 Hz, Im-4-CH2-CH2), 3.55 – 3.70 (m, 1H, ThioCH₃CH), 6.89 (ddd, 1H, ³J = 3.5 Hz, ⁴J = 1.4 Hz, ⁴J = 0.7 Hz, Thio-3-H), 6.91 (dd, 1H, ³J = 4.9 Hz, ³J = 3.5 Hz, Thio-4-H), 7.20 (dd, 1H, ³J = 4.9 Hz, ⁴J = 1.4 Hz, Thio-5-H), 8.73 (s, 1H, Im-2-H). ¹³C-NMR (75 MHz, CD₃OD, trifluoroacetate): δ [ppm] = 8.85 (+, Im-5-CH₃), 23.27 (+, ThioCHCH3), 23.47 (-, Im-4-CH2), 32.93 (+, ThioCH3CH), 41.31 (-, Im-4-CH2-CH2), 46.99 (-, ThioCH₃CH-CH₂), 124.27, 124.48 (+, Thio-C-3,4), 126.34 (C_quat, Im-C-5), 127.79 (+, Thio-C-5), 128.34 (Cquat, Im-C-4), 133.83 (+, Im-C-2), 149.93 (Cquat, Thio-C-2), 155.28 (Cquat,

C=N), 175.59 (Cquat, C=O). IR (cm^-1) = 3035, 2905, 1663, 1180, 1128. HRMS (EI-MS) calcd.

for C₁₅H₂₁N₅OS [M^+•] 319.1467; found 319.1465. C₁₅H₂₁N₅OS · 2 TFA (547.47).

N¹-(3,3-Diphenylpropanoyl)-N²-[2-(5-methyl-1H-imidazol-4-yl)ethyl]guanidine (4.80) The title compound was prepared from 4.59 (360 mg, 0.58 mmol) according to the general procedure. Purification by preparative HPLC (MeCN/0.1 % TFA (aq.): 35/65) yielded a white solid (182 mg, 52 %); mp 58 – 61 °C. ¹H-NMR (300 MHz, CD₃OD, trifluoroacetate): δ [ppm] = 2.18 (s, 3H, Im-5-CH3), 2.96 (t, 2H, ³J = 6.5 Hz, Im-4-CH2), 3.25 (d, 2H, ³J = 8.0 Hz, Ph2 CH-CH₂), 3.54 (t, 2H, ³J = 6.5 Hz, Im-4-CH₂-CH₂), 4.58 (t, 1H, ³J = 8.0 Hz, Ph₂CH), 7.13 – 7.31 (m, 10H, Ph-H), 8.71 (s, 1H, Im-2-H). ¹³C-NMR (75 MHz, CD3OD, trifluoroacetate): δ [ppm] = 8.80 (+, Im-5-CH₃), 23.43 (-, Im-4-CH₂), 41.24 (-, Im-4-CH₂-CH₂), 43.78 (-, Ph₂CH-CH₂), 48.04 (+, Ph₂CH), 126.30 (C_quat, Im-C-5), 127.84 (+, 2 Ph-C-4), 128.34 (C_quat, Im-C-4) 128.82 (+, 4 Ph-C), 129.73 (+, 4 Ph-C), 133.79 (+, Im-C-2), 144.49 (C_quat, 2 Ph-C-1), 155.24 (C_quat, C=N), 175.57 (C_quat, C=O). IR (cm^-1) = 3151, 2901, 1665, 1599, 1183, 1129. HRMS (EI-MS) calcd. for C₂₂H₂₅N₅O [M^+•] 375.2059; found 375.2051. C₂₂H₂₅N₅O · 2 TFA (603.51).

N¹-[2-(5-Methyl-1H-imidazol-4-yl)ethyl]-N²-[3-phenyl-3-(thiazol-2-yl)propanoyl]guanidine (4.81)

The title compound was prepared from 4.60 (270 mg, 0.43 mmol) according to the general procedure. Purification by preparative HPLC (MeCN/0.1 % TFA (aq.): 25/75) yielded a colorless semisolid compound (33 mg, 11 %). ¹H-NMR (300 MHz, CD₃OD, trifluoroacetate): δ [ppm] = 2.23 (s, 3H, Im-5-CH3), 2.99 (t, 2H, ³J = 6.6 Hz, Im-4-CH2), 3.21 (dd, 1H, ²J = 16.4 Hz, ³J = 6.6 Hz, PhThiazCH-CH₂), 3.51 – 3.63 (m, 3H, Im-4-CH₂-CH₂ + PhThiazCH-CH₂), 4.95 (dd, 1H, ³J = 8.5 Hz, ³J = 6.6 Hz, PhThiazCH), 7.24 – 7.37 (m, 5H, Ph-H), 7.47 (d, 1H,

3J = 3.4 Hz, Thiaz-5-H), 7.69 (d, 1H, ³J = 3.4 Hz, Thiaz-4-H), 8.72 (s, 1H, Im-2-H). ¹³C-NMR (75 MHz, CD3OD, trifluoroacetate): δ [ppm] = 8.83 (+, Im-5-CH3), 23.46 (-, Im-4-CH2), 41.35 (-, Im-4-CH₂-CH₂), 43.51 (-, PhThiazCH-CH₂), 45.92 (+, PhThiazCH), 121.24 (+, Thiaz-C-5), 126.32 (C_quat, Im-C-5), 128.36 (C_quat, Im-C-4), 128.93 (+, Ph-C-4), 129.08 (+, 2 Ph-C), 130.13 (+, 2 Ph-C), 133.81 (+, Im-C-2), 142.33 (Cquat, Ph-C-1), 142.87 (+, Thiaz-C-4), 155.23 (Cquat, C=N), 174.29, 174.89 (C_quat, Thiaz-C-2 + C=O). IR (cm^-1) = 3155, 2989, 2901, 1663, 1178, 1127. HRMS (EI-MS) calcd. for C₁₉H₂₂N₆OS [M^+•] 382.1576; found 382.1582. C₁₉H₂₂N₆OS · 3 TFA (724.55).

N¹-[3-(1H-Imidazol-4-yl)propyl]-N¹-methyl-N²-(3-phenylbutanoyl)guanidine (4.82)

The title compound was prepared from 4.61 (370 mg, 0.65 mmol) according to the general procedure. Purification by preparative HPLC (0.1 % TFA (aq.): 0 min: 15/85, 20 min: 35/65) yielded a colorless semisolid compound (189 mg, 52 %). ¹H-NMR (600 MHz, D₂O,

Structure-activity relationships of N^G-acylated imidazolylalkylguanidines 159

trifluoroacetate, COSY, 358 K): δ [ppm] = 1.89 (d, 3H, ³J = 7.0 Hz, PhCH3CH), 2.45 – 2.53 (m, 2H, Im-4-CH₂-CH₂), 3.20 (t, 2H, ³J = 7.6 Hz, Im-4-CH₂), 3.42 (d, 1H, ³J = 7.8 Hz, PhCH3CH-CH2), 3.55 (s, 3H, NCH3), 3.83 – 3.90 (m, 1H, PhCH3CH), 3.91 – 4.00 (m, 2H, Im-4-(CH₂)₂-CH₂), 7.78 (s, 1H, Im-5-H), 7.79 – 7.96 (m, 5H, Ph-H), 9.15 (s, 1H, Im-2-H). ¹³ C-NMR (150 MHz, D2O, trifluoroacetate, HSQC, HMBC, 358 K): δ [ppm] = 21.51 (-, Im-4-CH2), 22.03 (+, PhCH₃CH), 25.40 (-, Im-4-CH₂-CH₂), 37.20 (+, NCH₃), 37.26 (+, PhCH₃CH), 45.35 (-, PhCH3CH-CH2), 50.95 (-, Im-4-(CH2)2-CH2), 116.21 (+, Im-C-5), 127.57 (+, 2 Ph-C), 127.62 (+, Ph-C-4), 129.58 (+, 2 Ph-C), 133.06 (C_quat, Im-C-4), 134.00 (+, Im-C-2), 145.92 (C_quat, Ph-C-1), 153.46 (C_quat, C=N), 175.54 (C_quat, C=O). IR (cm^-1) = 3128, 2989, 2901, 1659, 1620, 1176, 1129. HRMS (EI-MS) calcd. for C₁₈H₂₅N₅O [M^+•] 327.2059; found 327.2064.

C18H25N5O · 2 TFA (555.47).

N¹-(3,3-Diphenylpropanoyl)-N²-[3-(1H-imidazol-4-yl)propyl]-N²-methylguanidine (4.83) The title compound was prepared from 4.62 (400 mg, 0.63 mmol) according to the general procedure. Purification by preparative HPLC (MeCN/0.1 % TFA (aq.): 0 min: 20/80, 20 min:

45/65) yielded a white solid (202 mg, 52 %); mp 52 – 56 °C. ¹H-NMR (600 MHz, D₂O, trifluoroacetate, 358 K): δ [ppm] = 2.42 – 2.50 (m, 2H, Im-4-CH2-CH2),3.15 (t, 2H, ³J = 7.5 Hz, Im-4-CH₂), 3.55 (s, 3H, NCH₃), 3.93 (d, 2H, ³J = 8.0 Hz, Ph₂CHCH₂), 3.95 (t, 2H, ³J = 7.2 Hz, Im-4-(CH2)2-CH2), 5.15 (t, 1H, ³J = 8.0 Hz, Ph2CH), 7.76 (s, 1H, Im-5-H), 7.80 – 7.96 (m, 10H, Ph-H), 9.15 (s, 1H, Im-2-H). ¹³C-NMR (150 MHz, D₂O, trifluoroacetate, HSQC, HMBC, 358 K): δ [ppm] = 21.50 (-, Im-4-CH2), 25.37 (-, Im-4-CH2-CH2), 37.24 (+, NCH3), 42.89 (-, Ph₂CH-CH₂), 47.53 (-, Ph₂CH), 51.10 (-, Im-4-(CH₂)₂-CH₂), 116.1 7 (-, Im-C-5), 127.78 (+, 4 Ph-C), 128.27 (+, 2 Ph-C-4), 129.68 (+, 4 Ph-C), 133.04 (Cquat, Im-C-4), 133.98 (+, Im-C-2), 143.74 (C_quat, Ph-C-1), 153.45 (C_quat, C=N), 174.77 (C_quat, C=O). IR (cm^-1) = 3136, 3028, 2868, 1659, 1620, 1177, 1126. HRMS (EI-MS) calcd. for C₂₃H₂₇N₅O [M^+•] 389.2216; found 389.2218. C₂₃H₂₇N₅O · 2 TFA (617.54).

4.4.2 Pharmacological methods 4.4.2.1 Materials

Histamine dihydrochloride was purchased from Alfa Aesar GmbH & Co. KG (Karlsruhe, Germany). Thioperamide maleate was from Tocris Bioscience (Ellisville, USA). [γ-³²P]GTP was synthesized according to a previously described method.⁴⁶ [³²P]P_i (8,500 – 9,100 Ci/mmol orthophosphoric acid) was from PerkinElmer Life Sciences (Boston, MA). All unlabeled nucleotides, glycerol-3-phosphate dehydrogenase, triose phosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase and lactate dehydrogenase were from Roche

(Mannheim, Germany). 3-Phosphoglycerate kinase and L-α-glycerol phosphate was from Sigma.

4.4.2.2 Steady-state GTPase activity assay

Im Dokument Synthesis and structure-activity relationships of NG-acylated arylalkylguanidines and related compounds as histamine receptor ligands: Searching for selective H (Seite 166-176)