Structure and cytotoxic properties of 1-hy­droxy-5-methyl-7-phenyl­pyrido[3,4-d]pyridazin-4(3H)-one and its mono- and disubstituted ethyl acetates

Wójcicka, A.; Becan, L.; Rembiałkowska, N.; Pyra, A.; Bryndal, I.

doi:10.1107/S2053229622009202

Structure and cytotoxic properties of 1-hydroxy-5-methyl-7-phenylpyrido[3,4-d]pyridazin-4(3H)-one and its mono- and disubstituted ethyl acetates

A. Wójcicka, L. Becan, N. Rembiałkowska, A. Pyra and I. Bryndal

Derivatives of pyrido[3,4-d]pyridazine, namely, 1-hydroxy-5-methyl-7-phenylpyrido[3,4-d]pyridazin-4(3H)-one dimethylformamide monosolvate, C₁₄H₁₁N₃O₂·C₃H₇NO (2), ethyl [1-(2-ethoxy-2-oxoethoxy)-5-methyl-4-oxo-7-phenyl-3,4-dihydropyrido[3,4-d]pyridazin-3-yl]acetate, C₁₈H₁₇N₃O₄ (3), and ethyl [(5-methyl-4-oxo-7-phenyl-3,4-dihydropyrido[3,4-d]pyridazin-1-yl)oxy]acetate, C₂₂H₂₃N₃O₆ (4), were synthesized with the aim of discovering new potential biologically active agents. The properties of all three derivatives were characterized by ¹H NMR, ¹³C NMR and FT–IR spectroscopic analysis. All the crystals were obtained by a solvent diffusion method from dimethylformamide (DMF) or dimethyl sulfoxide (DMSO) and characterized by single-crystal X-ray diffraction. The collected X-ray data revealed that the crystals of 2 and 4 belong to the triclinic space group P $\overline{1}$ , whereas the crystal of 3 belongs to the monoclinic space group P2₁/c. The presented derivatives crystallized with one molecule in the asymmetric unit, but only compound 2 crystallized as a solvate with DMF. Structure analysis showed that the molecule of 2 exists as its amide–imidic acid tautomer and that O-alkylation occurred before N-alkylation during the synthesis of the mono- and disubstituted derivatives, i.e. 3 and 4, respectively. The molecular geometries of the 5-methyl-7-phenylpyrido[3,4-d]pyridazine core within the studied derivatives differ in the mutual orientation of the rings. The interplanar angles between the heterocyclic ring and the bound aromatic ring are 1.71 (7), 18.16 (3) and 3.1 (1)° for 2, 3 and 4, respectively. The potential cytotoxicity of these compounds was evaluated against one normal (HaCat) and four human cancer cell lines (A549, DU145, MDA-MB-231 and SKOV-3).

Keywords: pyrido[3,4-d]pyridazine derivatives; synthesis; N-alkylation; O-alkylation; crystal structure; cytotoxic activity.

Read article Similar articles

Supporting information

	Crystallographic Information File (CIF) https://doi.org/10.1107/S2053229622009202/qf3056sup1.cif Contains datablocks 2, 3, 4, global
	Structure factor file (CIF format) https://doi.org/10.1107/S2053229622009202/qf30562sup2.hkl Contains datablock 2
	Chemical Markup Language (CML) file https://doi.org/10.1107/S2053229622009202/qf30562sup5.cml Supplementary material
	Structure factor file (CIF format) https://doi.org/10.1107/S2053229622009202/qf30563sup3.hkl Contains datablock 3
	Chemical Markup Language (CML) file https://doi.org/10.1107/S2053229622009202/qf30563sup6.cml Supplementary material
	Structure factor file (CIF format) https://doi.org/10.1107/S2053229622009202/qf30564sup4.hkl Contains datablock 4
	Chemical Markup Language (CML) file https://doi.org/10.1107/S2053229622009202/qf30564sup7.cml Supplementary material
	Portable Document Format (PDF) file https://doi.org/10.1107/S2053229622009202/qf3056sup8.pdf Additional figures

CCDC references: 2207705; 2207704; 2207703

Computing details top

Data collection: CrysAlis PRO (Rigaku OD, 2020) for (2), (3); CrysAlis PRO (Rigaku OD, 2015) for (4). Cell refinement: CrysAlis PRO (Rigaku OD, 2020) for (2), (3); CrysAlis PRO (Rigaku OD, 2015) for (4). Data reduction: CrysAlis PRO (Rigaku OD, 2020) for (2), (3); CrysAlis PRO (Rigaku OD, 2015) for (4). For all structures, program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2018 (Sheldrick, 2015); molecular graphics: DIAMOND (Brandenburg & Putz, 2014); software used to prepare material for publication: PLATON (Spek, 2020).

1-Hydroxy-5-methyl-7-phenylpyrido[3,4-d]pyridazin-4(3H)-one dimethylformamide monosolvate (2) top

Crystal data top

C₁₄H₁₁N₃O₂·C₃H₇NO	Z = 2
M_r = 326.35	F(000) = 344
Triclinic, P1	D_x = 1.400 Mg m⁻³
a = 6.8722 (2) Å	Cu Kα radiation, λ = 1.54184 Å
b = 11.0502 (3) Å	Cell parameters from 7662 reflections
c = 11.2090 (3) Å	θ = 4.3–75.4°
α = 65.618 (3)°	µ = 0.81 mm⁻¹
β = 89.798 (2)°	T = 100 K
γ = 87.085 (2)°	Needle, colourless
V = 774.14 (4) Å³	0.18 × 0.15 × 0.09 mm

Data collection top

Rigaku XtaLAB Synergy DW system with a HyPix-Arc 150 detector diffractometer	3149 independent reflections
Radiation source: Rotating-anode X-ray tube, Rigaku (Cu) X-ray Source	2827 reflections with I > 2σ(I)
Mirror monochromator	R_int = 0.018
Detector resolution: 10.0000 pixels mm^-1	θ_max = 75.8°, θ_min = 4.3°
ω scans	h = −8→8
Absorption correction: multi-scan (CrysAlis PRO; Rigaku OD, 2020)	k = −13→13
T_min = 0.644, T_max = 1.000	l = −11→13
10869 measured reflections

Refinement top

Refinement on F²	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: mixed
R[F² > 2σ(F²)] = 0.044	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.125	w = 1/[σ²(F_o²) + (0.068P)² + 0.2445P] where P = (F_o² + 2F_c²)/3
S = 1.07	(Δ/σ)_max = 0.001
3149 reflections	Δρ_max = 0.26 e Å⁻³
237 parameters	Δρ_min = −0.53 e Å⁻³
0 restraints	Extinction correction: SHELXL2018 (Sheldrick, 2015), Fc^*=kFc[1+0.001xFc²λ³/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.0035 (8)

Special details top

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq	Occ. (<1)
O1	0.56251 (15)	0.57479 (10)	0.64199 (9)	0.0336 (3)
H1	0.623980	0.537400	0.713697	0.050*
C1	0.6242 (2)	0.69751 (14)	0.57667 (12)	0.0270 (3)
N2	0.78400 (17)	0.73073 (12)	0.61302 (11)	0.0290 (3)
N3	0.83698 (16)	0.85878 (11)	0.54111 (10)	0.0267 (3)
H3	0.943753	0.881584	0.567844	0.032*
O4	0.81259 (13)	1.06599 (9)	0.38091 (9)	0.0291 (2)
C4	0.74557 (18)	0.95407 (13)	0.43446 (12)	0.0239 (3)
C5	0.45536 (18)	0.99695 (12)	0.27933 (12)	0.0227 (3)
C51	0.51416 (19)	1.13221 (13)	0.18729 (13)	0.0279 (3)
H51	0.430899	1.165143	0.108287	0.042*
H52	0.650440	1.126537	0.163166	0.042*
H53	0.499590	1.193383	0.230255	0.042*
N6	0.29158 (15)	0.95746 (10)	0.24670 (10)	0.0232 (2)
C7	0.22803 (18)	0.83520 (12)	0.32149 (12)	0.0219 (3)
C71	0.04117 (18)	0.80255 (12)	0.27739 (12)	0.0222 (3)
C72	−0.05964 (19)	0.89735 (13)	0.16785 (12)	0.0238 (3)
H72	−0.007941	0.982098	0.122002	0.029*
C73	−0.23431 (19)	0.86939 (13)	0.12510 (12)	0.0258 (3)
H73	−0.300666	0.934803	0.050269	0.031*
C74	−0.31231 (19)	0.74614 (14)	0.19136 (13)	0.0266 (3)
H74	−0.431782	0.726916	0.162254	0.032*
C75	−0.2141 (2)	0.65153 (14)	0.30034 (13)	0.0298 (3)
H75	−0.266948	0.567204	0.346295	0.036*
C76	−0.0388 (2)	0.67903 (13)	0.34298 (13)	0.0282 (3)
H76	0.027368	0.613064	0.417545	0.034*
C8	0.33272 (19)	0.74615 (13)	0.43018 (12)	0.0246 (3)
H8	0.288564	0.659736	0.479633	0.030*
C9	0.50491 (18)	0.78613 (13)	0.46566 (12)	0.0236 (3)
C10	0.56726 (18)	0.91398 (12)	0.39235 (12)	0.0222 (3)
O1N	0.6684 (3)	0.4638 (2)	0.88789 (17)	0.0376 (7)	0.611 (5)
C1N	0.8086 (4)	0.3886 (2)	0.9393 (2)	0.0291 (7)	0.611 (5)
H1N	0.890 (4)	0.338 (3)	0.891 (3)	0.035*	0.611 (5)
O1N'	0.7370 (4)	0.4178 (3)	0.8593 (3)	0.0302 (9)*	0.389 (5)
C1N'	0.7224 (5)	0.4373 (3)	0.9639 (4)	0.0230 (10)*	0.389 (5)
H1N'	0.630 (6)	0.495 (4)	0.978 (4)	0.028*	0.389 (5)
N1N	0.86445 (19)	0.36515 (12)	1.06150 (11)	0.0355 (3)
C2N	1.0296 (3)	0.27128 (17)	1.0960 (2)	0.0557 (5)
H21N	1.060941	0.248621	1.022055	0.083*
H22N	0.998795	0.190547	1.172305	0.083*
H23N	1.141804	0.310677	1.117131	0.083*
C3N	0.8029 (2)	0.40981 (16)	1.15938 (19)	0.0472 (4)
H31N	0.699026	0.479858	1.123019	0.071*
H32N	0.913547	0.445116	1.187269	0.071*
H33N	0.754060	0.335043	1.234874	0.071*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0351 (5)	0.0328 (5)	0.0236 (5)	−0.0133 (4)	−0.0083 (4)	−0.0009 (4)
C1	0.0288 (6)	0.0305 (7)	0.0202 (6)	−0.0082 (5)	−0.0013 (5)	−0.0082 (5)
N2	0.0305 (6)	0.0308 (6)	0.0226 (5)	−0.0089 (5)	−0.0041 (4)	−0.0071 (5)
N3	0.0261 (5)	0.0294 (6)	0.0244 (5)	−0.0088 (4)	−0.0043 (4)	−0.0102 (4)
O4	0.0282 (5)	0.0268 (5)	0.0324 (5)	−0.0079 (4)	−0.0054 (4)	−0.0115 (4)
C4	0.0239 (6)	0.0273 (6)	0.0237 (6)	−0.0046 (5)	−0.0002 (5)	−0.0132 (5)
C5	0.0226 (6)	0.0224 (6)	0.0258 (6)	−0.0030 (5)	−0.0002 (5)	−0.0123 (5)
C51	0.0272 (6)	0.0218 (6)	0.0330 (7)	−0.0047 (5)	−0.0051 (5)	−0.0090 (5)
N6	0.0223 (5)	0.0214 (5)	0.0262 (5)	−0.0036 (4)	−0.0014 (4)	−0.0100 (4)
C7	0.0221 (6)	0.0232 (6)	0.0224 (6)	−0.0044 (5)	0.0011 (5)	−0.0110 (5)
C71	0.0225 (6)	0.0239 (6)	0.0224 (6)	−0.0047 (5)	0.0008 (5)	−0.0114 (5)
C72	0.0265 (6)	0.0228 (6)	0.0235 (6)	−0.0051 (5)	0.0009 (5)	−0.0105 (5)
C73	0.0258 (6)	0.0285 (7)	0.0244 (6)	−0.0021 (5)	−0.0030 (5)	−0.0121 (5)
C74	0.0230 (6)	0.0337 (7)	0.0283 (6)	−0.0075 (5)	0.0008 (5)	−0.0173 (6)
C75	0.0304 (7)	0.0282 (7)	0.0297 (7)	−0.0117 (5)	0.0007 (5)	−0.0098 (5)
C76	0.0278 (7)	0.0262 (7)	0.0270 (6)	−0.0067 (5)	−0.0039 (5)	−0.0070 (5)
C8	0.0261 (6)	0.0251 (6)	0.0218 (6)	−0.0082 (5)	0.0000 (5)	−0.0083 (5)
C9	0.0244 (6)	0.0275 (6)	0.0204 (6)	−0.0049 (5)	0.0001 (5)	−0.0110 (5)
C10	0.0219 (6)	0.0253 (6)	0.0228 (6)	−0.0040 (5)	0.0005 (5)	−0.0129 (5)
O1N	0.0315 (10)	0.0425 (11)	0.0261 (10)	−0.0040 (8)	−0.0073 (7)	−0.0011 (8)
C1N	0.0314 (13)	0.0293 (12)	0.0226 (12)	−0.0112 (10)	−0.0027 (9)	−0.0055 (9)
N1N	0.0434 (7)	0.0327 (6)	0.0237 (6)	−0.0175 (5)	−0.0084 (5)	−0.0031 (5)
C2N	0.0631 (11)	0.0355 (8)	0.0799 (13)	−0.0145 (8)	0.0387 (10)	−0.0345 (9)
C3N	0.0382 (8)	0.0305 (8)	0.0738 (12)	−0.0038 (6)	0.0176 (8)	−0.0223 (8)

Geometric parameters (Å, º) top

O1—C1	1.3383 (16)	C73—H73	0.9500
O1—H1	0.8400	C74—C75	1.3859 (19)
C1—N2	1.2942 (17)	C74—H74	0.9500
C1—C9	1.4485 (18)	C75—C76	1.3905 (18)
N2—N3	1.3759 (15)	C75—H75	0.9500
N3—C4	1.3532 (17)	C76—H76	0.9500
N3—H3	0.8800	C8—C9	1.3982 (17)
O4—C4	1.2430 (15)	C8—H8	0.9500
C4—C10	1.4671 (16)	C9—C10	1.3984 (17)
C5—N6	1.3325 (16)	O1N—C1N	1.215 (4)
C5—C10	1.4188 (17)	C1N—N1N	1.339 (2)
C5—C51	1.4990 (17)	C1N—H1N	1.06 (3)
C51—H51	0.9800	O1N'—C1N'	1.279 (6)
C51—H52	0.9800	C1N'—N1N	1.412 (4)
C51—H53	0.9800	C1N'—H1N'	0.94 (4)
N6—C7	1.3569 (16)	N1N—C3N	1.431 (2)
C7—C8	1.3837 (18)	N1N—C2N	1.437 (2)
C7—C71	1.4908 (17)	C2N—H21N	0.9800
C71—C76	1.3965 (17)	C2N—H22N	0.9800
C71—C72	1.3983 (18)	C2N—H23N	0.9800
C72—C73	1.3892 (18)	C3N—H31N	0.9800
C72—H72	0.9500	C3N—H32N	0.9800
C73—C74	1.3893 (18)	C3N—H33N	0.9800

C1—O1—H1	109.5	C74—C75—H75	119.7
N2—C1—O1	119.90 (12)	C76—C75—H75	119.7
N2—C1—C9	123.63 (12)	C75—C76—C71	120.73 (12)
O1—C1—C9	116.47 (11)	C75—C76—H76	119.6
C1—N2—N3	116.34 (11)	C71—C76—H76	119.6
C4—N3—N2	128.17 (10)	C7—C8—C9	118.56 (12)
C4—N3—H3	115.9	C7—C8—H8	120.7
N2—N3—H3	115.9	C9—C8—H8	120.7
O4—C4—N3	120.11 (11)	C8—C9—C10	120.02 (12)
O4—C4—C10	124.99 (11)	C8—C9—C1	121.69 (12)
N3—C4—C10	114.89 (11)	C10—C9—C1	118.28 (11)
N6—C5—C10	121.55 (11)	C9—C10—C5	117.69 (11)
N6—C5—C51	115.52 (11)	C9—C10—C4	118.63 (11)
C10—C5—C51	122.91 (11)	C5—C10—C4	123.67 (11)
C5—C51—H51	109.5	O1N—C1N—N1N	120.2 (2)
C5—C51—H52	109.5	O1N—C1N—H1N	122.6 (15)
H51—C51—H52	109.5	N1N—C1N—H1N	117.2 (15)
C5—C51—H53	109.5	O1N'—C1N'—N1N	114.3 (3)
H51—C51—H53	109.5	O1N'—C1N'—H1N'	126 (3)
H52—C51—H53	109.5	N1N—C1N'—H1N'	120 (2)
C5—N6—C7	120.28 (11)	C1N—N1N—C3N	136.48 (18)
N6—C7—C8	121.79 (11)	C1N'—N1N—C3N	98.5 (2)
N6—C7—C71	115.72 (11)	C1N—N1N—C2N	107.44 (18)
C8—C7—C71	122.48 (11)	C1N'—N1N—C2N	145.4 (2)
C76—C71—C72	118.20 (11)	C3N—N1N—C2N	116.07 (14)
C76—C71—C7	121.91 (11)	N1N—C2N—H21N	109.5
C72—C71—C7	119.89 (11)	N1N—C2N—H22N	109.5
C73—C72—C71	120.95 (12)	H21N—C2N—H22N	109.5
C73—C72—H72	119.5	N1N—C2N—H23N	109.5
C71—C72—H72	119.5	H21N—C2N—H23N	109.5
C72—C73—C74	120.25 (12)	H22N—C2N—H23N	109.5
C72—C73—H73	119.9	N1N—C3N—H31N	109.5
C74—C73—H73	119.9	N1N—C3N—H32N	109.5
C75—C74—C73	119.33 (12)	H31N—C3N—H32N	109.5
C75—C74—H74	120.3	N1N—C3N—H33N	109.5
C73—C74—H74	120.3	H31N—C3N—H33N	109.5
C74—C75—C76	120.54 (12)	H32N—C3N—H33N	109.5

O1—C1—N2—N3	−179.77 (11)	C7—C8—C9—C10	0.42 (19)
C9—C1—N2—N3	1.1 (2)	C7—C8—C9—C1	−178.78 (11)
C1—N2—N3—C4	−1.9 (2)	N2—C1—C9—C8	−179.75 (12)
N2—N3—C4—O4	179.58 (12)	O1—C1—C9—C8	1.09 (19)
N2—N3—C4—C10	0.41 (19)	N2—C1—C9—C10	1.0 (2)
C10—C5—N6—C7	−0.34 (19)	O1—C1—C9—C10	−178.11 (11)
C51—C5—N6—C7	178.26 (11)	C8—C9—C10—C5	−2.92 (18)
C5—N6—C7—C8	−2.37 (19)	C1—C9—C10—C5	176.30 (11)
C5—N6—C7—C71	178.79 (10)	C8—C9—C10—C4	178.26 (11)
N6—C7—C71—C76	178.28 (11)	C1—C9—C10—C4	−2.52 (18)
C8—C7—C71—C76	−0.6 (2)	N6—C5—C10—C9	2.95 (18)
N6—C7—C71—C72	−2.10 (17)	C51—C5—C10—C9	−175.54 (11)
C8—C7—C71—C72	179.06 (12)	N6—C5—C10—C4	−178.30 (11)
C76—C71—C72—C73	−0.19 (19)	C51—C5—C10—C4	3.21 (19)
C7—C71—C72—C73	−179.82 (11)	O4—C4—C10—C9	−177.28 (12)
C71—C72—C73—C74	0.3 (2)	N3—C4—C10—C9	1.84 (17)
C72—C73—C74—C75	0.0 (2)	O4—C4—C10—C5	4.0 (2)
C73—C74—C75—C76	−0.3 (2)	N3—C4—C10—C5	−176.90 (11)
C74—C75—C76—C71	0.3 (2)	O1N—C1N—N1N—C3N	−1.8 (3)
C72—C71—C76—C75	−0.1 (2)	O1N—C1N—N1N—C2N	178.81 (19)
C7—C71—C76—C75	179.50 (12)	O1N'—C1N'—N1N—C3N	−179.6 (2)
N6—C7—C8—C9	2.31 (19)	O1N'—C1N'—N1N—C2N	−0.9 (5)
C71—C7—C8—C9	−178.93 (11)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1···O1N	0.84	1.80	2.6006 (19)	159
O1—H1···O1N′	0.84	1.77	2.588 (3)	164
N3—H3···O4ⁱ	0.88	1.96	2.8413 (14)	177
C75—H75···O1ⁱⁱ	0.95	2.60	3.4161 (16)	144
C2N—H22N···O4ⁱⁱⁱ	0.98	2.55	3.450 (2)	153
C3N—H31N···O1N^iv	0.98	2.56	3.415 (3)	146

Symmetry codes: (i) −x+2, −y+2, −z+1; (ii) −x, −y+1, −z+1; (iii) x, y−1, z+1; (iv) −x+1, −y+1, −z+2.

Ethyl [1-(2-ethoxy-2-oxoethoxy)-5-methyl-4-oxo-7-phenyl-3,4-dihydropyrido[3,4-d]pyridazin-3-yl]acetate (3) top

Crystal data top

C₁₈H₁₇N₃O₄	F(000) = 712
M_r = 339.34	D_x = 1.409 Mg m⁻³
Monoclinic, P2₁/c	Cu Kα radiation, λ = 1.54184 Å
a = 17.4344 (3) Å	Cell parameters from 1548 reflections
b = 13.0800 (3) Å	θ = 2.5–69.8°
c = 7.0192 (1) Å	µ = 0.84 mm⁻¹
β = 92.315 (1)°	T = 100 K
V = 1599.37 (5) Å³	Plate, colourless
Z = 4	0.17 × 0.03 × 0.03 mm

Data collection top

Rigaku XtaLAB Synergy DW system with a HyPix-Arc 150 detector diffractometer	3274 independent reflections
Radiation source: Rotating-anode X-ray tube, Rigaku (Cu) X-ray Source	2878 reflections with I > 2σ(I)
Mirror monochromator	R_int = 0.035
Detector resolution: 10.0000 pixels mm^-1	θ_max = 75.7°, θ_min = 2.5°
φ scans	h = −21→21
Absorption correction: multi-scan (CrysAlis PRO; Rigaku OD, 2020)	k = −15→16
T_min = 0.736, T_max = 1.000	l = −8→8
15272 measured reflections

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.050	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.123	H-atom parameters constrained
S = 1.10	w = 1/[σ²(F_o²) + (0.0533P)² + 0.7835P] where P = (F_o² + 2F_c²)/3
3274 reflections	(Δ/σ)_max < 0.001
228 parameters	Δρ_max = 0.31 e Å⁻³
0 restraints	Δρ_min = −0.20 e Å⁻³

Special details top

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
C1	0.20407 (9)	0.60829 (14)	0.3354 (2)	0.0230 (4)
O1	0.27974 (7)	0.59919 (9)	0.30055 (17)	0.0251 (3)
C11	0.30819 (10)	0.49653 (14)	0.3152 (2)	0.0242 (4)
H111	0.280079	0.451875	0.222334	0.029*
H112	0.301025	0.469441	0.444930	0.029*
C12	0.39222 (10)	0.49888 (13)	0.2738 (2)	0.0239 (4)
O12	0.42679 (7)	0.56808 (10)	0.20456 (18)	0.0296 (3)
O13	0.42359 (7)	0.40925 (9)	0.32548 (18)	0.0279 (3)
C13	0.50480 (10)	0.39724 (15)	0.2903 (3)	0.0289 (4)
H131	0.534376	0.455913	0.343799	0.035*
H132	0.512733	0.393650	0.151615	0.035*
C14	0.53061 (12)	0.29977 (16)	0.3857 (3)	0.0378 (5)
H141	0.500106	0.242594	0.333566	0.057*
H142	0.523598	0.304973	0.523192	0.057*
H143	0.584979	0.288096	0.362658	0.057*
N2	0.16413 (8)	0.52742 (11)	0.3611 (2)	0.0243 (3)
N3	0.08860 (8)	0.54126 (11)	0.4001 (2)	0.0247 (3)
H3	0.061443	0.485415	0.415974	0.030*
C4	0.05078 (10)	0.63117 (13)	0.4170 (2)	0.0229 (4)
O4	−0.01768 (7)	0.63137 (10)	0.46053 (18)	0.0272 (3)
C5	0.06606 (9)	0.82347 (13)	0.3958 (2)	0.0219 (4)
C51	−0.01659 (9)	0.84556 (14)	0.4338 (3)	0.0261 (4)
H511	−0.029101	0.816888	0.557765	0.039*
H512	−0.049690	0.814526	0.333548	0.039*
H513	−0.024832	0.919671	0.434967	0.039*
N6	0.11052 (8)	0.90527 (11)	0.37439 (19)	0.0231 (3)
C7	0.18631 (9)	0.89387 (13)	0.3400 (2)	0.0215 (3)
C71	0.23023 (10)	0.99101 (14)	0.3237 (2)	0.0233 (4)
C72	0.19108 (11)	1.08301 (14)	0.2915 (3)	0.0304 (4)
H72	0.136623	1.083014	0.279027	0.036*
C73	0.23094 (11)	1.17437 (16)	0.2777 (3)	0.0368 (5)
H73	0.203789	1.236386	0.254404	0.044*
C74	0.31059 (11)	1.17518 (15)	0.2979 (3)	0.0326 (4)
H74	0.337833	1.237841	0.290086	0.039*
C75	0.35012 (10)	1.08475 (14)	0.3293 (3)	0.0278 (4)
H75	0.404570	1.085344	0.342154	0.033*
C76	0.31046 (10)	0.99282 (14)	0.3420 (2)	0.0250 (4)
H76	0.338009	0.930930	0.363338	0.030*
C8	0.21977 (10)	0.79844 (13)	0.3214 (2)	0.0230 (4)
H8	0.272420	0.792202	0.293389	0.028*
C9	0.17444 (9)	0.71166 (13)	0.3448 (2)	0.0217 (3)
C10	0.09629 (9)	0.72315 (13)	0.3834 (2)	0.0213 (3)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C1	0.0225 (9)	0.0251 (9)	0.0215 (8)	−0.0003 (7)	0.0032 (6)	−0.0002 (7)
O1	0.0230 (6)	0.0202 (6)	0.0326 (7)	0.0016 (5)	0.0061 (5)	0.0010 (5)
C11	0.0275 (9)	0.0201 (9)	0.0253 (8)	0.0020 (7)	0.0050 (6)	0.0017 (7)
C12	0.0276 (9)	0.0209 (8)	0.0235 (8)	−0.0005 (7)	0.0036 (6)	−0.0029 (7)
O12	0.0272 (7)	0.0242 (7)	0.0380 (7)	−0.0034 (5)	0.0065 (5)	0.0023 (5)
O13	0.0260 (7)	0.0225 (7)	0.0359 (7)	0.0023 (5)	0.0080 (5)	0.0033 (5)
C13	0.0238 (9)	0.0273 (10)	0.0358 (10)	0.0027 (7)	0.0062 (7)	−0.0001 (8)
C14	0.0372 (11)	0.0323 (11)	0.0442 (11)	0.0073 (9)	0.0057 (8)	0.0005 (9)
N2	0.0241 (7)	0.0234 (8)	0.0257 (7)	0.0004 (6)	0.0045 (5)	−0.0003 (6)
N3	0.0237 (8)	0.0202 (7)	0.0308 (8)	−0.0035 (6)	0.0067 (6)	−0.0005 (6)
C4	0.0252 (9)	0.0221 (9)	0.0214 (8)	−0.0003 (7)	0.0018 (6)	0.0001 (6)
O4	0.0235 (6)	0.0242 (6)	0.0343 (7)	−0.0015 (5)	0.0066 (5)	0.0017 (5)
C5	0.0224 (8)	0.0232 (9)	0.0203 (8)	−0.0021 (7)	0.0025 (6)	−0.0012 (6)
C51	0.0238 (9)	0.0233 (9)	0.0315 (9)	0.0005 (7)	0.0054 (7)	−0.0006 (7)
N6	0.0246 (7)	0.0215 (7)	0.0236 (7)	−0.0007 (6)	0.0037 (5)	−0.0008 (6)
C7	0.0232 (8)	0.0226 (9)	0.0187 (8)	−0.0022 (7)	0.0016 (6)	−0.0002 (6)
C71	0.0256 (9)	0.0240 (9)	0.0206 (8)	−0.0022 (7)	0.0038 (6)	−0.0012 (7)
C72	0.0256 (9)	0.0257 (10)	0.0402 (10)	−0.0009 (7)	0.0052 (7)	−0.0001 (8)
C73	0.0329 (11)	0.0230 (10)	0.0546 (13)	0.0006 (8)	0.0042 (9)	0.0016 (9)
C74	0.0326 (10)	0.0239 (10)	0.0415 (11)	−0.0085 (7)	0.0049 (8)	−0.0012 (8)
C75	0.0242 (9)	0.0305 (10)	0.0289 (9)	−0.0038 (7)	0.0042 (7)	−0.0009 (7)
C76	0.0254 (9)	0.0254 (9)	0.0244 (8)	−0.0010 (7)	0.0025 (6)	−0.0011 (7)
C8	0.0204 (8)	0.0252 (9)	0.0235 (8)	−0.0007 (7)	0.0034 (6)	0.0000 (7)
C9	0.0241 (8)	0.0215 (9)	0.0197 (7)	−0.0002 (7)	0.0018 (6)	−0.0007 (6)
C10	0.0236 (8)	0.0219 (9)	0.0186 (7)	−0.0017 (7)	0.0017 (6)	0.0003 (6)

Geometric parameters (Å, º) top

C1—N2	1.283 (2)	C5—C10	1.418 (2)
C1—O1	1.3565 (19)	C5—C51	1.504 (2)
C1—C9	1.450 (2)	C51—H511	0.9800
O1—C11	1.434 (2)	C51—H512	0.9800
C11—C12	1.505 (2)	C51—H513	0.9800
C11—H111	0.9900	N6—C7	1.361 (2)
C11—H112	0.9900	C7—C8	1.386 (2)
C12—O12	1.201 (2)	C7—C71	1.490 (2)
C12—O13	1.338 (2)	C71—C72	1.397 (2)
O13—C13	1.456 (2)	C71—C76	1.400 (2)
C13—C14	1.501 (3)	C72—C73	1.388 (3)
C13—H131	0.9900	C72—H72	0.9500
C13—H132	0.9900	C73—C74	1.390 (3)
C14—H141	0.9800	C73—H73	0.9500
C14—H142	0.9800	C74—C75	1.382 (3)
C14—H143	0.9800	C74—H74	0.9500
N2—N3	1.368 (2)	C75—C76	1.392 (2)
N3—C4	1.356 (2)	C75—H75	0.9500
N3—H3	0.8800	C76—H76	0.9500
C4—O4	1.244 (2)	C8—C9	1.397 (2)
C4—C10	1.465 (2)	C8—H8	0.9500
C5—N6	1.333 (2)	C9—C10	1.408 (2)

N2—C1—O1	119.35 (16)	C5—C51—H512	109.5
N2—C1—C9	124.47 (15)	H511—C51—H512	109.5
O1—C1—C9	116.16 (15)	C5—C51—H513	109.5
C1—O1—C11	113.92 (13)	H511—C51—H513	109.5
O1—C11—C12	107.68 (14)	H512—C51—H513	109.5
O1—C11—H111	110.2	C5—N6—C7	120.34 (15)
C12—C11—H111	110.2	N6—C7—C8	122.05 (15)
O1—C11—H112	110.2	N6—C7—C71	115.20 (15)
C12—C11—H112	110.2	C8—C7—C71	122.75 (15)
H111—C11—H112	108.5	C72—C71—C76	118.69 (16)
O12—C12—O13	124.33 (16)	C72—C71—C7	119.84 (15)
O12—C12—C11	126.99 (16)	C76—C71—C7	121.47 (16)
O13—C12—C11	108.68 (14)	C73—C72—C71	120.68 (17)
C12—O13—C13	116.01 (13)	C73—C72—H72	119.7
O13—C13—C14	106.99 (15)	C71—C72—H72	119.7
O13—C13—H131	110.3	C72—C73—C74	120.02 (18)
C14—C13—H131	110.3	C72—C73—H73	120.0
O13—C13—H132	110.3	C74—C73—H73	120.0
C14—C13—H132	110.3	C75—C74—C73	119.96 (17)
H131—C13—H132	108.6	C75—C74—H74	120.0
C13—C14—H141	109.5	C73—C74—H74	120.0
C13—C14—H142	109.5	C74—C75—C76	120.26 (17)
H141—C14—H142	109.5	C74—C75—H75	119.9
C13—C14—H143	109.5	C76—C75—H75	119.9
H141—C14—H143	109.5	C75—C76—C71	120.39 (17)
H142—C14—H143	109.5	C75—C76—H76	119.8
C1—N2—N3	116.83 (15)	C71—C76—H76	119.8
C4—N3—N2	127.43 (14)	C7—C8—C9	118.59 (15)
C4—N3—H3	116.3	C7—C8—H8	120.7
N2—N3—H3	116.3	C9—C8—H8	120.7
O4—C4—N3	119.87 (16)	C8—C9—C10	119.50 (16)
O4—C4—C10	124.68 (16)	C8—C9—C1	123.25 (15)
N3—C4—C10	115.45 (15)	C10—C9—C1	117.24 (15)
N6—C5—C10	121.09 (15)	C9—C10—C5	118.40 (15)
N6—C5—C51	115.55 (15)	C9—C10—C4	118.54 (15)
C10—C5—C51	123.36 (15)	C5—C10—C4	123.01 (15)
C5—C51—H511	109.5

N2—C1—O1—C11	−5.8 (2)	C73—C74—C75—C76	−0.4 (3)
C9—C1—O1—C11	172.95 (14)	C74—C75—C76—C71	−0.2 (3)
C1—O1—C11—C12	−179.80 (13)	C72—C71—C76—C75	0.3 (2)
O1—C11—C12—O12	−13.6 (2)	C7—C71—C76—C75	−178.98 (15)
O1—C11—C12—O13	167.01 (13)	N6—C7—C8—C9	−2.0 (2)
O12—C12—O13—C13	−1.0 (2)	C71—C7—C8—C9	178.07 (15)
C11—C12—O13—C13	178.39 (13)	C7—C8—C9—C10	1.0 (2)
C12—O13—C13—C14	171.25 (15)	C7—C8—C9—C1	−177.68 (15)
O1—C1—N2—N3	178.51 (13)	N2—C1—C9—C8	178.16 (16)
C9—C1—N2—N3	−0.1 (2)	O1—C1—C9—C8	−0.5 (2)
C1—N2—N3—C4	−0.8 (2)	N2—C1—C9—C10	−0.5 (2)
N2—N3—C4—O4	−177.17 (15)	O1—C1—C9—C10	−179.14 (13)
N2—N3—C4—C10	2.1 (2)	C8—C9—C10—C5	0.5 (2)
C10—C5—N6—C7	0.0 (2)	C1—C9—C10—C5	179.22 (14)
C51—C5—N6—C7	179.79 (14)	C8—C9—C10—C4	−176.93 (14)
C5—N6—C7—C8	1.6 (2)	C1—C9—C10—C4	1.8 (2)
C5—N6—C7—C71	−178.54 (14)	N6—C5—C10—C9	−1.0 (2)
N6—C7—C71—C72	−17.4 (2)	C51—C5—C10—C9	179.22 (14)
C8—C7—C71—C72	162.49 (16)	N6—C5—C10—C4	176.29 (15)
N6—C7—C71—C76	161.87 (15)	C51—C5—C10—C4	−3.5 (2)
C8—C7—C71—C76	−18.2 (2)	O4—C4—C10—C9	176.72 (15)
C76—C71—C72—C73	0.1 (3)	N3—C4—C10—C9	−2.5 (2)
C7—C71—C72—C73	179.41 (17)	O4—C4—C10—C5	−0.6 (3)
C71—C72—C73—C74	−0.7 (3)	N3—C4—C10—C5	−179.77 (15)
C72—C73—C74—C75	0.8 (3)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N3—H3···O4ⁱ	0.88	1.93	2.7717 (19)	160
C14—H141···O12ⁱⁱ	0.98	2.63	3.190 (2)	116
C14—H142···O12ⁱⁱⁱ	0.98	2.65	3.411 (3)	135
C13—H132···O12^iv	0.99	2.80	3.746 (2)	161
C51—H512···O4^v	0.98	2.79	3.335 (2)	116

Symmetry codes: (i) −x, −y+1, −z+1; (ii) −x+1, y−1/2, −z+1/2; (iii) −x+1, −y+1, −z+1; (iv) −x+1, −y+1, −z; (v) x, −y+3/2, z−1/2.

Ethyl [(5-methyl-4-oxo-7-phenyl-3,4-dihydropyrido[3,4-d]pyridazin-1-yl)oxy]acetate (4) top

Crystal data top

C₂₂H₂₃N₃O₆	Z = 2
M_r = 425.43	F(000) = 448
Triclinic, P1	D_x = 1.371 Mg m⁻³
a = 8.679 (2) Å	Cu Kα radiation, λ = 1.54184 Å
b = 8.751 (2) Å	Cell parameters from 1514 reflections
c = 15.137 (4) Å	θ = 3.1–72.4°
α = 92.24 (2)°	µ = 0.84 mm⁻¹
β = 106.06 (3)°	T = 100 K
γ = 109.46 (3)°	Needle, colourless
V = 1030.7 (5) Å³	0.09 × 0.03 × 0.02 mm

Data collection top

Rigaku Xcalibur Onyx diffractometer	4142 independent reflections
Radiation source: fine-focus sealed X-ray tube, Enhance (Cu) X-ray Source	2089 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.068
Detector resolution: 8.1956 pixels mm^-1	θ_max = 77.3°, θ_min = 3.1°
ω scans	h = −10→10
Absorption correction: multi-scan (CrysAlis PRO; Rigaku OD, 2015)	k = −8→10
T_min = 0.840, T_max = 1.000	l = −17→19
7128 measured reflections

Refinement top

Refinement on F²	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.063	H-atom parameters constrained
wR(F²) = 0.165	w = 1/[σ²(F_o²) + (0.063P)²] where P = (F_o² + 2F_c²)/3
S = 0.98	(Δ/σ)_max < 0.001
4142 reflections	Δρ_max = 0.35 e Å⁻³
284 parameters	Δρ_min = −0.38 e Å⁻³
0 restraints	Extinction correction: SHELXL2018 (Sheldrick, 2015), Fc^*=kFc[1+0.001xFc²λ³/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.0037 (6)

Special details top

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
C1	0.2620 (4)	0.4605 (4)	0.3410 (2)	0.0254 (7)
O1	0.1154 (3)	0.4540 (3)	0.35841 (16)	0.0280 (5)
C11	−0.0362 (4)	0.3256 (4)	0.3014 (2)	0.0278 (7)
H111	−0.131455	0.312960	0.327715	0.033*
H112	−0.015212	0.221076	0.301129	0.033*
C12	−0.0874 (4)	0.3619 (4)	0.2024 (2)	0.0271 (7)
O12	−0.0317 (3)	0.4891 (3)	0.17669 (17)	0.0319 (6)
C13	−0.2667 (5)	0.2383 (5)	0.0501 (3)	0.0419 (10)
H131	−0.284006	0.343818	0.042431	0.050*
H132	−0.377843	0.148709	0.019592	0.050*
O13	−0.2094 (3)	0.2259 (3)	0.14844 (17)	0.0335 (6)
C14	−0.1360 (6)	0.2276 (6)	0.0046 (3)	0.0553 (12)
H141	−0.025470	0.315251	0.035544	0.083*
H142	−0.174650	0.239485	−0.061125	0.083*
H143	−0.122656	0.121111	0.009848	0.083*
N2	0.2563 (3)	0.3601 (3)	0.27490 (19)	0.0255 (6)
N3	0.4096 (3)	0.3724 (3)	0.26150 (19)	0.0250 (6)
C31	0.3876 (5)	0.2649 (4)	0.1803 (2)	0.0291 (7)
H311	0.294619	0.158906	0.175297	0.035*
H312	0.494912	0.243630	0.186311	0.035*
C32	0.3434 (4)	0.3423 (4)	0.0937 (2)	0.0259 (7)
O32	0.3488 (3)	0.4824 (3)	0.09355 (17)	0.0342 (6)
C33	0.2566 (5)	0.2991 (4)	−0.0702 (2)	0.0340 (8)
H331	0.355936	0.394237	−0.072688	0.041*
H332	0.157605	0.334695	−0.076461	0.041*
O33	0.2984 (3)	0.2349 (3)	0.01799 (16)	0.0303 (6)
C34	0.2136 (7)	0.1640 (6)	−0.1464 (3)	0.0586 (13)
H341	0.190424	0.204147	−0.206420	0.088*
H342	0.111686	0.072779	−0.145100	0.088*
H343	0.310542	0.126304	−0.137717	0.088*
C4	0.5693 (4)	0.4836 (4)	0.3110 (2)	0.0267 (7)
O4	0.6969 (3)	0.4861 (3)	0.28866 (18)	0.0376 (6)
C5	0.7260 (4)	0.7091 (4)	0.4497 (2)	0.0294 (8)
C51	0.9019 (4)	0.7287 (5)	0.4444 (3)	0.0377 (9)
H511	0.909036	0.754376	0.382928	0.057*
H512	0.922899	0.626558	0.454786	0.057*
H513	0.988388	0.817905	0.492179	0.057*
N6	0.7226 (3)	0.8078 (3)	0.51761 (19)	0.0277 (6)
C7	0.5707 (4)	0.8014 (4)	0.5292 (2)	0.0257 (7)
C71	0.5809 (4)	0.9194 (4)	0.6049 (2)	0.0248 (7)
C72	0.7405 (4)	1.0315 (4)	0.6607 (2)	0.0289 (8)
H72	0.843074	1.028627	0.650965	0.035*
C73	0.7501 (5)	1.1461 (4)	0.7300 (2)	0.0345 (8)
H73	0.858905	1.221882	0.766524	0.041*
C74	0.6019 (5)	1.1506 (4)	0.7460 (2)	0.0338 (8)
H74	0.608836	1.229495	0.793324	0.041*
C75	0.4441 (5)	1.0397 (4)	0.6929 (2)	0.0337 (8)
H75	0.342569	1.041059	0.704692	0.040*
C76	0.4330 (5)	0.9267 (4)	0.6228 (2)	0.0302 (8)
H76	0.323325	0.852674	0.586150	0.036*
C8	0.4162 (4)	0.6887 (4)	0.4729 (2)	0.0257 (7)
H8	0.310806	0.683071	0.482375	0.031*
C9	0.4185 (4)	0.5840 (4)	0.4022 (2)	0.0232 (7)
C10	0.5727 (4)	0.5921 (4)	0.3879 (2)	0.0261 (7)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C1	0.0263 (17)	0.0302 (18)	0.0248 (17)	0.0126 (14)	0.0118 (14)	0.0075 (14)
O1	0.0188 (11)	0.0366 (13)	0.0285 (13)	0.0093 (10)	0.0085 (10)	0.0013 (10)
C11	0.0184 (16)	0.0282 (17)	0.0296 (18)	0.0040 (13)	0.0024 (14)	−0.0013 (14)
C12	0.0145 (15)	0.0309 (18)	0.0331 (19)	0.0079 (13)	0.0044 (14)	−0.0007 (15)
O12	0.0307 (13)	0.0221 (12)	0.0394 (15)	0.0068 (10)	0.0083 (11)	0.0056 (10)
C13	0.035 (2)	0.047 (2)	0.035 (2)	0.0129 (18)	0.0019 (17)	−0.0007 (18)
O13	0.0305 (13)	0.0299 (13)	0.0324 (14)	0.0041 (10)	0.0071 (11)	−0.0015 (11)
C14	0.052 (3)	0.073 (3)	0.036 (2)	0.020 (2)	0.011 (2)	−0.002 (2)
N2	0.0244 (14)	0.0324 (15)	0.0254 (14)	0.0150 (12)	0.0104 (12)	0.0070 (12)
N3	0.0229 (14)	0.0295 (15)	0.0250 (15)	0.0111 (11)	0.0091 (12)	0.0034 (12)
C31	0.0325 (18)	0.0296 (17)	0.0302 (19)	0.0150 (14)	0.0125 (16)	0.0064 (15)
C32	0.0257 (17)	0.0241 (16)	0.0266 (18)	0.0072 (13)	0.0084 (14)	0.0021 (14)
O32	0.0399 (15)	0.0307 (13)	0.0326 (14)	0.0139 (11)	0.0104 (11)	0.0057 (11)
C33	0.039 (2)	0.037 (2)	0.0289 (19)	0.0167 (16)	0.0106 (16)	0.0064 (16)
O33	0.0381 (14)	0.0281 (12)	0.0272 (13)	0.0155 (10)	0.0094 (11)	0.0022 (10)
C34	0.089 (4)	0.067 (3)	0.030 (2)	0.048 (3)	0.010 (2)	0.007 (2)
C4	0.0220 (16)	0.0311 (17)	0.0247 (17)	0.0099 (13)	0.0027 (14)	0.0058 (14)
O4	0.0255 (13)	0.0459 (15)	0.0457 (16)	0.0141 (11)	0.0167 (12)	0.0000 (12)
C5	0.0295 (18)	0.0333 (18)	0.0277 (18)	0.0122 (15)	0.0108 (15)	0.0102 (15)
C51	0.0249 (19)	0.049 (2)	0.038 (2)	0.0105 (16)	0.0107 (16)	0.0020 (18)
N6	0.0233 (14)	0.0339 (15)	0.0252 (15)	0.0096 (12)	0.0070 (12)	0.0050 (12)
C7	0.0256 (17)	0.0289 (17)	0.0241 (17)	0.0108 (14)	0.0082 (14)	0.0094 (14)
C71	0.0256 (16)	0.0275 (16)	0.0210 (16)	0.0095 (13)	0.0063 (14)	0.0076 (13)
C72	0.0231 (17)	0.0320 (18)	0.0270 (18)	0.0089 (14)	0.0017 (14)	0.0044 (15)
C73	0.036 (2)	0.0266 (18)	0.0299 (19)	0.0030 (15)	0.0042 (16)	0.0026 (15)
C74	0.053 (2)	0.0227 (17)	0.0270 (19)	0.0155 (16)	0.0112 (18)	0.0040 (14)
C75	0.046 (2)	0.0274 (18)	0.0304 (19)	0.0134 (16)	0.0156 (17)	0.0039 (15)
C76	0.0330 (19)	0.0269 (17)	0.0320 (19)	0.0107 (14)	0.0116 (16)	0.0069 (15)
C8	0.0231 (16)	0.0293 (17)	0.0250 (17)	0.0099 (13)	0.0071 (14)	0.0065 (14)
C9	0.0192 (15)	0.0253 (16)	0.0197 (16)	0.0040 (12)	0.0021 (13)	0.0045 (13)
C10	0.0248 (17)	0.0274 (17)	0.0254 (17)	0.0094 (14)	0.0067 (14)	0.0045 (14)

Geometric parameters (Å, º) top

C1—N2	1.285 (4)	C34—H341	0.9800
C1—O1	1.353 (4)	C34—H342	0.9800
C1—C9	1.456 (4)	C34—H343	0.9800
O1—C11	1.432 (4)	C4—O4	1.238 (4)
C11—C12	1.519 (5)	C4—C10	1.461 (5)
C11—H111	0.9900	C5—N6	1.329 (4)
C11—H112	0.9900	C5—C10	1.422 (5)
C12—O12	1.185 (4)	C5—C51	1.504 (5)
C12—O13	1.345 (4)	C51—H511	0.9800
C13—O13	1.454 (4)	C51—H512	0.9800
C13—C14	1.506 (6)	C51—H513	0.9800
C13—H131	0.9900	N6—C7	1.361 (4)
C13—H132	0.9900	C7—C8	1.385 (5)
C14—H141	0.9800	C7—C71	1.475 (5)
C14—H142	0.9800	C71—C76	1.405 (5)
C14—H143	0.9800	C71—C72	1.406 (5)
N2—N3	1.371 (4)	C72—C73	1.387 (5)
N3—C4	1.378 (4)	C72—H72	0.9500
N3—C31	1.447 (4)	C73—C74	1.387 (5)
C31—C32	1.512 (5)	C73—H73	0.9500
C31—H311	0.9900	C74—C75	1.381 (5)
C31—H312	0.9900	C74—H74	0.9500
C32—O32	1.211 (4)	C75—C76	1.382 (5)
C32—O33	1.331 (4)	C75—H75	0.9500
C33—O33	1.468 (4)	C76—H76	0.9500
C33—C34	1.493 (5)	C8—C9	1.390 (4)
C33—H331	0.9900	C8—H8	0.9500
C33—H332	0.9900	C9—C10	1.393 (4)

N2—C1—O1	119.9 (3)	H341—C34—H342	109.5
N2—C1—C9	124.7 (3)	C33—C34—H343	109.5
O1—C1—C9	115.4 (3)	H341—C34—H343	109.5
C1—O1—C11	114.7 (2)	H342—C34—H343	109.5
O1—C11—C12	111.2 (3)	O4—C4—N3	119.8 (3)
O1—C11—H111	109.4	O4—C4—C10	124.8 (3)
C12—C11—H111	109.4	N3—C4—C10	115.4 (3)
O1—C11—H112	109.4	N6—C5—C10	121.6 (3)
C12—C11—H112	109.4	N6—C5—C51	115.3 (3)
H111—C11—H112	108.0	C10—C5—C51	123.0 (3)
O12—C12—O13	125.3 (3)	C5—C51—H511	109.5
O12—C12—C11	126.0 (3)	C5—C51—H512	109.5
O13—C12—C11	108.6 (3)	H511—C51—H512	109.5
O13—C13—C14	110.4 (3)	C5—C51—H513	109.5
O13—C13—H131	109.6	H511—C51—H513	109.5
C14—C13—H131	109.6	H512—C51—H513	109.5
O13—C13—H132	109.6	C5—N6—C7	120.7 (3)
C14—C13—H132	109.6	N6—C7—C8	121.1 (3)
H131—C13—H132	108.1	N6—C7—C71	116.3 (3)
C12—O13—C13	115.4 (3)	C8—C7—C71	122.6 (3)
C13—C14—H141	109.5	C76—C71—C72	117.5 (3)
C13—C14—H142	109.5	C76—C71—C7	121.7 (3)
H141—C14—H142	109.5	C72—C71—C7	120.8 (3)
C13—C14—H143	109.5	C73—C72—C71	120.9 (3)
H141—C14—H143	109.5	C73—C72—H72	119.6
H142—C14—H143	109.5	C71—C72—H72	119.6
C1—N2—N3	116.9 (3)	C74—C73—C72	120.4 (3)
N2—N3—C4	126.5 (3)	C74—C73—H73	119.8
N2—N3—C31	112.5 (3)	C72—C73—H73	119.8
C4—N3—C31	120.7 (3)	C75—C74—C73	119.6 (3)
N3—C31—C32	110.2 (3)	C75—C74—H74	120.2
N3—C31—H311	109.6	C73—C74—H74	120.2
C32—C31—H311	109.6	C74—C75—C76	120.5 (4)
N3—C31—H312	109.6	C74—C75—H75	119.8
C32—C31—H312	109.6	C76—C75—H75	119.8
H311—C31—H312	108.1	C75—C76—C71	121.2 (3)
O32—C32—O33	125.0 (3)	C75—C76—H76	119.4
O32—C32—C31	124.6 (3)	C71—C76—H76	119.4
O33—C32—C31	110.4 (3)	C7—C8—C9	118.6 (3)
O33—C33—C34	107.2 (3)	C7—C8—H8	120.7
O33—C33—H331	110.3	C9—C8—H8	120.7
C34—C33—H331	110.3	C8—C9—C10	120.9 (3)
O33—C33—H332	110.3	C8—C9—C1	122.0 (3)
C34—C33—H332	110.3	C10—C9—C1	117.1 (3)
H331—C33—H332	108.5	C9—C10—C5	117.1 (3)
C32—O33—C33	114.8 (3)	C9—C10—C4	119.2 (3)
C33—C34—H341	109.5	C5—C10—C4	123.7 (3)
C33—C34—H342	109.5

N2—C1—O1—C11	2.7 (4)	C8—C7—C71—C72	179.7 (3)
C9—C1—O1—C11	−176.4 (3)	C76—C71—C72—C73	−0.9 (5)
C1—O1—C11—C12	−72.1 (3)	C7—C71—C72—C73	177.9 (3)
O1—C11—C12—O12	−12.4 (5)	C71—C72—C73—C74	0.9 (5)
O1—C11—C12—O13	168.7 (3)	C72—C73—C74—C75	0.3 (5)
O12—C12—O13—C13	3.9 (5)	C73—C74—C75—C76	−1.3 (5)
C11—C12—O13—C13	−177.2 (3)	C74—C75—C76—C71	1.2 (5)
C14—C13—O13—C12	76.7 (4)	C72—C71—C76—C75	−0.1 (5)
O1—C1—N2—N3	−179.5 (3)	C7—C71—C76—C75	−178.9 (3)
C9—C1—N2—N3	−0.5 (5)	N6—C7—C8—C9	−1.6 (5)
C1—N2—N3—C4	−1.1 (5)	C71—C7—C8—C9	178.9 (3)
C1—N2—N3—C31	−174.5 (3)	C7—C8—C9—C10	−0.1 (5)
N2—N3—C31—C32	81.7 (3)	C7—C8—C9—C1	179.0 (3)
C4—N3—C31—C32	−92.2 (4)	N2—C1—C9—C8	−179.7 (3)
N3—C31—C32—O32	9.4 (5)	O1—C1—C9—C8	−0.6 (5)
N3—C31—C32—O33	−170.9 (3)	N2—C1—C9—C10	−0.5 (5)
O32—C32—O33—C33	1.1 (5)	O1—C1—C9—C10	178.5 (3)
C31—C32—O33—C33	−178.6 (3)	C8—C9—C10—C5	1.2 (5)
C34—C33—O33—C32	178.7 (3)	C1—C9—C10—C5	−178.0 (3)
N2—N3—C4—O4	−176.6 (3)	C8—C9—C10—C4	−178.0 (3)
C31—N3—C4—O4	−3.7 (5)	C1—C9—C10—C4	2.8 (4)
N2—N3—C4—C10	3.3 (5)	N6—C5—C10—C9	−0.6 (5)
C31—N3—C4—C10	176.2 (3)	C51—C5—C10—C9	178.3 (3)
C10—C5—N6—C7	−1.0 (5)	N6—C5—C10—C4	178.5 (3)
C51—C5—N6—C7	179.9 (3)	C51—C5—C10—C4	−2.5 (6)
C5—N6—C7—C8	2.2 (5)	O4—C4—C10—C9	175.9 (3)
C5—N6—C7—C71	−178.2 (3)	N3—C4—C10—C9	−4.1 (5)
N6—C7—C71—C76	179.0 (3)	O4—C4—C10—C5	−3.3 (6)
C8—C7—C71—C76	−1.5 (5)	N3—C4—C10—C5	176.8 (3)
N6—C7—C71—C72	0.2 (5)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C11—H111···O4ⁱ	0.99	2.44	3.053 (4)	120
C13—H131···O32ⁱⁱ	0.99	2.65	3.454 (5)	138
C14—H141···O12	0.98	2.60	3.113 (5)	113
C33—H331···O32ⁱⁱⁱ	0.99	2.54	3.445 (5)	152
C33—H332···O12ⁱⁱ	0.99	2.50	3.278 (4)	135
C73—H73···O12^iv	0.95	2.44	3.271 (4)	145

Symmetry codes: (i) x−1, y, z; (ii) −x, −y+1, −z; (iii) −x+1, −y+1, −z; (iv) −x+1, −y+2, −z+1.

Conditions included in Lipinski's rule and Veber's rule calculated with Molinspiration for compounds 2–4 top

Compound	MW	LogP	Hydrogen-bond donors	Hydrogen-bond acceptors	RotB	PSA
2	253.26	1.65	2	5	1	78.62
3	425.44	2.92	0	9	10	109.63
4	339.35	2.62	1	7	6	94.19

Comparison of selected geometrical parameters (Å, °) of compounds 2–4 top

	2	3	4
Bond distances
C1—O1	1.3383 (16)	1.3565 (19)	1.353 (4)
C1—N2	1.2942 (17)	1.283 (2)	1.285 (4)
N2—N3	1.3759 (15)	1.368 (2)	1.371 (4)
C4—N3	1.3532 (17)	1.356 (2)	1.378 (4)
C4—O4	1.2430 (15)	1.244 (2)	1.238 (4)
C4—C10	1.4671 (16)	1.465 (2)	1.461 (5)
C5—C10	1.4671 (16)	1.418 (2)	1.422 (5)
C5—C51	1.4990 (17)	1.504 (2)	1.504 (5)
C5—N6	1.3325 (16)	1.333 (2)	1.329 (4)
C7—N6	1.3569 (16)	1.361 (2)	1.361 (4)
C7—C71	1.4908 (17)	1.490 (2)	1.475 (5)
C7—C8	1.3837 (18)	1.386 (2)	1.385 (5)
C8—C9	1.3982 (17)	1.397 (2)	1.390 (4)
C9—C10	1.3984 (17)	1.408 (2)	1.393 (4)

Bond angles
O1—C1—N2	119.90 (12)	119.35 (16)	119.9 (3)
O1—C1—C9	116.47 (11)	116.16 (15)	115.4 (3)
C1—N2—N3	116.34 (11)	116.83 (15)	116.9 (3)
N2—N3—C4	128.17 (10)	127.43 (14)	126.5 (3)
N2—C1—C9	123.63 (12)	124.47 (15)	124.7 (3)
N3—C4—O4	120.11 (11)	119.87 (16)	119.8 (3)
O4—C4—C10	124.99 (11)	124.68 (16)	124.8 (3)
N3—C4—C10	114.89 (11)	115.45 (15)	115.4 (3)
C5—N6—C7	120.28 (11)	120.34 (15)	120.7 (3)
N6—C5—C10	121.55 (11)	121.09 (15)	121.6 (3)
N6—C5—C51	115.52 (11)	115.55 (15)	115.3 (3)

Torsion angles
O1—C1—N2—N3	-179.77 (11)	178.51 (13)	-179.5 (3)
O1—C1—C9—C8	1.09 (19)	-0.5 (2)	-0.6 (5)
C1—N2—N3—C4	-1.9 (2)	-0.8 (2)	-1.1 (5)
N2—N3—C4—O4	179.58 (12)	-177.17 (15)	-176.6 (3)
O4—C4—C10—C5	4.0 (2)	-0.6 (3)	-3.3 (6)
C4—C10—C5—C51	3.21 (19)	-3.5 (2)	-2.5 (6)
C4—C10—C5—N6	-178.30 (11)	176.29 (15)	178.5 (3)
C51—C5—N6—C7	178.26 (11)	179.79 (14)	179.9 (3)
C5—N6—C7—C71	178.79 (10)	-178.54 (14)	-178.2 (3)
N6—C7—C71—C72	-2.10 (17)	-17.4 (2)	0.2 (5)

Cytotoxicity of compound 2 (IC₅₀, mM)* top

	24 h	72 h
HACAT	3.24	1.17
A549	1.20	1.10
DU145	4.60	0.73
SKOV-3	0.90	0.37
MDA-MB-231	0.36	0.27

Note: (*) compound concentration that reduces cell proliferation by 50%, as was estimated by the MTT assay. The results are presented in millimolar concentration. The data correspond to mean values (±SD) for n ≥ 3.

Format		BIBTeX
		EndNote
		RefMan
		Refer
		Medline
		CIF
		SGML
		Text
		Plain Text

Format		BIBTeX
		EndNote
		RefMan
		Refer
		Medline
		CIF
		SGML
		Text
		Plain Text

Search IUCr Journals		doi		Advanced search
Author		volume	page

Structure and cytotoxic properties of 1-hy­droxy-5-methyl-7-phenyl­pyrido[3,4-d]pyridazin-4(3H)-one and its mono- and disubstituted ethyl acetates

Supporting information

Structure and cytotoxic properties of 1-hydroxy-5-methyl-7-phenylpyrido[3,4-d]pyridazin-4(3H)-one and its mono- and disubstituted ethyl acetates