Hydronium (cyclo­heptyl­ammonio)­methyl­ene-1,1-bis­phospho­nate (hydronium incadronate)

The structure of the title compound, H₃O⁺·C₈H₁₈NO₆P₂^-, adopts a zwitterionic form containing an alkyl­ammonium group, a hydro­nium ion, and two negatively charged phosphon­ate groups. The cyclo­heptyl side chain adopts a twist-chair conformation. The crystal packing is dominated by an extensive hydrogen-bonding network.

S1. Comment

Incadronate (INC), a patented α-nitrogen-containing bisphosphonate (Yamanouchi Pharmaceutical Co., Bisphonal), is a potent inhibitor of osteoclastic bone resorption. α-Nitrogen bisphosphonates are an unusual type of nitrogen-containing bisphosphonate, since the hydroxyl group found in most clinically used bisphosphonates is replaced by an H atom, and the N atom is located α rather than γ (pamidronate, Aredia) or δ (alendronate, Fosamax; risedronate, Actonel) with respect to the backbone C atom.

Incadronate has been shown to be ten times more potent than alendronate when used to treat patients with malignancy-associated hypercalcemia (Usui et al., 1997) and 50-fold more potent than pamidronate in treating tumor-induced hypercalcemia in rats (Takahashi et al., 1998). In addition to its use in the treatment of bone disorders, incadronate (and other bisphosphonates) has shown potential as a cholesterol-lowering agent. For example, of seven drugs tested, incadronate was the most potent inhibitor of squalene synthase and cholesterol biosysnthesis in rats (Amin et al., 1992). In addition, in other related work, it has been shown that incadronate specifically induces apoptosis in human myeloma cells (Shipman et al., 1998).

Incadronate is a low nanomolar inhibitor of farnesyl pyrophosphate synthase, and in bone resorption most likely functions by inhibiting this enzyme (van Beek et al., 1999). However, the exact nature of the interaction between FPP synthase and bisphosphates is unknown. One possibility is that they act as azaisoprenoid analogs which can dock in the geranyl pyrophosphate binding site (Martin et al., 1999).

In order to begin to explore these interactions in more detail, it is desirable to obtain high resolution crystal structures of such bisphosphonates for use in quantitative structure–activity relationship studies and for calibrating the results of other spectroscopic techniques. The crystal structure of hydronium incadronate, (I), is reported herein.

The α-N atom in (I) (Fig. 1) has two H atoms, giving it a +1 charge. The phosphonate groups both have an O atom that is protonated (O3 and O6) [P1—O3 = 1.560 (3) Å and P2—O6 = 1.562 (3) Å], and two O atoms that are unprotonated (O1, O2, O4 and O5) [P1—O1 = 1.509 (3) Å, P1—O2 = 1.496 (3) Å, P2—O4 = 1.528 (3) Å and P2—O5 = 1.479 (3) Å], resulting in both phosphonate groups being negatively charged. With the +1 charge on the α-N atom, the overall 2- charge on the phosphonate groups, and the presence of the hydronium ion, incadronate exists in the zwitterionic form common to many bisphosphonates (Vega et al., 1996, 1998, 2002).

The cycloheptyl side chain of (I) exists in a twist-chair conformation, as determined by inspection of the torsion angles (Table 1) and comparison with the results of Allen et al. (1993). The PCP backbone of the bisphosphonate group has a similar conformation to those found in two other bisphosphonates [isozoledronate, ISZ, and three hydrate forms of risedronate, namely monohydrate (RMH), dihydrate (RDH) and hemi-pentahydrate (RHP)] studied recently [INC 115.0 (2)°, RHP 112.4 (2)°, RDH 113.30 (15)°, RMH 113.22 (13)° and ISZ 114.8 (1)°] (Gossman et al., 2002, 2003). Examining the orientation of the phosphonate group to the side chain shows that the angle between the bisphosphonate group and the side chain is also very similar [C1—N1—C2 = 119.0 (3)°] to those found in isozoledronate and risedronate (Gossman et al., 2002, 2003), even with the α-nitrogen substitution.

One major difference in the structure of (I) to those previously examined is the orientation of the phosphonate group with respect to the ring. The cycloheptyl ring is nearly perpendicular to the first phosphonate group [P1—C1—N1—C2 = 178.2 (3)°], whereas in the four previously examined structures, the first phosphonate group adopts a more extended form [ISZ: P1—C5—C6—C7 = 62.0 (2)°; RHP: P1—C1—C2—C3 = 52.8 (6)°, RMH: P1—C1—C2—C3 57.8 (3)°; RDH: P1—C1—C2—C3 = 61.7 (3)°]. The crystals of incadronate are held together through an extensive hydrogen-bond network which consist of at least eight hydrogen bonds (Table 2).

S2. Experimental

Crystals of (I) were grown by vapor diffusion of ethanol into water.

S3. Refinement

Four frame series were filtered for statistical outliers and corrected for absorption by integration using SHELXTL/XPREP (Bruker, 2001), then were sorted, merged and scaled using SAINT/SADABS (Bruker, 2001). Crystal decay was monitored by collecting identical frames at the beginning and end of the experiment. No correction for decay as a function of X-ray exposure time was applied.

The proposed model includes one hydronium solvate. Donor H-atom positions were refined under restraint to idealized O—H and N—H distances with an effective s.u. of 0.03 Å. The remaining H atoms were included as riding idealized contributors. H atom U_iso values were assigned as 1.2U_eq of adjacent non-H atoms. The highest peaks in the final difference Fourier map were in the vicinity of the bisphosphonate moiety, suggesting possible additional disorder of the H atoms; however, models incorporating a more complex disordered scheme failed to converge with chemically reasonable geometry. The final map had no other significant features. A final analysis of variance between observed and calculated structure factors showed no dependence on amplitude or resolution.

Computing details

Data collection: SMART (Bruker, 2001); cell refinement: SAINT (Bruker, 2001); data reduction: SAINT; program(s) used to solve structure: SHELXTL (Bruker, 2001); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: CIFTAB in SHELXTL.

Figures

Fig. 1. SHELXTL (Bruker, 2001) plot showing the atom-numbering scheme and ellipsoids at the 35% probability level. H atoms are shown as small spheres of arbitrary radii.

(I)

Crystal data

H3O^+·C8H18NO6P2^−	F(000) = 648
Mr = 305.20	Dx = 1.497 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 920 reflections
a = 14.144 (5) Å	θ = 3.0–27.3°
b = 10.907 (3) Å	µ = 0.35 mm^−1
c = 9.052 (3) Å	T = 193 K
β = 104.196 (5)°	Tabular, colourless
V = 1353.8 (8) Å^3	0.30 × 0.24 × 0.08 mm
Z = 4

Data collection

Siemens Platform/CCD diffractometer	2463 independent reflections
Radiation source: normal-focus sealed tube	1685 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.109
profile data from ω scans	θmax = 25.3°, θmin = 2.4°
Absorption correction: integration (XPREP; Bruker, 2001)	h = 0→17
Tmin = 0.912, Tmax = 0.974	k = −13→0
7489 measured reflections	l = −10→10

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.058	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.162	H-atom parameters constrained
S = 1.05	w = 1/[σ^2(Fo^2) + (0.0958P)^2 + 0.401P] where P = (Fo^2 + 2Fc^2)/3
2463 reflections	(Δ/σ)max < 0.001
186 parameters	Δρmax = 0.47 e Å^−3
10 restraints	Δρmin = −0.48 e Å^−3

Special details

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 (Ų)

	x	y	z	Uiso*/Ueq
C1	0.1263 (3)	0.6456 (4)	0.0783 (4)	0.0233 (9)
H1	0.1273	0.6090	−0.0226	0.028*
C2	0.2676 (3)	0.5026 (4)	0.2218 (5)	0.0269 (9)
H2	0.3128	0.5737	0.2523	0.032*
C3	0.2836 (3)	0.4116 (4)	0.3559 (5)	0.0334 (11)
H3A	0.2564	0.4475	0.4371	0.040*
H3B	0.2470	0.3355	0.3206	0.040*
C4	0.3898 (3)	0.3791 (5)	0.4231 (5)	0.0407 (12)
H4A	0.3928	0.3212	0.5084	0.049*
H4B	0.4245	0.4546	0.4667	0.049*
C5	0.4448 (4)	0.3224 (5)	0.3146 (6)	0.0561 (16)
H5A	0.5054	0.2841	0.3755	0.067*
H5B	0.4042	0.2566	0.2555	0.067*
C6	0.4714 (4)	0.4130 (7)	0.2043 (6)	0.071 (2)
H6A	0.4982	0.4872	0.2629	0.085*
H6B	0.5248	0.3765	0.1657	0.085*
C7	0.3928 (3)	0.4540 (5)	0.0680 (5)	0.0417 (12)
H7A	0.3998	0.4052	−0.0209	0.050*
H7B	0.4060	0.5406	0.0468	0.050*
C8	0.2860 (3)	0.4454 (4)	0.0766 (5)	0.0318 (10)
H8A	0.2444	0.4872	−0.0131	0.038*
H8B	0.2665	0.3580	0.0719	0.038*
N1	0.1633 (2)	0.5476 (3)	0.1970 (4)	0.0240 (8)
H1A	0.153 (3)	0.570 (4)	0.285 (3)	0.029*
H1B	0.122 (3)	0.481 (3)	0.168 (5)	0.029*
O1	−0.05693 (19)	0.6934 (3)	−0.0896 (3)	0.0347 (8)
O2	−0.0358 (2)	0.5668 (3)	0.1522 (3)	0.0306 (7)
O3	−0.0082 (2)	0.7976 (3)	0.1587 (3)	0.0357 (8)
H3C	−0.008 (4)	0.796 (4)	0.250 (3)	0.043*
O4	0.1420 (2)	0.8775 (3)	−0.0062 (3)	0.0282 (7)
O5	0.2342 (2)	0.8175 (3)	0.2638 (3)	0.0337 (7)
O6	0.2945 (2)	0.7462 (3)	0.0426 (3)	0.0283 (7)
H6	0.280 (3)	0.719 (4)	−0.043 (3)	0.034*
P1	−0.00294 (7)	0.67396 (10)	0.07450 (12)	0.0257 (3)
P2	0.20327 (8)	0.78327 (10)	0.10099 (11)	0.0250 (3)
O7	0.1207 (3)	0.0673 (3)	0.1356 (4)	0.0488 (10)
H7C	0.102 (4)	0.003 (3)	0.083 (5)	0.059*
H7D	0.098 (4)	0.130 (3)	0.086 (5)	0.059*
H7E	0.090 (3)	0.067 (4)	0.209 (4)	0.059*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.022 (2)	0.027 (2)	0.023 (2)	0.0041 (17)	0.0094 (16)	0.0030 (17)
C2	0.020 (2)	0.035 (3)	0.026 (2)	−0.0007 (18)	0.0065 (16)	−0.0026 (19)
C3	0.038 (3)	0.034 (3)	0.034 (2)	0.006 (2)	0.019 (2)	0.003 (2)
C4	0.041 (3)	0.049 (3)	0.028 (2)	0.004 (2)	0.002 (2)	0.006 (2)
C5	0.037 (3)	0.089 (5)	0.044 (3)	0.027 (3)	0.015 (2)	0.019 (3)
C6	0.036 (3)	0.125 (6)	0.054 (4)	−0.002 (3)	0.017 (3)	0.028 (4)
C7	0.041 (3)	0.049 (3)	0.042 (3)	0.006 (2)	0.023 (2)	0.006 (2)
C8	0.031 (2)	0.036 (3)	0.031 (2)	0.004 (2)	0.0119 (19)	−0.0007 (19)
N1	0.0254 (18)	0.028 (2)	0.0186 (18)	0.0004 (15)	0.0066 (15)	−0.0001 (15)
O1	0.0236 (15)	0.059 (2)	0.0223 (15)	0.0029 (14)	0.0076 (12)	0.0067 (14)
O2	0.0309 (16)	0.0346 (18)	0.0297 (16)	−0.0047 (13)	0.0141 (13)	0.0026 (13)
O3	0.050 (2)	0.0318 (19)	0.0343 (18)	0.0054 (14)	0.0269 (16)	0.0018 (14)
O4	0.0333 (16)	0.0326 (18)	0.0224 (14)	0.0012 (13)	0.0143 (12)	0.0004 (12)
O5	0.0459 (18)	0.0383 (19)	0.0186 (15)	−0.0062 (14)	0.0108 (13)	−0.0011 (13)
O6	0.0228 (15)	0.0422 (19)	0.0207 (14)	−0.0039 (13)	0.0068 (12)	−0.0007 (14)
P1	0.0236 (6)	0.0340 (7)	0.0220 (6)	0.0019 (5)	0.0101 (4)	0.0041 (5)
P2	0.0272 (6)	0.0311 (7)	0.0179 (5)	−0.0038 (5)	0.0079 (4)	−0.0005 (4)
O7	0.067 (3)	0.036 (2)	0.058 (2)	0.0171 (18)	0.043 (2)	0.0148 (17)

Geometric parameters (Å, º)

C1—N1	1.515 (5)	C6—H6B	0.9900
C1—P2	1.837 (4)	C7—C8	1.534 (6)
C1—P1	1.845 (4)	C7—H7A	0.9900
C1—H1	1.0000	C7—H7B	0.9900
C2—N1	1.519 (5)	C8—H8A	0.9900
C2—C8	1.533 (5)	C8—H8B	0.9900
C2—C3	1.541 (6)	N1—H1A	0.88 (3)
C2—H2	1.0000	N1—H1B	0.93 (3)
C3—C4	1.517 (6)	O1—P1	1.509 (3)
C3—H3A	0.9900	O2—P1	1.496 (3)
C3—H3B	0.9900	O3—P1	1.560 (3)
C4—C5	1.526 (7)	O3—H3C	0.83 (3)
C4—H4A	0.9900	O4—P2	1.528 (3)
C4—H4B	0.9900	O5—P2	1.479 (3)
C5—C6	1.516 (7)	O6—P2	1.562 (3)
C5—H5A	0.9900	O6—H6	0.81 (3)
C5—H5B	0.9900	O7—H7C	0.85 (3)
C6—C7	1.512 (7)	O7—H7D	0.84 (3)
C6—H6A	0.9900	O7—H7E	0.87 (3)
N1—C1—P2	113.9 (3)	C6—C7—C8	118.5 (4)
N1—C1—P1	107.5 (2)	C6—C7—H7A	107.7
P2—C1—P1	115.0 (2)	C8—C7—H7A	107.7
N1—C1—H1	106.7	C6—C7—H7B	107.7
P2—C1—H1	106.7	C8—C7—H7B	107.7
P1—C1—H1	106.7	H7A—C7—H7B	107.1
N1—C2—C8	111.6 (3)	C2—C8—C7	113.2 (4)
N1—C2—C3	105.9 (3)	C2—C8—H8A	108.9
C8—C2—C3	113.0 (4)	C7—C8—H8A	108.9
N1—C2—H2	108.7	C2—C8—H8B	108.9
C8—C2—H2	108.7	C7—C8—H8B	108.9
C3—C2—H2	108.7	H8A—C8—H8B	107.7
C4—C3—C2	114.0 (4)	C1—N1—C2	119.2 (3)
C4—C3—H3A	108.8	C1—N1—H1A	110 (3)
C2—C3—H3A	108.8	C2—N1—H1A	109 (3)
C4—C3—H3B	108.8	C1—N1—H1B	105 (3)
C2—C3—H3B	108.8	C2—N1—H1B	108 (3)
H3A—C3—H3B	107.7	H1A—N1—H1B	104 (4)
C3—C4—C5	116.6 (4)	P1—O3—H3C	119 (3)
C3—C4—H4A	108.1	P2—O6—H6	112 (3)
C5—C4—H4A	108.1	O2—P1—O1	115.58 (17)
C3—C4—H4B	108.1	O2—P1—O3	112.85 (16)
C5—C4—H4B	108.1	O1—P1—O3	106.62 (18)
H4A—C4—H4B	107.3	O2—P1—C1	106.30 (17)
C6—C5—C4	114.1 (5)	O1—P1—C1	107.55 (16)
C6—C5—H5A	108.7	O3—P1—C1	107.57 (18)
C4—C5—H5A	108.7	O5—P2—O4	116.52 (17)
C6—C5—H5B	108.7	O5—P2—O6	109.58 (16)
C4—C5—H5B	108.7	O4—P2—O6	110.22 (15)
H5A—C5—H5B	107.6	O5—P2—C1	109.89 (17)
C7—C6—C5	118.6 (4)	O4—P2—C1	104.50 (17)
C7—C6—H6A	107.7	O6—P2—C1	105.49 (18)
C5—C6—H6A	107.7	H7C—O7—H7D	110 (4)
C7—C6—H6B	107.7	H7C—O7—H7E	106 (4)
C5—C6—H6B	107.7	H7D—O7—H7E	102 (4)
H6A—C6—H6B	107.1
N1—C2—C3—C4	−166.2 (4)	N1—C1—P1—O2	−17.0 (3)
C8—C2—C3—C4	71.4 (5)	P2—C1—P1—O2	−144.9 (2)
C2—C3—C4—C5	−58.4 (6)	N1—C1—P1—O1	−141.3 (3)
C3—C4—C5—C6	74.5 (6)	P2—C1—P1—O1	90.7 (2)
C4—C5—C6—C7	−77.1 (7)	N1—C1—P1—O3	104.1 (3)
C5—C6—C7—C8	23.5 (8)	P2—C1—P1—O3	−23.8 (3)
N1—C2—C8—C7	152.8 (4)	N1—C1—P2—O5	−42.6 (3)
C3—C2—C8—C7	−87.9 (4)	P1—C1—P2—O5	82.1 (2)
C6—C7—C8—C2	49.8 (6)	N1—C1—P2—O4	−168.3 (2)
P2—C1—N1—C2	−53.3 (4)	P1—C1—P2—O4	−43.7 (2)
P1—C1—N1—C2	178.2 (3)	N1—C1—P2—O6	75.5 (3)
C8—C2—N1—C1	−60.6 (5)	P1—C1—P2—O6	−159.91 (19)
C3—C2—N1—C1	176.1 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1A···O4^i	0.88 (3)	2.02 (3)	2.893 (4)	176 (4)
N1—H1B···O1^ii	0.93 (3)	2.16 (3)	3.066 (5)	166 (4)
O3—H3C···O1^i	0.83 (3)	1.75 (3)	2.539 (4)	157 (5)
O6—H6···O5^iii	0.81 (3)	1.75 (3)	2.554 (4)	170 (5)
O7—H7C···O4^iv	0.85 (3)	1.75 (4)	2.493 (4)	144 (5)
O7—H7E···O2^v	0.87 (3)	1.63 (3)	2.503 (4)	179 (5)
O7—H7D···O1^ii	0.84 (3)	2.01 (3)	2.760 (5)	148 (5)
O7—H7D···O3^ii	0.84 (3)	2.40 (4)	3.117 (5)	144 (4)

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