DAVID A. GROSSIE AND K. TURNBULL 379 Scattering factors used are those of Cromer & Waber (1974). Investigation used XTAL/PC (Hall & Stewart, 1990; Grossie, 1990). Table 1" presents the final atomic coordinates and equivalent isotropic thermal parameters. Selected derived values in the form of interatomic distances and angles are tabu- lated in Table 2. A drawing of the molecular struc- ture is shown in Fig. 1. Related literature. The structures of other sydnones have been reported by Barnighausen, Jellinek, Munnik & Vos (1963), Hope & Thiessen (1969) and King, Preston, Suffolk & Turnbull (1979). The syd- none ring in the title compound is virtually identical (within errors) to the other sydnones reported even though there should be considerable structural strain from the ring fusion. * Lists of structure factors, anisotropic thermal parameters, H-atom parameters, dihedral angles and least-squares planes have been deposited with the British Library Document Supply Centre as Supplementary Publication No. SUP 54519 (18 pp.). Copies may be obtained through The Technical Editor, International Union of Crystallography, 5 Abbey Square, Chester CHI 2HU, England. [CIF reference: ST0533] We thank the Polymer Branch of the Materials Directorate, Wright Laboratory, Wright-Patterson Air Force Base, for diffractometer time. References BARNIGHAUSEN, H., JELLINEK, F., MUNNIK, J. & Vos, A. (1963). Acta Cryst. 16, 471-475. CROMER, D. T. ~ WABER, J. T. (1974). International Tables for X-ray Crystallography, Vol. IV, Table 2.2B. Birmingham: Kynoch Press. (Present distributor Kluwer Academic Publishers, Dordrecht.) GROSSIE, D. A. (1990). Desktop Crystallography: XTAL for the Personal Computer. International Union of Crystallography Meeting, Bordeaux, France. HALL, S. R. & STEWART, J. M. (1990). Editors. XTAL3.0 Refer- ence Manual. Univs. of Western Australia, Australia, and Maryland, USA. HOPE, H. & THIESSEN, W. E. (1967). J. Am. Chem. Soc. 89, 5977-5978. HOPE, H. & THIESSEN, W. E. (1969). Acta Cryst. B25, 1237-1247. KING, T. J., PRESTON, P. N., SUFFOLK, J. S. & TURNBULL, K. (1979). J. Chem. Soc. Perkin Trans. 2, pp. 1751-1757. LOWE, J. D. & TURNBULL, K. (1986). J. Heterocycl. Chem. 23, 125-128. ROBERTSON, B. E. & WANG, H. (1990). REGWT. XTAL3.0 Refer- ence Manual, edited by S. R. HALL & J. M. STEWART. Univs. of Western Australia, Australia, and Maryland, USA. Perth: Lamb. Acta Cryst. (1992). C48, 379-382 Structure of the Anti-Malarial Drug Primaquine Diphosphate BY J. R. RUBIN ABL- Basic Research Program, NCI-FCRDC, PO Box B, Frederick, Maryland 21701, USA AND P. SWAMINATHAN AND M. SUNDARALINGAM* Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA (Received 20 February 1991; accepted 17 July 1991) Abstract. 8-(4-Amino- 1-methylbutylamino)- 6-methoxyquinoline bis(dihydrogenphosphate), C15H23N302÷.2(H2PO4)-, Mr = 455.35, triclinic, P1, Z = 2, a = 7.389 (6), b = 8.862 (4), c = 16.055 (10) A, a = 97.57 (2), fl = 100.21 (3), y = 77.01 (2) °, V= 1003.6 (5) A 3, Dm = 1.495 (by flotation), Dx = 1.507 g cm -3, ,t(Cu Ka) = 1.5418 A, #(Cu Ka) = 24.48 cm -l, F(000)= 480, room temperature, R = 0.068 for 3448 observed reflections. The above work- ing cell is related to the reduced cell with angles a = 82.43, fl = 79.79 and y= 77.01 ° by the transfor- mation (-1 0 0/0 -1 0/0 0 1). Primaquine diphos- * Present address: Department of Chemistry and Biotechnology Center, The Ohio State University, Rightmire Hall, 1060 Carmack Road, Columbus, Ohio 43210, USA. phate was crystallized in the dicationic form with protonation on the quinoline ring nitrogen atom and on the terminal amino group. One dihydrogenphos- phate anion is chelated by the quinoline ring and the butylamino side chain. The other dihydrogenphos- phate anion is hydrogen bonded to the terminal amino group. The C(14) atom is nearly in the plane of the quinoline ring with a C(9)--C(8)--N(13)-- C(14) torsion angle of 169 °. The butyl-diamino side chain is kinked by rotation about the C(14)--C(16) bond with a N(13)--C(14)--C(16)--C(17) torsion angle of -59 °. The C(15) methyl substituent is inline with the rest of the butyl chain. The terminal amino group N(19) is hydrogen bonded to three symmetry- related phosphate groups while N(1) and N(13) are 'chelated' to a fourth phosphate group. 0108-2701/92/020379-04503.00 © 1992 International Union of Crystallography
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`380 ANTI-MALARIAL DRUG PRIMAQUINE DIPHOSPHATE Experimental. Primaquine diphosphate (Sigma Chemical Co.) was crystallized from an acidic aqueous ethanol solution (pH 2.5) in the form of orange rods. Data were collected using a 0.15 × 0.2 x 0.5 mm crystal on an Enraf-Nonius CAD-4 dif- fractometer using o9--20 scans. 15 centered reflections in the 0 range 20-30 ° were used to determine the unit-cell constants. Out of a total of 3793 reflections collected up to a 20 limit of 140 ° (h = 0---, + 9, k = - 10----+ 10, l = - 19---, + 19), 3448 reflections with I/tr(1) > 2 were considered observed and used for the structure analysis. Three reflections were monitored every 2 h during data collection and showed a varia- tion of 5% in intensity. No corrections for absorp- tion were made. The structure was solved by the Patterson method and refined by full-matrix least squares based on IFol. A difference Fourier map revealed all the H atoms including the one bound to N(1) of the qui- noline ring. Anisotropic thermal parameters of the heavy atoms and isotropic thermal parameters of H atoms were refined. The H-atom coordinates were not refined. R = 0.068, wR = 0.096, S = 2.69, weight = 1/[tr2(F) + (0.03Fo)2], max A/tr = 0.05, max. excursion in the final difference map =-0.7 to + 1.0 e A-3. Scattering factors for non-H atoms Ni9 °~ t Ci7 Ci4 Oit Ct2 Fig. 1. Primaquine diphosphate with non-H atoms drawn as 50% probability ellipsoids and H atoms drawn as spheres of arbi- trary size. The nitrogen atoms N(1) and N(19) are positively charged while the two phosphate groups are negatively charged. from Cromer & Waber (1965) and for H atoms from Stewart, Davidson & Simpson (1965). A locally modified version of the SDP program package from Enraf-Nonius (Frenz, 1982) was used. The positional parameters are listed in Table 1.* A thermal ellipsoid drawing of the structure is given in Fig. 1 and a packing diagram in Fig. 2. Bond lengths, angles and torsion angles are given in Table 2 and hydrogen-bond distances in Table 3. Related literature. Primaquine is the drug of choice for the treatment of Plasmodium vivax malaria (Webster, 1985). It inhibits protein biosynthesis (Olenick & Hahn, 1972; Olenick, 1975) by binding to DNA (Whichard, Morris, Smith & Holbrook, 1968) and this may be its mode of action. The primaquine dication contains two different functional groups known to bind nucleic acids. The N(1) protonated quinoline ring is analogous to the planar heterocyclic cationic acridine and phenanthroline dyes such as proflavin and ethidium which can intercalate * Lists of structure factors and anisotropic thermal parameters have been deposited with the British Library Document Supply Centre as Supplementary Publication No. SUP 54537 (14 pp.). Copies may be obtained through The Technical Editor, Interna- tional Union of Crystallography, 5 Abbey Square, Chester CH1 2HU, England. [CIF reference: CR0331] Fig. 2. Packing of the primaquine diphosphate structure viewed down a*. Notice how the aromatic dications stack and the NH groups are involved in hydrogen-bonding interactions with the neighboring phosphate groups. A similar mode of interaction can be envisioned of two primaquine dications with adjacent sugar-phosphate strands of a DNA in the groove.
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`J. R. RUBIN, P. SWAMINATHAN AND M. SUNDARALINGAM 381 Table 1. Fractional positional parameters for all atoms of primaquine diphosphate Bcq = (4/3)Y.,Yjfloae.a j. x y N(l) 0.2469 (3) 0.5713 C(2) 0.2876 (5) 0.7068 C(3) 0.3169 (5) 0.7421 C(4) 0.3052 (4) 0.6349 C(5) 0.2400 (4) 0.3809 C(6) 0.1944 (4) 0.2448 C(7) 0.1692 (4) 0.2118 C(8) 0.1867 (4) 0.3152 C(9) 0.2300 (4) 0.4601 C(10) 0.2575 (4) 0.4910 O(11) 0.1663 (4) 0.1301 C(12) 0.1863 (5) 0.1545 N(13) 0.1614 (4) 0.2839 C(14) 0.1511 (4) 0.1280 C(15) 0.3375 (6) 0.0162 C(16) 0.0999 (5) 0.1362 C(17) -0.0834 (5) 0.2402 C(18) - 0.0875 (6) 0.2476 N(19) -0.2516 (5) 0.3542 P(I) 0.2787 (1) 0.5426 OI(Pi) 0.4097 (4) 0.3785 O2(PI) 0.4183 (4) 0.6542 O3(Pl) 0.1851 (4) 0.5417 O4(PI) 0.1490 (3) 0.5832 P(2) -0.6551 (I) 0.1979 OI(P2) -0.8639 (4) 0.1811 O2(P2) - 0.5466 (4) 0.0472 O3(P2) - 0.6288 (3) 0.3362 O4(P2) -0.5860 (4) 0.1971 H(N1) 0.230 0.555 H(C2) 0.280 0.776 H(C3) 0.340 0.845 H(C4) 0.324 0.654 H(C5) 0.261 0.407 H(C7) 0.141 0.124 HI(C12) 0.184 0.081 H2(C12) 0.110 0.241 H3(C12) 0.290 0.191 H(NI3) 0.166 0.359 H(CI4) 0.055 0.104 HI(C15) 0.338 -0.074 H2(C15) 0.375 0.014 H3(C15) 0.408 0.054 H i (C 16) 0.096 0.053 H2(C16) 0.182 0.163 HI(CI7) -0.184 0.204 H2(C 17) - 0.089 0.325 HI(CI8) -0.084 0.144 H2(C18) 0.027 0.299 HI(NI9) -0.259 0.433 H2(NI9) -0.230 0.371 H3(NI9) -0.345 0.294 H(OIPI) 0.384 0.333 H(O2PI) 0.449 0.677 H(O 1P2) - 0.944 0.261 H(O2P2) - 0.502 - 0.030 Table 2. Bond distances (A) and angles (°) & the primaqu&e diphosphate structure N(I)----C(2) 1.328 (4) N(1)----C(9) 1.373 (4) z Bcq or B(A 2) C(2)----C(3) 1.381 (4) (3) 0.4248 (2) 2.36 (6) C(3)----C(4) 1.369 (5) (4) 0.4589 (2) 3.00 (9) C(4)---C(10) 1.419 (4) (4) 0.5460 (2) 3.10 (I0) C(5)--C(6) 1.364 (4) (4) 0.5979 (2) 2.85 (7) C(5)---C(10) 1.409 (4) (4) 0.6147 (2) 2.50 (7) C(6)--C(7) 1.408 (4) (3) 0.5765 (2) 2.27 (7) C(6)---O(1 I) 1.358 (4) (3) 0.4875 (2) 2.19 (7) C(7)---C(8) 1.386 (4) (3) 0.4332 (2) 1.98 (6) C(8)---C(9) 1.435 (4) (3) 0.4733 (2) 1.99 (7) C(8)--N(I 3) 1.354 (4) (3) 0.5624 (2) 2.18 (7) C(9)---C(10) 1.408 (4) (3) 0.6181 (I) 3.13 (7) O(11)---C(12) 1.430 (4) (4) 0.7088 (2) 3.25 (9) (3) 0.3476 (2) 2.51 (7) C(2)--N(1)--C(9) 122.4 (3) 0.3052 (2) 2.33 (7) N(1)--<2(2)--C(3) 121.1 (4) 0.3242 (2) 3.40 (9) C(2)--C(3)--C(4) 119.3 (4) 0.2106 (2) 2.82 (8) C(3)--C(4)--<3(10) 120.3 (4) 0.1775 (2) 3.12 (9) C(6)--C(5)--C(10) 118.1 (5) 0.0837 (2) 3.80 (10) C(5)--C(6)--C(7) 121.7 (4) 0.0435 (2) 3.54 (8) C(5)---C(6)--O(11) 125.0 (1) 0.1858 (1) 2.03 (2) C(7)---C(6)--O(11) 113.4 (3) 0.1698 (2) 4.06 (7) C(6)--C(7)--C(8) 122.6 (3) 0.2138 (2) 4.00 (8) C(7)--C(8)---C(9) 115.8 (3) 0.2611 (1) 3.40 (7) C(7)--C(8)--N(13) 122.6 (3) 0.1062 (1) 4.92 (7) C(9)--C(8)--N(13) 121.7 (1) -0.0656 (1) 2.19 (2) N(1)---~(9)--C(8) 120.1 (3) - 0.0870 (2) 4.18 (9) N(I)---C(9)---C(10) 118.7 (3) -0.1121 (1) 3.66 (7) C(8)----C(9)----C(10) 121.2 (3) -0.1026 (2) 3.48 (6) C(4)----C(10)--C(5) 121.1 (3) 0.0285 (1) 3.89 (7) C(4)---C(10)--C(9) 118.2 0.366 5 (l) 0.415 3 (l) 0.567 4 (l) 0.658 4 (l) 0.673 3 (I) 0.464 4 (1) 0.734 5 (1) 0.724 4 (1) 0.734 5 (1) 0.315 3 (1) 0.330 2 (1) 0.301 5 (1) 0.386 4 (l) 0.296 5 (1) 0.180 4 (1) 0.189 5 (1) 0.187 4(1) 0.211 5 (1) 0.053 4 (l) 0.086 13 (3) 0.076 6 (1) -0.012 4 (1) 0.045 9 (2) 0.117 6(1) O. ! 76 9 (2) -0.096 5 (1) -0.078 4 (1) between the base pairs of double helical nucleic acids (Berman & Young, 1981). The butyl-diamino side chain of primaquine is similar in structure to the aliphatic amine putrescine (Woo, Seeman & Rich, 1979) and the central segment of spermine (Jain, Zon & Sundaralingam, 1989), which can bind to the phosphodiester groups of the nucleic acid backbone. The crystal structure of the related antimalarial drug, chloroquine, which is also in the bis(dihydrogen- N(l 3)--C(14) 1.469 (4) C(l 4)--C(l 5) 1.513 (5) C(14)---C(16) 1.506 (4) C(16)--C(17) 1.510 (5) C(I 7)--C(18) 1.511 (5) C(l 8)---N(19) 1.465 (6) P(1)----OI(PI) 1.573 (3) P(I)--O2(PI) 1.556 (3) P(I)---O3(PI) 1.497 (2) P(I)--O4(PI) 1.488 (2) P(2)--OI(P2) 1.556 (3) P(2)--O2(P2) 1.566 (3) P(2)---O3(P2) 1.494 (3) P(2)--O4(P2) 1.507 (2) (3) C(5)----C(10)--CO) 120.7 (3) (4) C(6)--O(I 1)--C(12) 117.3 (3) (4) C(8)--N(I 3)--C(14) 122.9 (3) (4) N(13)---C(14)---C(15) 110.6 (3) (3) N(13)----C(14)---C(16) 109.6 (3) (3) C(15)---C(14)--C(16) 109.5 (3) (3) C(14)--C(16)--C(17) i18.2 (3) (3) C(16)--C(17)---C(18) 107.8 (4) (3) C(17)---C(18)--N(19) 114.3 (4) (3) OI(P1)---P(1)---O2(PI) 103.9 (2) (3) OI(PI)--P(I)--O3(PI) 108.6 (2) (3) OI(PI)--P(I)--O4(P1) 109.7 (2) (3) O2(P1)---P(1)---O3(P1) 106.4 (2) (3) O2(Pl)--P(l)--O4(P1) 112.4 (2) (3) O3(PI)--P(I)--O4(P1) 115.2 (2) (3) Ol(P2)--P(2)---O2(P2) 103.7 (2) (3) Ol(a2)--a(2)--O3(P2) 110.6 (2) Ol(P2)--P(2)--O4(P2) 111.2 (2) O2(P2)--P(2)---O3(P2) 108.7 (2) O2(P2)--P(2)--O4(P2) 108.4 (2) O3(P2)--P(2)---O4(P2) 113.8 (2) Table 3. Hydrogen-bonding distances (A) in the pri- maquine diphosphate structure A--H...B Sym. Trans. A...B N(I)---H(N 1)...O3(P 1) 1 0 0 0 2.575 (4) N(I 3)--H(N 13)-..O3(P1) 1 0 0 0 2.878 (3) N(19)---HI(N19).-.O3(P2) 2 - 1 1 0 2.780 (4) N(I 9)---H2(N 19)...O4(P1) 2 0 1 0 2.801 (4) N(i 9)--H 3(N 19).-.O4(P2) 1 0 0 0 3.058 (4) Ol (PI)--H(O 1PI)-..O4(P2) 1 1 0 0 2.603 (4) O2(PI)--H(O2P 1)...O3(P2) 2 0 1 0 2.588 (4) OI(P2)---H(O2P2)...O4(PI) 2 - 1 1 0 2.619 (3) O2(P2)---H(O4P2)-..O4(P2) 2 - 1 0 0 2.607 (4) Symmetry codes: (1) x, y, z; (2) - x, - y, - z. phosphate) form, has been determined (Karle & Karle, 1988; Preston & Stewart, 1970). This research was supported by the National Cancer Institute, and DHHS (under contract N01- CO1-74101 with ABL-BRP) to JRR and NIH (GM- 17378) to MS. We thank Drs Tuli P. Haromy and S. T. Rao for assistance in the preparation of the manuscript. References BERMAN, H. M. & YOUNG, P. R. (1981). Ann. Bio. Biophys. BioEng. 10, 87-114. CROMER, D. T. & WAmV.R, J. T. (1965). Acta Cryst. 18, 104-109.
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`382 ANTI-MALARIAL DRUG PRIMAQUINE DIPHOSPHATE Fv, ENz, B. A. (1982). The Enraf-Nonius CAD4-SDP. A Real-Time System for Concurrent X-ray Data Collection and Crystal Struc- ture Solution. In Computing in Crystallography, edited by H. SCI-IENK, R. OLTHOF-HAZEKAMP, H. VAN KONINGSVELD & G. C. BAssi. Delft Univ. Press. JAr~, S., ZON, G. & Stn~AgAL~6AM, M. (1989). Biochemistry, 28, 2360-2364. KARLE, J. M. & KARLE, I. L. (1988). Acta Cryst. CA4, 1605-1608. Ot~r~cK, J. G. (1975). Antibiotics, 3, 516-520. OL~aCK, J. G. & HAr~, F. E. (1972). Antimicrobial Agents Chemotherapy, 1, 259-264. PUSrON, H. S. & STEWART, J. M. (1970). Chem Commun. pp. 1142-1143. STEWART, R. F., DAVrDSON, E. R. & SIMPSON, W. T. (1965). J. Chem. Phys. 42, 3175-3187. W~STEg, L. T. (1985). The Pharmacological Basis of Therapeutics, 7th edition, edited by G. GILMAN, L. S. GOODMAN, T. W. RALL & F. MURAD, pp. 1051--1054. WmcnARD, L. P., MogPas, C. R., S~TH, J. M. & HOLBROOK, D. J. (1968). Mol. Pharmacol. 4, 630--639. Woo, N. H., SEEMAN, N. C. & RICH, A. (1979). Biopolymers, 18, 539-545. Acta Cryst. (1992). C48, 382-384 Strueture of 2-Chloro-7,12-dihydropyridoi3,2-b:5,4-b']diindole BY MARIA B. SZr, ARADZrNSKA AND ALEKSANDF.R W. ROSZAK Departments of Chemistry and of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada 72N 1N4 MARK L. TRUDELL AND JAMES M. COOK Department of Chemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201, USA AND PENELOPE W. CODDING* Departments of Chemistry and of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada T2N 1N4 (Received 16 May 1991; accepted 12 August 1991) Abstract. CI7HIoC1N3, Mr = 291.74, trigonal, P31, a = 8.3291 (5), c = 17.1142 (14) A, V = 1028.2 (1) A 3, Z = 3, Dx = 1.413 Mg m -3, a(Cu Ka) = 1.54178/~, /z = 2.44 mm- x, F(000) = 450, T = 293 K, R = 0.038 for 1287 unique observed reflections. The pyridodi- indole skeleton is planar (r.m.s. = 0.039 A, and X 2= 0.62 for 20 atoms). In the crystal, the molecules stack in pairs with the terminal A and E rings of adjacent molecules (x, y, z and x + 1, y + 1, z) above one another at a distance of 3.44 (7)A. The other inter- molecular interaction in this structure is a hydrogen bond between the indole N(12)--H(12) group and the pyridine N(5) atom from a symmetry-related molecule at - x + y, 1 - x, - ~ + z; the N...N dis- tance is 2.874 (5)A, the H...N distance is 1.92 (5)A and the angle NmH...N is 162 (4) °. Interestingly, the other hydrogen-donor group, the indole N(7)---H(7) group, is not involved in hydrogen bonding. The C--C1 bond length is 1.728 (4)/~. Experimental. The title compound (I) was prepared by Trudell, Basile, Shannon, Skolnick & Cook (1987). Single crystals were obtained by slow evapor- * Author to whom correspondence should be addressed. 0108-2701/92/020382-03503.00 ation from methanol/ethyl acetate solution. A rec- tangular solid of dimensions 0.44 x 0.20 x 0.08 mm was used for data collection on an Enraf-Nonius CAD-4F diffractometer with Ni-filtered CuKa radiation. Accurate unit-cell parameters were obtained from a least-squares refinement of the angles of 25 reflections with 31 < 0 < 45 °. An at--20 scan mode was used; three standards measured every 2000s indicated no crystal deterioration [003 682 (17), 245 482 (18), 312 237 (7)]; intensities for 4360 reflections were collected [h: -10--,10, k: - 10---,10, l: - 21---,0; maximum (sin0/,t) = 0.6257 A-1]; 1470 unique reflections (Rint = 0.076) of which 183 were regarded as unobserved [I < 2.50-(/)]. No absorption correction was applied. c1 H ~ I T~ ~ 3 9 5 8 "% 6 H (I) © 1992 International Union of Crystallography
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