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Volume 68 
Part 9 
Pages o341-o343  
September 2012  

Received 28 May 2012
Accepted 16 July 2012
Online 1 August 2012

Novel pseudopolymorph of the active metabolite of perindopril

aInstitute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924 Lódz, Poland,bPolfarmex S.A., Józefów 9, 99-300 Kutno, Poland,cDepartment of Synthesis and Technology of Drugs, Medical University, Lódz, Muszynskiego 1, 90-145 Lódz, Poland, and dDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University Bratislava, Odbojárov 10, SK-832 32 Bratislava, Slovakia
Correspondence e-mail: waldemar.maniukiewicz@p.lodz.pl

The dimethyl sulfoxide hemisolvate of perindoprilat [systematic name: (1S)-2-((S)-{1-[(2S,3aS,7aS)-2-carboxyoctahydro-1H-indol-1-yl]-1-oxopropan-2-yl}azaniumyl)pentanoate dimethyl sulfoxide hemisolvate], C17H28N2O5·0.5C2H6OS, an active metabolite of perindopril, has been synthesized, structurally characterized by single-crystal X-ray diffraction and compared with its ethanol disolvate analogue [Pascard et al. (1991). J. Med. Chem. 34, 663-669]. Both compounds crystallize in the orthorhombic P212121 space group in the same zwitterionic form, with a protonated alanine N atom and an anionic carboxylate group at the n-alkyl chain. The three structural units present in the unit cell (two zwitterions and the solvent molecule) are held together by a rich system of O-H...O, N-H...O and C-H...O hydrogen-bond contacts.

Comment

Perindopril, a perhydroindole derivative (systematic name: (2S,3aS,7aS)-1-((2S)-2-{[(2S)-1-ethoxy-1-oxopentan-2-yl]amino}propanoyl)-2,3,3a,4,5,6,7,7a-octahydroindole-2-carboxylic acid), is a powerful angiotensin-converting enzyme (ACE) inhibitor, a zinc metalloenzyme involved in the control of blood pressure (Opie, 1994[Opie, L. H. (1994). Angiotensin Converting Enzyme Inhibitors, 2nd ed., pp. 229-238. New York: Wiley-Liss.]). Furthermore, this prodrug possesses vasculoprotective or antithrombotic properties, important in terms of cardiovascular morbidity (Remková et al., 2008[Remková, A., Kratochvílová, H. & Durina, J. (2008). J. Hum. Hypertens. 22, 338-345.]; Remková & Remko, 2010[Remková, A. & Remko, M. (2010). Physiol. Res. 59, 13-23.]). Perindopril is metabolized in vivo to its biologically active diacid form, namely perindoprilat, by hepatic esterase through the hydrolysis of ester groups (Kelly & O'Malley, 1990[Kelly, J. G. & O'Malley, K. (1990). Clin. Pharmacokinet. 19, 177-196.]). The prodrug also undergoes glucuronidation and further hydrolysis to biologically inactive perindoprilat glucuronide (Grislain et al., 1990[Grislain, L., Mocquard, M. T., Dabe, J. F., Bertrand, M., Luijten, W., Marchand, B., Resplandy, G. & Devvissaguet, M. (1990). Xenobiotica B, 20, 787-800.]). Apart from that, a few other metabolites are formed, such as dehydrated perindopril and the diastereoisomers of dehydrated perindoprilat, which are also inactive (Medenica et al., 2007[Medenica, M., Ivanovic, D., Maskovic, M., Jancic, B. & Malenovic, A. (2007). J. Pharm. Biomed. Anal. B, 44, 1087-1094.]). The tert-butylamine and L-arginine salts of perindopril represent its commercially-used pharmaceutically-effective forms. Only the enantiomer having all five asymmetric C atoms in the S configuration is used as an antihypertensive agent. The R enantiomer is a by-product in the synthesis of perindopril (Vincent & Schiavi, 1991[Vincent, M. & Schiavi, P. (1991). Modelling, Synthesis and Pharmacological Study of Perindopril, an Angiotensin I Converting Enzyme Inhibitor, in Molecular Recognition Mechanisms, edited by M. Delaage, ch. 5. Paris: VCH Publisher/Lavoisier TEC and DOC.]). Although perindopril

[Scheme 1]
was first synthesized in 1982 (Vincent et al., 1982[Vincent, M., Remond, G., Portevin, B., Serkiz, B. & Laubie, M. (1982). Tetrahedron Lett. 23, 1677-1680.]), its three-dimensional structure was unknown until 2011, when we presented the first crystal structures of two tert-butylamine salts [see Cambridge Structural Database (CSD, Version 5.31; Allen, 2002[Allen, F. H. (2002). Acta Cryst. B58, 380-388.]) refcodes IVEGIA and IVEGOG (Remko et al., 2011[Remko, M., Bojarska, J., Jezko, P., Sieron, L., Olczak, A. & Maniukiewicz, W. (2011). J. Mol. Struct. 997, 103-109.])] as part of our studies of perindoprilat polymorphism. Up to now, only one crystal structure of perindoprilat has been reported (Pascard et al., 1991[Pascard, C., Guilhem, J., Vincent, M., Remond, G., Portevin, B. & Laubie, M. (1991). J. Med. Chem. 34, 663-669.]; CSD refcode SIWBUV), in the form of its ethanol disolvate, (II).

This work concerns the crystal structure of perindoprilat dimethyl sulfoxide hemisolvate, (I)[link], studied at 100 K and refined to an R factor of 0.027. The asymmetric unit of (I)[link] contains two perindoprilat zwitterionic molecules (A and B) and one dimethyl sulfoxide solvent molecule (Fig. 1[link]). Both perindoprilat molecules have an S configuration at all five chiral C atoms. The Flack parameter of 0.028 (11) (Flack, 1983[Flack, H. D. (1983). Acta Cryst. A39, 876-881.]) confirms this assignment. Two H atoms at each alanine N2 atom were unequivocally located in the electron-density map, which together with the equalized C-O bond lengths in the carboxylate groups confirms the presence of the zwitterionic form of perindoprilat in the studied crystal (Fig. 1[link]).

The conformations of the two crystallographically independent zwitterions of (I)[link] and of the ethanol disolvate, (II) (Pascard et al., 1991[Pascard, C., Guilhem, J., Vincent, M., Remond, G., Portevin, B. & Laubie, M. (1991). J. Med. Chem. 34, 663-669.]), are similar due to several features present in the structures, i.e. the rigid bicyclic system, an O3...N2 intermolecular hydrogen bond, several planar amide fragments and many groups involved in hydrogen bonds (Table 1[link] and Fig. 2[link]). The six-membered rings of both molecules of (I)[link] possess the same slightly deformed chair conformation, as indicated by the Cremer-Pople puckering parameters (Cremer & Pople, 1975[Cremer, D. & Pople, J. A. (1975). J. Am. Chem. Soc. 97, 1354-1358.]), having total puckering amplitudes Q of 0.5524 (15) and 0.5387 (15) Å and with [theta] = 164.60 (16) and 166.69 (16)° for molecules A and B, respectively. The proline rings are in an envelope conformation, with a puckering amplitude Q of 0.3776 (14) Å and [varphi] = 285.5 (2)° for molecule A, and with Q = 0.3928 (15) Å and [varphi] = 287.8 (2)° for molecule B. The amide systems are planar and the C15-terminal carboxylate groups are axial. The dihedral angles between the alanine methyl group and the amide plane (O1/C9/C10/C16) are nearly identical in both molecules [67.80 (16)° in A and 68.75 (15)° in B]. On the other hand, the conformations of the terminal alkyl chain, being the most obviously flexible part of (I)[link], are quite different for molecules A and B (Fig. 3[link]). They adopt either a synclinal or an antiperiplanar conformation, with N2-C11-C12-C13 torsion angles of 73.78 (15) and -179.38 (12)° for molecules A and B, respectively.

Another point of interest is the packing motifs of (I)[link], which are dominated by intermolecular O-H...O and N-H...O hydrogen bonds (Table 1[link] and Fig. 2[link]). The analysis of these hydrogen bonds shows that molecules A and B generate separate 11-membered chains, with a graph-set motif of C(11) [according to the graph-set definition of Etter et al. (1990[Etter, M. C., MacDonald, J. C. & Bernstein, J. (1990). Acta Cryst. B46, 256-262.]) and Bernstein et al. (1995[Bernstein, J., Davis, R. E., Shimon, L. & Chang, N.-L. (1995). Angew. Chem. Int. Ed. Engl. 34, 1555-1573.])], through O5A-H5OA...O2A(x + [{1\over 2}], -y + [{1\over 2}], -z) and O5B-H5OB...O2B(x - [{1\over 2}], -y + [{1\over 2}], -z + 1) interactions that run in the [100] direction. Dimethyl sulfoxide molecules bridge the perindoprilat molecules via N2A-H2NA...O1S and N2B-H2ND...O1S hydrogen bonds. As a result, nine-membered rings with the graph-set motif R32(9) are generated (Fig. 2[link]). The crystal packing is also stabilized by the formation of hydrogen-bonded layers, which contain R66(38) rings formed via O5A-H5OAv...O2A, O5B-H5OB...O2Bii, N2B-H2NCii...O3Aiii, N2A-H2NBiv...O3Bvi and N2B-H2NCvi...O3A hydrogen bonds (symmetry codes as in Fig. 2[link]). In addition to the hydrogen bonds listed in Table 1[link], geometry calculations show several weak C-H...O separations, with H...O distances in the range 2.29-2.58 Å and C-H...O angles in the range 129-168°.

[Figure 1]
Figure 1
A view of the molecular structure of (I)[link], showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level. Dashed lines indicate hydrogen bonds.
[Figure 2]
Figure 2
The intermolecular O-H...O and N-H...O hydrogen bonds of (I)[link] (dashed lines) determining the packing of molecules in the crystal structure. Only H atoms participating in hydrogen bonds are shown. [Symmetry codes: (iii) x - [{1\over 2}], -y + [{1\over 2}], -z + 1; (iv) -x + 1, y + [{1\over 2}], -z + [{1\over 2}]; (v) x - [{1\over 2}], -y + [{1\over 2}], -z; (vi) -x + [{1\over 2}], -y + 1, z + [{1\over 2}]; (vii) -x + [{1\over 2}], -y + 1, z - [{1\over 2}].]
[Figure 3]
Figure 3
A superimposition of molecule A of (I)[link] (light grey; turquoise in the electronic version of the paper), molecule B of (I)[link] (dark grey; dark blue in the electronic version of the paper) and (II) (medium grey; dark grey in the electronic version of the paper) on their common amide plane. H atoms have been omitted for clarity.

Experimental

Perindoprilat was synthesized according to the method of Vincent et al. (1982[Vincent, M., Remond, G., Portevin, B., Serkiz, B. & Laubie, M. (1982). Tetrahedron Lett. 23, 1677-1680.]). Crystals of (I)[link] suitable for single-crystal X-ray structure analysis were obtained via controlled evaporation of a dimethyl sulfoxide-ethanol (1:1 v/v) solution at room temperature.

Crystal data
  • C17H28N2O5·0.5C2H6OS

  • Mr = 379.49

  • Orthorhombic, P 21 21 21

  • a = 10.3504 (7) Å

  • b = 16.0908 (11) Å

  • c = 24.4828 (16) Å

  • V = 4077.5 (5) Å3

  • Z = 8

  • Cu K[alpha] radiation

  • [mu] = 1.21 mm-1

  • T = 100 K

  • 0.40 × 0.30 × 0.15 mm

Data collection
  • Bruker SMART APEXII CCD area-detector diffractometer

  • Absorption correction: multi-scan (SADABS; Sheldrick, 2003[Sheldrick, G. M. (2003). SADABS. University of Göttingen, Germany.]) Tmin = 0.680, Tmax = 0.835

  • 71530 measured reflections

  • 7427 independent reflections

  • 7382 reflections with I > 2[sigma](I)

  • Rint = 0.030

Refinement
  • R[F2 > 2[sigma](F2)] = 0.027

  • wR(F2) = 0.070

  • S = 1.04

  • 7427 reflections

  • 499 parameters

  • H atoms treated by a mixture of independent and constrained refinement

  • [Delta][rho]max = 0.29 e Å-3

  • [Delta][rho]min = -0.20 e Å-3

  • Absolute structure: Flack (1983[Flack, H. D. (1983). Acta Cryst. A39, 876-881.]), with 3264 Friedel pairs

  • Flack parameter: 0.028 (11)

Table 1
Hydrogen-bond geometry (Å, °)

D-H...A D-H H...A D...A D-H...A
N2A-H2NA...O1S 0.905 (19) 2.017 (19) 2.8912 (15) 161.9 (16)
N2A-H2NB...O3B 0.898 (17) 1.981 (17) 2.7204 (14) 138.5 (15)
O5A-H5OA...O2Ai 0.93 (2) 1.70 (2) 2.5972 (14) 162.4 (19)
N2B-H2NC...O3Aii 0.856 (19) 1.990 (19) 2.8157 (15) 161.8 (16)
N2B-H2ND...O1S 0.887 (19) 1.989 (19) 2.8710 (16) 172.2 (17)
O5B-H5OB...O2Biii 0.79 (2) 1.79 (2) 2.5773 (15) 170 (2)
Symmetry codes: (i) [x+{\script{1\over 2}}, -y+{\script{1\over 2}}, -z]; (ii) [-x+2, y-{\script{1\over 2}}, -z+{\script{1\over 2}}]; (iii) [x-{\script{1\over 2}}, -y+{\script{1\over 2}}], -z+1.

H atoms were located in difference Fourier maps. C-bound H atoms were subsequently geometrically optimized and allowed for as riding atoms, with C-H = 0.98 Å for methyl, 0.99 Å for methylene and 1.00 Å for methine groups, and with Uiso(H) = 1.5Ueq(C) for methyl H atoms and 1.2Ueq(C) for methylene and methine H atoms. H atoms bonded to N and O atoms were refined freely.

Data collection: APEX2 (Bruker, 2005[Bruker (2005). APEX2. Bruker AXS Inc., Madison, Wisconsin, USA.]); cell refinement: SAINT-Plus (Bruker, 2008[Bruker (2008). SAINT-Plus. Bruker AXS Inc., Madison, Wisconsin, USA.]); data reduction: SAINT-Plus; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); molecular graphics: PLATON (Spek, 2009[Spek, A. L. (2009). Acta Cryst. D65, 148-155.]) and Mercury (Macrae et al., 2008[Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe, P., Pidcock, E., Rodriguez-Monge, L., Taylor, R., van de Streek, J. & Wood, P. A. (2008). J. Appl. Cryst. 41, 466-470.]); software used to prepare material for publication: PLATON.


Supplementary data for this paper are available from the IUCr electronic archives (Reference: FG3257 ). Services for accessing these data are described at the back of the journal.


Acknowledgements

The authors thank Professor M. L. Glówka for helpful suggestions and comments.

References

Allen, F. H. (2002). Acta Cryst. B58, 380-388.  [ISI] [CrossRef] [details]
Bernstein, J., Davis, R. E., Shimon, L. & Chang, N.-L. (1995). Angew. Chem. Int. Ed. Engl. 34, 1555-1573.  [CrossRef] [ChemPort] [ISI]
Bruker (2005). APEX2. Bruker AXS Inc., Madison, Wisconsin, USA.
Bruker (2008). SAINT-Plus. Bruker AXS Inc., Madison, Wisconsin, USA.
Cremer, D. & Pople, J. A. (1975). J. Am. Chem. Soc. 97, 1354-1358.  [CrossRef] [ChemPort] [ISI]
Etter, M. C., MacDonald, J. C. & Bernstein, J. (1990). Acta Cryst. B46, 256-262.  [CrossRef] [ISI] [details]
Flack, H. D. (1983). Acta Cryst. A39, 876-881.  [CrossRef] [details]
Grislain, L., Mocquard, M. T., Dabe, J. F., Bertrand, M., Luijten, W., Marchand, B., Resplandy, G. & Devvissaguet, M. (1990). Xenobiotica B, 20, 787-800.  [CrossRef] [ChemPort]
Kelly, J. G. & O'Malley, K. (1990). Clin. Pharmacokinet. 19, 177-196.  [CrossRef] [ChemPort] [PubMed]
Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe, P., Pidcock, E., Rodriguez-Monge, L., Taylor, R., van de Streek, J. & Wood, P. A. (2008). J. Appl. Cryst. 41, 466-470.  [ISI] [CrossRef] [ChemPort] [details]
Medenica, M., Ivanovic, D., Maskovic, M., Jancic, B. & Malenovic, A. (2007). J. Pharm. Biomed. Anal. B, 44, 1087-1094.  [CrossRef] [ChemPort]
Opie, L. H. (1994). Angiotensin Converting Enzyme Inhibitors, 2nd ed., pp. 229-238. New York: Wiley-Liss.
Pascard, C., Guilhem, J., Vincent, M., Remond, G., Portevin, B. & Laubie, M. (1991). J. Med. Chem. 34, 663-669.  [CrossRef] [PubMed] [ChemPort] [ISI]
Remko, M., Bojarska, J., Jezko, P., Sieron, L., Olczak, A. & Maniukiewicz, W. (2011). J. Mol. Struct. 997, 103-109.  [ISI] [CSD] [CrossRef] [ChemPort]
Remková, A., Kratochvílová, H. & Durina, J. (2008). J. Hum. Hypertens. 22, 338-345.  [ISI] [PubMed]
Remková, A. & Remko, M. (2010). Physiol. Res. 59, 13-23.  [PubMed]
Sheldrick, G. M. (2003). SADABS. University of Göttingen, Germany.
Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.  [CrossRef] [details]
Spek, A. L. (2009). Acta Cryst. D65, 148-155.  [ISI] [CrossRef] [details]
Vincent, M., Remond, G., Portevin, B., Serkiz, B. & Laubie, M. (1982). Tetrahedron Lett. 23, 1677-1680.  [CrossRef] [ChemPort] [ISI]
Vincent, M. & Schiavi, P. (1991). Modelling, Synthesis and Pharmacological Study of Perindopril, an Angiotensin I Converting Enzyme Inhibitor, in Molecular Recognition Mechanisms, edited by M. Delaage, ch. 5. Paris: VCH Publisher/Lavoisier TEC and DOC.


Acta Cryst (2012). C68, o341-o343   [ doi:10.1107/S0108270112032349 ]