Title of Invention

PERINDOPRIL

Abstract

A process for preparation of a pharmaceutical acceptable salt of perindopril of formula (1) and Perindopril hydrates such as herein described , comprising the steps of subjecting a compound of formula (II) to de-protection of carboxylic group COOR attached to the heterocyclic ring in presence of a base to obtain corresponding free acid ; Hll Hlim COOEt COOR o COOH 0 (II) (I) wherein R represents a carboxyl protecting group.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & The Patents Rules, 2003 PROVISIONAL / COMPLETE SPECIFICATION (See section 10 and rule 13) 1. TITLE OF THE INVENTION " PERINDOPRIL" 2. APPLICANT (S) (a) NAME : (b) NATIONALITY : (c) ADDRESS CIPLA LIMITED INDIAN 289 Bellasis Road, Mumbai Central, Mumbai 400 008, India. 3. PREAMBLE TO THE DESCRIPTION PROVISIONAL The following specification describes the invention COMPLETE The following specification particularly describes the invention and the manner in which it is to be performed. 4. DESCRIPTION (Description shall start from next page) 5. CLAIMS (not applicable for provisional specification. Claims should start with the preamble "I/we claim" on separate page) 6. DATE AND SIGNATURE (to be given at the end of last page of specification) 7. ABSTRACT OF THE INVENTION (to be given along with complete specification on separate page) Note:- GRANTED *Repeat boxes in case of more than one entry. *To be signed by the applicant(s) or by authorized registered patent agent. *Name of the applicant should be given in full, family name in the beginning. *Complete address of the applicant should be given stating the postal index no./code, state and country *Strike out the column which is/are not applicable. 13-9-2006 1 WO 2004/046172 PCT/GB2003/004981 2 PERINDOPRIL This invention relates to a process for preparing a pharmaceutical!}' acceptable salt of perindopril, and a novel polymorphic form thereof. Perindopril is the international non-proprietary name of (2S,3aS,7aS)-l-{2-[l- (ethoxycarbonyl)-(S)-butylamino]-(S)-propionyl}-octahydroindole-2-carboxylic acid. Perindopril is .known to have therapeutic apphcation as an angiotensin - converting enzyme (ACE) inhibitor. ACE is a peptidyl dipeptidase which catalyzes the conversion of angiotensin I to angiotensin II, as well as causing the degradation of bradykinin. Angiotensin II is a vasoconstrictor which also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE has, therefore, been shown to have therapeutic utility in patients sruffering from disease states such as hypertension and congestive heart failure. In addition, it has been discovered that ACE inhibitors are useful in treating cognitive disorders. Perindopril has the following structural formula (I) CH3 COOEt (I) Perindopril is described in US patent no. 4508729. Preparative processes described in this US patent are carried out in an alcoholic medium, and in the presence of a neutral dehydrating agent and an organic or inorganic cyanoborohydride. Deprotection processes can. be carried out where necessary, for example with reference to hydrolysis and/or hyclrogenolysis. US patent no. 4914214 describes a process for the preparation of perindopril and its 1-butylamine salt. The process comprises condensation of a protected ester of (2S,3aS,7aS)-2-carboxyperhydroindole with the (S,S) diastereoisomer of N-[('S)-l-carbethoxvbutyl]-('S)- WO 2004/046172 P'CT/'GB2003/004981 3 alanine, followed by deprotection employing charcoal containing 5% palladium and water. Tertiary-butylamine is then added to yield the t-butylaniine salt of perindopril. PCT patent application WO 01/87835 describes a novel crystalline form, namely a crystalline form, of the t-butylamine salt of perindopril, processes of preparing the same and pharmaceutical formulations, containing the same. PCT patent application WO 01/87836 describes a novel crystalline form, namely . crystalline form, of the t-butylamine salt of perindopril, processes of preparing the same and . pharmaceutical formulations containing the same. PCT patent application WO 01/87835 describes a novel crystalline form, namely crystalline form, of the t-butylamine salt of perindopril, processes of preparing the same and pharmaceutical formulations containing the same. PCT patent application WO 01/58868 describes a process of preparing .perindopril or phannaceuticaUy acceptable salts thereof, which process' provides perindopril, or a salt thereof, with improved purity. More particularly, the level of known impurities associated with perindopril or a salt thereof, prepared according, to PCT'patent application WO 01/58868, is described as being less than 0.2 or 0.1% by weight. Intermediate process steps are carried out in the presence of 1-hydroxybenzotriazole, dicyclohexylcarbodiimide and . optionally triethylamine, and at a temperature in the range of 20 to 77EC, followed by deprotection and where required salt conversion. Prior art processes for the preparation of perindopril, or pharmaceutically acceptable salts thereof, have generally tended to be time-consuming and have often resulted in-undesirable associated impurities, such as diketopiperazine analogues. There is, therefore,, a need for an improved process for preparing perindopril, or pharmaceutically acceptable salts thereof, which alleviates the above mentioned problems. We have now developed a process for preparing a pharmaceutically acceptable salt of perindopril, which is advantageous in terms of a faster reaction time compared.to known processes for the preparation of a pharmaceutically acceptable salt of perindopril, and also in obviating the production of undesirable impurities so as to achieve a highly pure product. In accordance with one aspect of the present invention, there is provided a process for preparing a pharmaceutically acceptable salt of perindopril of formula (I) from a protected' precursor compound of formula (.II) WO 2004/046172 PCT/GB2003/004981 4 (II) wherein .R represents a carboxyl protecting group, which process comprises subjecting a compound of formula (II) to deprotection of the carboxybc group COOR attached- to the heterocyclic ring so as to yield the corresponding free acid which deprotection is carried out in the presence of a base which forms a pharmaceutical^ acceptable salt with said free acid formed by said deprotection. Typically, R can represent any suitable carboxyl protecting group that can be selectively removed by a process according to the present' invention. Preferably, R can represen optionally substituted aralkyl, especially optionally substituted benzyl. R can, therefore, typically represent unsubstituted benzyl: alternatively substituted benzyl can be employed, such as 4-halo substituted, or 4-C1 alkoxy substituted benzyl, especially 4-C1 benzyl, or 4-methoxy benzyl. Suitably, deprotection as employed in a process according to the present invention can comprise hydrogenolysis in the presence of a noble metal catalyst, preferably palfadium-on-chacoal. The process of the present invention is advantageous in achieving a highly pure product. A pharmaceutically acceptable salt of perindopril prepared by a process according. to the present invention is preferably more than about 99% w/w pure; and more preferably xnore than about 99.5% w/w pure. The purity of a pharmaceutical acceptable salt of ' perindopril prepared by a process according to the present invention can be further enhanced by an optional crystallisation step m a suitable solvent, such as ethyl acetate: isopropanol or the like, so as to obtain a pharmaceutically acceptable salt of perindopril which is preferably about 99.8% w/w pure. WO 2004/046172 PC T/GB2003/004981 5 Preferably, the base employed in the process of the present invention is selected so as to form a pharmaceutically acceptable salt with the free acid formed by the deprotection as indicated above, whereby it is possible to obtain a pharaiaceutically acceptable salt of perindopril directly from such a reaction work-up. In a particularly preferred embodiment according to the present invention the base comprises t-butylamine and as such a preferred process according to the present invention can provide a highly pure t-butylamine salt of perindopril directly from the reaction process. According to the above preferred embodiment of the present invention, there is provided a process for preparing perindopril t-butylamine (which is well known to those of skill in the art as being perindopril erburnine) from a protected precursor compound of formula (II) substantially as hereinbefore described (preferably a benzyl protected precursor compound of formula (II) where R represents benzyl), which process comprises subjecting a compound of formula (II) to deprotection (preferably hydrogenolysis in the presence of a noble metal catalyst such as palladium-on-chacoal) of the carboxylic group COOR attached to the heterocyclic ring so as to yield the corresponding free acid, which deprotection is carried out in the presence of t-butylamine so as to form.the t-butylamine salt of perindopril. Suitably a precursor compound of formula (II) is initially dissolved' in an alkanol solvent, such as isopropanol or the like, followed by addition of the base thereto. .This is further followed by the deprotection of the carboxylic group COOR, suitably by the addition of palladium-on-charcoal and hydrogenation for several hours. The alkanol solvent is suitably concentrated under vacuum and replaced by a water immiscible solvent, such as. ethyl acetate or the like. The resulting solids can then be cooled and filtered to yield a pharmaceutically acceptable salt of perindopril. The process according to the present invention substantially as hereinbefore described may further comprises hydrating a pharmaceutically acceptable salt of perindopril obtained by the process.so as to yield a pharmaceutically acceptable salt of hydrated perindopril of formula (la) WO 2004/046172 PCT'GB2(lO3/004981 6 H»«' CH3 COOEt COOH nH-,0 Pa) wherein n is an integer of 1 to 5, or a reciprocal of integers 2 to 5. Hydration can be by way of the addition of water or by drying in air. Preferably n is 1, whereby a pharmaceutically acceptable salt of perindopril monohydrate is formed by a process according to the present invention. The present invention also provides a process for preparing a monohydrate of a pharmaceutically acceptable salt of perindopril, which process comprises hydrating a pharmaceutically acceptable salt of perindopril so as to yield said monohydrate. Hydration can be by way of the addition of water or by drying in air, and preferably perindopril t-butylamine is hydrated to yield perindopril t-butylamine monohydrate. The present invention further provides a pharmaceutically acceptable salt of perindopril optionally in hydrated form, prepared by a process substantially as hereinbefore described. In particular, a pharmaceutically acceptable salt of hydrated perindopril. of formula (la) is provided HUH' CH3 COOEt COOH nH20 (la) 7 WO 2004/046172 PCT/GB2003/004981 wherein n is an integer of 1 to 5, or a reciprocal of integers 2 to 5. Preferably, n is 1. A preferred pharmaceutically acceptable salt of hydrated perindopril of formula (la) is the t-butylamine salt. la a particularly preferred embodiment the present invention provides perindopril t-butylamine (or erbumine) monohydrate. The present invention also provides perindopril t-butylamine monohydrate having an X-ray diffractograna, or substantially the same X-ray diifractogranx as set out in Figure 1. More particularly, perindopril t-butylamine monohydrate according to the present invention can be characterised as having an.X-ray powder diffraction partem with characteristic peaks (20): 9.5504, 14.8600, 15.7486, 16.5400, 20.0400, 21.0499, 22.0600, 24.1744, 26.3300 and 27.1600. Further characterising data for perindopril t-butylarnine monohydrate according to. the present invention as obtained by X-ray diffraction is shown in following Table 1.Table 1 Peak No. 26 (deg) d (A) I/II FWHM (deg) Intensity (Counts) j Integrated I (Counts) 1 8.6400 10.22611 10 0.57600 151 6899 2 9.5504 9.25324 73 0.50470 1090 . 28204 3 10.5940 8.34394 5 0.97200 79 4071 4 13.6000 6.50569 6 0.42860 91 2112 5 14.1400 6.25844 14 0.47120 "I 215 5210 6 14.8600 5.95678 22 0.59000 332 10293 7 15.7486 5.62262 75 0.14270 1111 49244 8 16.5400 5.35533 30 0.72500 450 J 15749 : . i 9 17.5400 5.05220 16 0.67120 231 9128 10 18.6100 4.76406 17 J 0.56000 249 7981 11 ' 20.0400 4.42722 31 j 0.51660 458 13471 12 21.0499 4.21704 100 0.90700 | 1488 ! 63860 23998 13 22.0600 4.02618 50 0.59480 747 14 23 1600 3.83738 17 0.71720 ! i j 253 22014 WO 2004/046172 PCT/GB2003/00498 8 Perindopril as provided by the present invention has therapeutic utility as an ACE. inhibitor. . In addition, the present invention further provides a 'method of inhibiting ACE in a patient in need thereof comprising administering to said patient an effective ACE inhibitory amount of perindopril (preferably perindopril t-butylamine mpnohydrate) as provided according to the present invention. The present invention also provides use of perindopril as provided according to the' present invention (preferably perindopril t-butylamine inonohydrate) in the manufacture of a medicament for inhibiting ACE. A patient can be in need of treatment to inhibit ACE; for example when the patient is suffering from hypertension, chronic congestive heart failure, or the like. Inhibition of ACE reduces levels of angiotensin II and thus inhibits the vasopressor hypertensive and hyperaldosteronemic effects caused thereby. Inhibition of ACE would also potentiate endogenous levels of bradyMnin. An effective ACE inhibitory amount of perindopril as provided according to the present invention is that amount which is effective in inhibiting ACE in a patient in need thereof which results, for example, in a hypotensive effect. In effecting treatment of a patient, perindopril as provided according io the present invention can be administered in any form or mode which makes the compound bioavailable PCT/GB2003/OO4981 9 WO 2004/046172 in effective amounts, including oral and parenteral route's. For example, penndopril as provided according to the present invention can be administered orally, subcutaneously, intramuscularly, intravenously, transdennally, intranasally, rectally. and the like. Oral administration is generally prefened. One skilled in the art- of preparing formulations can readily select the proper form and mode of adniinistration depending upon the disease state to be treated and the stage of the disease. Penndopril as provided according to the present invention can be administered in the form of pharmaceutical compositions or medicaments which are prepared by combining the penndopril according to the present invention with pharmaceutically acceptable carriers', diluents or excipients therefor, the proportion and nature of which are determined by the chosen route of administration., and standard pharmaceutical practice. In another embodiment, the present invention provides pharmaceutical compositions comprising an effective ACE inhibitory amount of perindopril as provided according to the present invention (preferably perindopril t-butylamine monohydrate), together with one or more pharmaceutically acceptable carriers, diluents or excipients therefor. By "pharmaceutically acceptable" it is meant that the carrier, diluent or excipient must be compatible with perindopril as provided according to the present invention, and not be deleterious to a recipient thereof. The pharmaceutical compositions or medicaments are prepared in a manner well known in the pharmaceutical art The carrier, diluent or excipient may be a solid, serni-solid, or liquid material, which can serve as a vehicle or medium for the active ingredient Suitable carriers, diluents or excipients are well known in the art. Pharmaceutical compositions according to the present invention may be adapted for oral or parenteral use and may be administered to the patient in the form of tablets, capsules, suppositories, solutions, suspensions or the like. The pharmaceutical compositions may be administered orally, for example, with, an inert diluent or with an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, a monohydrate according to the present invention may be incorporated with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups and the like. The tablets, pills, capsules, and the like may also contain one or more of the following adjuvants: binders, such as microcrystalline cellulose, gum tiagacanth or gelatin; excipients, - 10 WO2004/046I72 PCT/GB2003/004981 such as starch or lactose; disintegrating agents such as alginic acid, corn starch and the like lubricants, such as magnesium stearate; glidants, such as colloidal silicon dioxide; and sweetening agents, such as sucrose or saccharin. When the dosage unit form is a capsule it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example,'as coatings. Thus, tablets or pills may be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the active ingredient, sucrose as a sweetening agent and certain preservatives Materials used.in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used. For the purpose of parenteral administration perindopril as provided according to the present invention may be incorporated into a solution or suspension. The solutions or suspensions may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oik, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabem antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylene diaminetetraaceric acid; and buffers such as acetates, citrates or phosphates The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. The present invention will now be further illustrated by the following Figure and Examples, which do not limit the scope of the invention m any way. Figure 1: X-ray diffraction pattern of perindopril erbumine monohydrate according to the present invention. The sample was analysed using a Shimadzu-6000 x-ray diffractometer The source used was Ka monochromatic radiation of Cu having wavelength of 1.5406 A° The Divergent Slit used was 1°. The Receiving Slit was 0.30mm. The Scintillation counter was used as the detector, with the range being from 3° to 40° (20) with a scan speed of 2° per minute. Example 1 The benzyl ester of (2S,3aS,7aS)-l-{2-[l-(ethox)arbonyl)-(Sj-butylamjno]-(S)-propionyl}-octahydroindole-2-carboxylic acid, namely 'benzyl perindopril. dOcms'i was dissolved in isopropanol (100ml). To the clear solution, t-butylaraine (2.5"msi and 10% W/W ^ WO 2004/0!46172 PCT/GB2003/004981 11 palladium on charcoal (2gms) was added. The reaction mixture was bydrogenated at a pressure of lkg/cm2 for 2 hours. The reaction mass was filtered to remove the.catalyst. The solvent was concentrated under vacuum and isopropanol was replaced by simultaneous addition of ethyl acetate. The solids obtained were cooled to OEC and filtered to obtain penndopril erbumine- (7.8gms). ' Example 2 Perindopril erbumine (lOgrns) was suspended in acetone (80ml). To this was added water (0.4ml) and the contents heated to dissolve the solids and cooled to ambient. The. resulting slurry was filtered to obtain perindopril erbumine monohydrate (9.4gms). Example 3 Perindopril erbumine (20grns) was suspended in ethyl acetate (300ml). To this was added water (1.5ml) and the contents heated to dissolve the solids and cooled to 10EC. The resulting slurry was filtered to obtain perindopril erbumine monohydrate (17gms). Example 4 Perindopril erbumine (5gms) was suspended in acetonitrile (75ml). To this was added water (0.4ml) and the contents heated to dissolve the solids and cooled to OEC. The resulting slurry was filtered to obtain perindopril erbumine monohydrate (2.9gms). Example 5 Perindopril erbumine (20gms) was suspended in ethyl acetate (300ml). The contents' were heated to dissolve the solids and cooled to 10EC. The resulting slurry was filtered and dried in air having a relative humidity of at least 75% to give penndopril erbumine monohydrate (17gms). Example 6 Preparation of penndopril erbumine monohydrate Raw Materials :- 1. Perindopril erbumine anhydrous =10 gm 2. Isopropyl alcohol = 70 ml. WO 2004/046172 PC T/GB2003/0U4981 12 ' 3. Water =2 ml 4. Ethyl acetate = 85ml Procedure :•- 1. Charge 10 gm of perindopril erbumine (anhydrous.) in round bottom flask. Add 70'mJ isopropyl alcohol. Stir for l/2A hr. (around 95% product dissolved). 2. Add 2 ml of water. Stir for 15 ruin (clear solution obtained). 3. Stirreaction mass at 38-40°C for 2 hrs. 4. Distill out isopropyl alcohol completely under vacuum (below 600 mm) below 40°C. (Gel type material observed.) 5. Charge 30 ml ethyl acetate. Stir for 15 min below 40°C (clear solution observed). ' Distill under vacuum below 40°C (semi-solid observed). 6. Charge 40 ml ethyl acetate at 36-38C. Stir for 15 min (free solid observed). 7. Stir 1 hr at room temperature (25-30 C). (Free crystalline solid observed.) 8. Cool to 100c Stir for 2 hrs. 9. Filter solid and wash with 15 ml ethyl acetate. Suck dry for 2 hrs: 10. Dry under vacuum below 40°C for 12 hrs. Water Content =3.2-3.8% M.P =145-150°C. Example 7 The following tablets were prepared: (a) Formulation I: WO 2004/046172 PCT/GB2003/O04981l 13 Magnesium stearate Total weight 0.4 45.0 mg 0.8 90.0 mg 1.6 180.0 mg _J Procedure: Sift the above ingredients through respective sieves. Mix the ingredients in a suitable blender. Compress the tablets in the suitable toolings. (b) Formulation. II; 1 Strengths - 2mg 4 mg 8 mg Ingredients 2mg ... 4mg 8 mg Perindopril Erbuinine Monohydrate Maize starch 10 mg 10 mg 10 mg Lactose anhydrous 25 mg 25.0 mg 25.0 mg Microcrystalline cellulose 52.2 mg 49.20 mg 45.20 mg Yellow oxide of Iron - 1.0 Red oxide of Iron - - 1 1.0 | Hydrogenated castor oil 0.8 mg 0.8 mg 0.8 mg Total weight 90.0 mg 90.0 mg 90.0 mg Procedure: 1) Dissolve Perindopril Erbumine Monohydrate in ethanol. 2) Granulate the above ingredients except hydrogenated castor oil with the above solution. Dry the granules and size. 3) Lubricate with hydrogenated castor oil in suitable blender. Compress the granules in the suitable tooling Pharmaceutical composition prepared according to present invention is a synergistic composition exhibiting surprising results 14 We claim: A process for preparation of a pharmaceutical acceptable salt of perindopril of formula (1) and Perindopril hydrates such as herein described , comprising the steps of subjecting a compound of formula (II) to de-protection of carboxylic group COOR attached to the heterocyclic ring in presence of a base to obtain corresponding free acid ; Hll Hlim COOEt COOR o COOH 0 (II) (I) wherein R represents a carboxyl protecting group. 2. The process according to claim 1, wherein R represents optionally substituted aralkyl. 3. The process according to claim 2, wherein R represents unsubstituted benzyl. 4. The process according to claim 2, wherein R represents 4-halo substituted, or 4-C1_4 alkoxy substituted benzyl. 5. The process according to claim 4, wherein R represents 4-C1 benzyl, or 4-methoxy benzyl. 6. The process according to claim 1 to 5, wherein de-protection comprises hydrogenolysis in the presence of a noble metal catalyst. 7. The process according to claim 6, wherein the noble metal catalyst comprises palladium-on-charcoal. 8. The process according to claims 1 to 7, wherein said base comprises 1-butylamine. 15 9. A process for preparing compound of formula (II) as claimed in claim 1, wherein the process comprises subjecting a compound of formula (II) to deprotection of the carboxylic group COOR attached to the heterocyclic ring so as to yield the corresponding free acid, which deprotection is carried out in the presence of t-butylamine so as to from the t-butylamine salt of perindopril. 10. The process according to claim 9, wherein R represents unsubstituted benzyl. 11. The process according to claim 9 or 10, wherein deprotection comprises hydrogenolysis in the presence of palladium-on-chacoal. 12. The process according to claim 1 to 11, which further comprises hydrating a pharmaceutically acceptable salt of perindopril obtained by said process so as to yield a pharmaceutically acceptable salt of hydrated perindopril of formula (la). wherein n is an integer of 1 to 5, or a reciprocal of integers 2 to 5. 13. The process according to claim 12, wherein n is 1. 14. The process according to claims 12 to 13, wherein perindopril t-butylamine is hydrated to yield perindopril t-butylamine monohydrate. AGENT FOR THE APPLICANT Dated this 9th day of June 2005

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