FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION
1-(2-SUBSTITUTEDAMINO-1-OXOPROPYL)OCTAHYDROCYCLOPENTA [b] PYRROLE-2-CARBOXYLIC ACID AND SALTS THEREOF
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D4-MIDC Area, Chikalthana,
Aurangabad - 431 210 (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The invention provides 1-(2-substitutedamino-1-oxopropyl)
octahydrocyclopenta[b]pyrrole-2-carboxylic acid and salts thereof. The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The invention provides 1-(2-substitutedamino-1-oxopropyl)octahydro cyclopenta[b]pyrrole-2-carboxylic acid or salts thereof having the structure of formula-ll and process of preparation of the same. The invention further provides a pharmaceutical composition comprising 1-(2-substitutedamino-1-oxopropyl) octahydrocyclopenta [b]pyrrole-2-carboxylic acid and salts thereof. The invention also provides a pharmaceutical composition of ramipril or salts thereof having 1-(2-substituted amino-1-oxopropyl)octahydro cyclopenta[b]pyrrole-2-carboxylic acid and salts thereof content of 1% or less.
Ramipril is chemically known as [2S,3aS,6aS]-1-[(2S)-2-[[(1S)-1-(ethoxy carbonyl)-3-phenylpropyl] amino]-1-oxopropyl] octahydrocyclopenta[b] pyrrole-2-carboxylic acid having structure as depicted in formula I.
H3CH2CO^^O HOOC^
Kj °
Formula I
Ramipril, marketed under the name Altace®, is a non-sulfhydryl angiotensin converting enzyme inhibitor and is indicated for the treatment of hypertension and congestive heart failure.
There are several patents and patent applications cited in the literature, which refer -to processes for the preparation of ramipril such as U.S. Patent No. 4,587,258, U.S. Patent No. 5,061,722, U.S. Patent No. 5,348,944, U.S. Patent No. 6,407,262, U.S. Patent No. 7,094,920, U.S. Application 2004-0048346, International application (PCT) Nos. WO 2006-059347, WO 2005-108366, WO 2005-068422 and WO 2005-121084.

The inventors while developing a formulation of ramipril have found that compound of formula II is produced by the interaction of ramipril of formula I with an amine compound of formula III, as depicted in scheme 1.
R o HOOC
H3CH2CO^O HOOC
N H
(R")(R')NH - ^ ^ 1
O
II
III
Scheme I
wherein R is selected from the group comprising of -NH-C(R1)(R2)(R3), -N(R5)(R6) or an amino acid residue; wherein Ri, R2, R3, R4 and R5 are each and independently selected from the group of -H, CrC6 alkyl and substituted CrC6 alkyl, wherein substituents are selected from -OH, -COOH, -NH2 and the like, with a proviso that Ri, R2 and R3 are not -H or CrC6 alkyl simultaneously and R4 and R5 are not -H or C1-C6 alkyl simultaneously, and salts thereof.
In one aspect of the invention there is provided a compound of formula II,
FU ^O H00C/,

V^
Formula II
wherein R is selected from the group comprising of -NH-C(Ri)(R2)(R3), -N(R5)(R6) or an amino acid residue; wherein R-i, R2, R3, R4 and R5 are each and independently selected from the group of -H, C1-C6 alkyl and substituted CrC6 alkyl, wherein substituents are selected from -OH, -COOH, -NH2 and the like, with a proviso that Ri, R2 and R3 are not -H or C1-C6 alkyl simultaneously and R4 and R5 are not -H or CrC6 alkyl simultaneously, and salts thereof.
The specific compounds of the invention include;

1-[2-[[1-[N-(2-hydroxymethyl-1,3-dihydroxy propan-2-yl) carbamoyl] -3-phenyl propyl] amino]-1-oxopropyl] octahydrocyclopenta[b]pyrrole-2-carboxylic acid;
1-[2-[[1-[N-(1,3-dihydroxy-2-methyl propan-2-yl) carbamoyl] -3-phenyl propyl] amino]-1-oxopropyl] octahydrocyclopenta[b]pyrrole-2-carboxylicacid;
1-[2-[[1-[N-(1-hydroxy-2-methyl propan-2-yl) carbamoyl] -3-phenyl propyl] amino]-1-oxopropyl] octahydrocyclopenta[b]pyrrole-2-carboxylic acid;
1-[2-[[1-[N-(1-carboxy-2-methyl propan-2-yl) carbamoyl] -3-phenyl propyl] amino]-1-oxopropyl] octahydrocyclopenta[b]pyrrole-2-carboxylic acid;
1-[2-[[1-[N-(1-amino-2-methyl propan-2-yl) carbamoyl] -3-phenyl propyl] amino]-1-oxopropyl] octahydrocyclopenta[b]pyrrole-2-carboxylic acid;
1-[2-[[1-[N-(1-carboxy propan-2-yl) carbamoyl] -3-phenyl propyl] amino]-1-oxopropyl] octahydrocyclopenta[b]pyrrole-2-carboxylic acid;
1-[2-[[1-[N-(1,2-dicarboxy ethyl) carbamoyl] -3-phenyl propyl] amino]-1-oxopropyl] octahydrocyclopenta[b]pyrrole-2-carboxylicacid;
1-[2-[[1-[N-(1,3-dicarboxy propyl) carbamoyl] -3-phenyl propyl] amino]-1-oxopropyl] octahydrocyclopenta[b]pyrrole-2-carboxylic acid;
1-[2-[[1-[N-(carboxy methyl) carbamoyl] -3-phenyl propyl] amino]-1-oxopropyl] octahydrocyclopenta[b]pyrrole-2-carboxylicacid;
1-[2-[[1-[N-(1-carboxy-2-methyl propyl) carbamoyl] -3-phenyl propyl] amino]-1-oxopropyl] octahydrocyclopenta[b]pyrrole-2-carboxylic acid; and salts thereof.

In this disclosure, substituted C-i-C6 alkyl refer to mono-, di- or tri- substituted d-C6 alkyl as defined above; wherein the substitutuents may be present at same or different carbon atoms and are independently selected from OH, COOH, NH2 and the like.
In this disclosure, the term "salts" refers to pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, P-hydroxybutyric, galactaric and galacturonic acid. Suitable pharmaceutically acceptable base addition salts include metallic salts, such as salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or salts made from organic bases including primary, secondary and tertiary amines, substituted amines including cyclic amines, such as caffeine, arginine, diethylamine, N-ethylpiperidine, histidine, glucamine, isopropylamine, lysine, morpholine, N-ethyl morpholine, piperazine, piperidine, triethylamine, trimethylamine or ammonia.
In this disclosure, amino acid residue is attached via amino group to the carbonyl group of compound and is selected from the group comprising of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.


In this disclosure, C1-C6 alkyl refer to saturated, straight, or branched chain hydrocarbon radicals derived from a hydrocarbon moiety containing between one and six carbon atoms by removal of a single hydrogen atom. The non-limiting examples of d-C6 alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, neopentyl, and n-hexyl and the like.
Numerous asymmetric centers may exist in the compounds of the present invention. The present invention contemplates the various stereoisomers and mixtures thereof. The term "stereoisomer" refers to both geometric (e.g., cis and trans isomers) and/or optical isomers (e.g., R and S enantiomers) of a compound of the invention. Racemic, enantiomeric, diastereomeric, rotameric and epimeric mixtures of isomers are contemplated by the present invention.
In another aspect of the invention there is provided a pharmaceutical composition containing compound of formula II in association with a pharmaceutically acceptable excipient and/or carrier wherein the composition may comprise a preparation such as solid compositions, liquid compositions or other compositions for oral administration or as injections, liniments or suppositories for parenteral administration.
The non-limiting examples of solid composition include compressed tablets, pills, capsules, dispersible powders, granules, hard capsules and soft capsules. The non-limiting examples of liquid composition include emulsions, solutions, suspensions, syrups and elixirs. The non-limiting examples of injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions.
The compound of formula II is produced when a blend of ramipril of formula I with an amine compound of formula III and other pharmaceutical excipients is obtained that is heated to 40-100 °C for 30-40 hours or kept at ambient temperature for longer duration.


The R'-NH2 is amine compound of formula III which include tromethamine, 2-Amino-2-methyl-1-propanol, 2-Amino-2-methyl-1,3-propanediol, N-(1,1-Dimethyl-2-hydroxyethyl)-3-amino-2-hydroxypropanesulfonic acid, N,N-Bis(2-hydroxyethyl) glycine, 2,2'-(Propane-1,3-diyldiimino)bis[2-(hydroxymethyl)propane-1,3-diol], 4-(Cyclohexylamino)-l-butanesulfonic acid, 3-(Cyclohexylamino)-1-propanesulfonic acid, 3-(Cyclohexylamino)-2-hydroxy-1-propanesulfonic acid, 2-(Cyclohexyl amino)ethanesulfonic acid, 3-[N-Bis(hydroxyethyl)amino]-2-hydroxypropane sulfonic acid, 4-(2-Hydroxyethyl)piperazine-1-propanesulfonic acid, N-Glycylglycine, N-(2-Hydroxyethyl)piperazine-N'-(4-butanesulfonic acid), 4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid, 4-(2-Hydroxyethyl)-1-piperazine ethanesulfonic acid hemisodium salt, 4-(2-Hydroxyethyl)-1-piperazine ethanesulfonic acid Potassium salt, 4-(2-Hydroxyethyl)-1-piperazineethane sulfonic acid sodium salt hydrate, 3-Morpholino-2-hydroxypropanesulfonic acid, Piperazine-N,N'-bis(2-hydroxypropanesulfonic acid N-Tris(Hydroxymethyl) methyl -4-aminobutanesulfonicacid,N-(Tris(hydroxymethyl)methyl)-3-aminopropane sulfonic acid, N-[Tris(hydroxymethyl)methyl]-3-amino-2-hydroxypropanesulfonic acid, Triethanolamine, N-[Tris(hydroxymethyl)methyl]-2-aminoethanesulfonic acid, N-[Tris(hydroxymethyl)methyl]-2-aminoethanesulfonic acid hemisodium salt, N-(Tris(hydroxymethyl)methyl)glycine, Tris(hydroxymethyl) methylamine, Tris(hydroxymethyl)methylamine acetate and Tris(hydroxymethyl) methylamine Hydrochloride.
In yet another aspect of the invention there is provided pharmaceutical composition of ramipril.
In this disclosure, pharmaceutical composition of ramipril refer to a pharmaceutical composition of ramipril and salts thereof with a content of compound of formula II content of 1% or less.
The invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the


invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
Example
Preparation of 1-[2-[[1-[N-(2-hydroxymethyl-1,3-dihydroxypropan-2-yl) carbamoyl]-3-phenylpropyl]amino]-1-oxopropyl]octahydrocyclopenta[b] pyrrole-2-carboxylic acid
Ramipril, the active pharmaceutical ingredient, (1.25 g) was micronised, mixed with tromethamine (TRIS Buffer) (10.0 g) and sifted through 40 # sieve. The mixture was then added to pregelatinised starch (Starch 1500 LM) (98.2 g) to get uniform blend. The blend was then lubricated using sodium stearyl fumarate (0.55 g). The lubricated blend (100 g) of ramipril thus obtained was heated to 90°C for 36 hours under stirring. The temperature was brought to 30 °C, charged with dichloromethane (500 ml) and refluxed for 30 minutes. The mixture was then filtered and solid was washed with dichloromethane (75 ml). The filtrate was concentrated to yield a residue (11.7g), from which 6.79 g was redissolved in dichloromethane (60 ml) and cooled to 10°C. Diisopropyl ether (30 ml) was added to yield a precipitate. The liquid was decanted and the precipitate was dried under vacuum. The amount of impurity present in the dried solid (5 g) was found to be 15.92% by HPLC. The solid (5 g) was purified by preparative HPLC to obtain 360 mg of title compound which was then characterized.
Melting Point : 137 °C (with decomposition).
HPLC Purity : 95.54%.
IR (KBr, cm"1) : 3301, 3086, 3028, 2950, 2868, 1635, 1530, 1496, 1454,
1383, 1293, 1050, 1028, 979, 918.
1H NMR (400 MHz, DMSO/D20, 5) : 1.08 (3H,d), 1.21-1.91 (10H,m), 2.22 -2.31(1H,m), 2.51-2.55 (2H,m), 3.43 (1H,m), 3.48-3.56 (6H, m), 4.05-4.11 (1H, m), 4.13-4.19 (1H, m), 7.10-7.15 (3H, m), 7.19-7.23 (2H, m). Mass(m/e) :492(M++1).

We claim:
1. A compound of formula II,

^^

HOOC,
o
Formula II

wherein R is selected from the group comprising of -NH-C(R-i)(R2)(R3), -N(R5)(Re) or an amino acid residue; wherein R1, R2, R3, R4 and R5 are each and independently selected from the group of -H, C1-C6 alkyl and substituted C-i-C6 alkyl, wherein substituents are selected from -OH, -COOH, -NH2 and the like, with a proviso that R1, R2 and R3 are not -H or C1-C6 alkyl simultaneously and R4 and R5 are not -H or C1-C6 alkyl simultaneously, and salts thereof.
2. A compound as claimed in claim 1, comprising of;
1-[2-[[1-[N-(2-hydroxymethyl-1, 3-dihydroxy propan-2-yl) carbamoyl]-3-phenyl propyl] amino]-1-oxopropyl] octahydrocyclopenta[b]pyrrole-2-carboxylic acid;
1-[2-[[1-[N-(1,3-dihydroxy-2-methyl propan-2-yl) carbamoyl] -3-phenyl propyl] amino]-1-oxopropyl] octahydrocyclopenta[b]pyrrole-2-carboxylicacid;
1-[2-[[1-[N-(1-hydroxy-2-methyl propan-2-yl) carbamoyl] -3-phenyl propyl] amino]-1-oxopropyl] octahydrocyclopenta[b]pyrrole-2-carboxylic acid;
1-[2-[[1-[N-(1-carboxy-2-methyl propan-2-yl) carbamoyl] -3-phenyl propyl] amino]-1-oxopropyl] octahydrocyclopenta[b]pyrrole-2-carboxylic acid;
1-[2-[[1-[N-(1-amino-2-methyl propan-2-yl) carbamoyl] -3-phenyl propyl] amino]-1-oxopropyl] octahydrocyclopenta[b]pyrrole-2-carboxylic acid;

1-[2-[[1-[N-(1-carboxy propan-2-yl) carbamoyl] -3-phenyl propyl] amino]-1-oxopropyl] octahydrocyclopenta[b]pyrrole-2-carboxylic acid;
1-[2-[[1-[N-(1,2-dicarboxy ethyl) carbamoyl] -3-phenyl propyl] amino]-1-oxopropyl] octahydrocyclopenta[b]pyrrole-2-carboxylicacid;
1-[2-[[1-[N-(1,3-dicarboxy propyl) carbamoyl] -3-phenyl propyl] amino]-1-oxopropyl] octahydrocyclopenta[b]pyrrole-2-carboxylic acid;
1-[2-[[1-[N-(carboxy methyl) carbamoyl] -3-phenyl propyl] amino]-1-oxopropyl] octahydrocyclopenta[b]pyrrole-2-carboxylicacid;
1-[2-[[1-[N-(1-carboxy-2-methyl propyl) carbamoyl] -3-phenyl propyl] amino]-1-oxopropyl] octahydrocyclopenta[b]pyrrole-2-carboxylic acid;
and salts thereof.
3. A compound as claimed in claim 2, wherein the compound is 1-[2-[[1-[N-(2-hydroxymethyl-1, 3-dihydroxy propan-2-yl) carbamoyl] -3-phenyl propyl] amino]-1-oxopropyl] octahydrocyclopenta[b]pyrrole-2-carboxylic acid.
4. A process of preparation of compound of formula-ll and salts thereof, the process comprising, heating ramipril of formula-l with an amine compound of formula III and other pharmaceutical excipients
H3CH2CO.^O HOOC R oHOOC
X A N- /S (R")(R')NH - — ^.^ X X /N.
H \ H\Y III I H A H
i II
Scheme I
5. The process of preparation of claim 4, wherein amine compound of formula III comprises of tromethamine, 2-Amino-2-methyl-1-propanol, 2-Amino-2-methyl-

1,3-propanediol, N-(1,1-Dimethyl-2-hydroxyethyl)-3-amino-2-hydroxypropane
sulfonic acid, N,N-Bis(2-hydroxyethyl) glycine, 2,2'-(Propane-1,3-
diyldiimino)bis[2-(hydroxymethyl)propane-1,3-diol], 4-(Cyclohexylamino)-1 -
butanesulfonic acid, 3-(Cyclohexylamino)-1-propanesulfonic acid, 3-
(Cyclohexylamino)-2-hydroxy-1 -propanesulfonic acid, 2-(Cyclohexyl
amino)ethanesulfonic acid, 3-[N-Bis(hydroxyethyl)amino]-2-hydroxypropane sulfonic acid, 4-(2-Hydroxyethyl)piperazine-1-propanesulfonic acid, N-Glycylglycine, N-(2-Hydroxyethyl)piperazine-N'-(4-butanesulfonic acid), 4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid, 4-(2-Hydroxyethyl)-1-piperazine ethanesulfonic acid hemisodium salt, 4-(2-Hydroxyethyl)-1-piperazine ethanesulfonic acid Potassium salt, 4-(2-Hydroxyethyl)-1-piperazineethane sulfonic acid sodium salt hydrate, 3-Morpholino-2-hydroxypropanesulfonic acid, Piperazine-N,N'-bis(2-hydroxypropanesulfonic acid N-Tris(Hydroxymethyl) methyl -4-aminobutanesulfonicacid,N-(Tris(hydroxymethyl)methyl)-3-aminopropane sulfonic acid, N-[Tris(hydroxymethyl)methyl]-3-amino-2-hydroxypropanesulfonic acid, Triethanolamine, N-[Tris(hydroxymethyl)methyl]-2-aminoethanesulfonic acid, N-[Tris(hydroxymethyl)methyl]-2-aminoethanesulfonic acid hemisodium salt, N-(Tris(hydroxymethyl)methyl)glycine, Tris(hydroxymethyl) methylamine, Tris(hydroxymethyl)methylamine acetate and Tris(hydroxymethyl) methylamine Hydrochloride.
6. The process of claim 4, wherein the heating is carried out at 40 °C or more.
7. A pharmaceutical composition comprising compound of formula II and salts thereof.

Formula II
wherein R is selected from the group comprising of -NH-C(Ri)(R2)(R3), -N(R5)(R6) or an amino acid residue; wherein R-i, R2, R3, R4 and R5 are each and

independently selected from the group of -H, C1-C6 alkyl and substituted CrC6 alkyl, wherein substituents are selected from -OH, -COOH, -NH2 and the like, with a proviso that R1, R2 and R3 are not -H or CrC6 alkyl simultaneously and R4 and R5 are not -H or CrC6 alkyl simultaneously, and salts thereof.
8. A pharmaceutical composition of ramipril or salts thereof having compound of formula II content of 1% or less.
9. The composition as claimed in claim 7 and 8, wherein composition comprise a preparation such as solid compositions, liquid compositions or other compositions for oral administration or as injections, liniments or suppositories for parenteral administration.

Abstract
The invention provides 1-(2-substitutedamino-1-oxopropyl)octahydro cyclopenta[b]pyrrole-2-carboxylic acid or salts thereof having the structure of formula-!I and process of preparation of the same. The invention further provides a pharmaceutical composition comprising 1-(2-substitutedamino-1-oxopropyl) octahydrocyclopenta [b]pyrrole-2-carboxylic acid and salts thereof. The invention also provides a pharmaceutical composition of ramipril or salts thereof having 1-(2-substituted amino-1-oxopropyl)octahydro cyclopenta[b]pyrrole-2-carboxylic acid and salts thereof content of 1% or less.