FIELD OF THE INVENTION
The present invention relates to novel nitrosated and nitrosylated derivatives of 2,3-dihydro-lH-pyrrolizin moiety, preferably 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2, 3-dihydro-lH-pyrrolizin-5-yl -acetic acid also known as Licofelone (ML 3000); and processes for preparing such compounds. The present invention also relates to the pharmaceutical compositions comprising such compounds or mixtures thereof, and a pharmaceutically acceptable carrier. These compounds are useful as potent cyclooxygenase-2 and 5-lipoxygenase inhibitors.
BACKGROUND OF THE INVENTION
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed drugs in the world but their use as anti-inflammatory, analgesic, antipyretic and antithrombotic agents is limited by their adverse effects.
The most common adverse effects of NSAIDs are related with gastrointestinal system and include abdominal pain or discomfort, heartburn, dyspepsia and perforations of the gastrointestinal tract. Inhibition of cyclooxygenase (COX) and therefore prostaglandin (PG) production is the common mechanism of action of NSAIDs. Prostaglandins have been proven to be cytoprotective and antisecretory. A decrease in the level of prostaglandins engendered by inhibition of cyclooxygenase disturbs this protective mechanism. A second hypothesis focuses on leukotrienes that are formed by the 5-lipooxygenase enzymes from arachidonic acid. Leukotrines have been reported to play an important role in acidic gastrointestinal ulceration. Inhibiting cyclooxygenase may increase the metabolism of arachidonic acid via the leukotriene pathway. Such compounds, which inhibit both cyclooxygenase and 5-lipooxygenase enzymes, are, for example, reported in US Patent Application No. 20020028953 and Tetrahedron 55 (1999)5145-5156.
It is now well established that COX exists in two isoforms: COX-1, which is constitutively expressed and present in the endothelium, stomach and kidney; and COX-2, which is induced by pro-inflammatory cytokines and endotoxins. Thus the side effects of NSAIDs are associated with their ability to inhibit COX-1 where as their therapeutic anti-inflammatory effects are attributed to their ability to inhibit COX-2.
Out of many non-steroidal anti-inflammatory drugs (NSAIDs) available, the pyrrolizin derivatives are very prominent and are considered as much effective COX-II and Lipox-V constituents compared to the traditional NSAIDs. 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid (Licofelone, ML 3000) is one such unique pyrrolizin
derivative possessing optimal gastrointestinal tolerability and high analgesic and anti-inflammatory activity with anti-pyretic and antiaggregatory properties. These are due to balanced and selective inhibition of both cyclooxygenase-2 and 5-lipooxygenase. The drug is used for the treatment of osteoarthritis and rheumatoid arthritis. Licofelone has been found to be as effective as naproxen and celecoxib in the treatment of osteoarthritis and superior to naproxen for gastrointestinal tolerance.
Certain adverse reactions have been found with licofelone. At a dose of 100 mg/kg, the drug is reported to cause ulcers in rabbits. It caused a slight reduction in urine output in rats. Gastrointestinal disorders occurred in 14% of licofelone recipients (200 mg twice-daily). The incidence of gastrointestinal duodenal ulcers during the first 6 weeks of the study in which low-dose aspirin was taken was 5.6% in licofelone recipients. The incidence of gastric ulcer in no low-dose aspirin is 2.4% in licofelone recipients. In patients with osteoarthritis, 32% of licofelone reported adverse events. The incidence of patients who had haematology values within the normal range prior to treatment, but values below the lower normal limit after 13 weeks of treatment was lower in the licofelone groups as compared to naproxen.
A more recent approach to reduce the gastrointestinal toxicity of the conventional NSAIDs has been the development of nitric oxide (NO) releasing NSAIDs [Hawkey, C.J. Future treatments for arthritis: new NSAIDs, NO-NSAIDs or no NSAIDs? Gastroenterology 1995, 109:614-6: Drugs of the Future 1997,22(11): 1231-1233].
Nitric oxide has been reported to play an important role in maintaining the integrity of gastro-duodenal mucosa and exerts many of the same effects as endogenous prostaglandins. Moreover, nitric oxide is an important signaling molecule and cytotoxic effector molecule of non-specific immune responses. Thus local delivery of nitric oxide could substitute prostaglandins in restoring the balance between aggressive and defensive factors in the GI tract that would be shifted by COX-1 inhibition.
Prodrugs refer to compounds which are drug precursors which, following administration to a subject and subsequent absorption, is converted to an active species in vivo via some process, such as metabolism. More preferred prodrugs produce products from the conversion process which are generally accepted as safe. The pharmaceutical industry of today have started showing considerable interest in extensive research to develop novel nitrosated and nitosylated derivatves of NSAIDs as prodrugs thus predicting practical advantage of these newer drugs over COX-2 inhibitors.
Several references disclose the structure of licofelone but no such reference or published literature is available regarding the development of nitrosated and nitrosylated derivatives of licofelone as prodrugs. The fact that the same has not been studied earlier coupled with the endeavor to improve the therapeutic potential of the drug and minimize, reduce or obliterate the existing adverse effects of licofelone, prompted the inventors to carry out the present invention.
The US patent number 5,260,451 relates to substituted pyrrole compounds, specifically licofelone, as well as the pharmaceutically compatible salts or esters thereof; pharmaceutical composition comprising licofelone; and its use as potent cyclooxygenase-2 and/or 5-lipoxygenase inhibitors suitable to prevent allergically induced maladies and to treat the set of rheumatic illnesses. However, no disclosure is made in the said patent relating to any derivatives of licofelone, which may have improved efficacy and lesser toxicity.
Hence there still exists a need to develop novel derivatives of licofelone which would have better efficacy and lesser toxicity, and are also amenable to formulation into different dosage forms.
SUMMARY OF THE INVENTION
An objective of the present invention is to provide novel nitrosated and nitrosylated derivatives of 2,3-dihydro-lH-pyrrolizin moiety, preferably 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid or their tautomeric forms, analogues, isomers, polymorphs, solvates, or pharmaceutically acceptable salts thereof.
It is an objective of the present invention to provide novel nitrosated and nitrosylated derivatives of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2, 3-dihydro-lH-pyrrolizin-5-yl-acetic acid of formula (1), or their tautomeric forms, analogues, isomers, polymorphs, solvates, or pharmaceutically acceptable salts thereof.(Formula Removed) wherein R' is(Figer Removed)
and where Z is Nitric oxide releasing moiety such as -NO2, -ONO, -ONO2, S-NO and C-NO and Y is halogen atom preferably a chlorine atom
It is also an objective of the present invention to provide process for the preparation of novel nitrosated and nitrosylated derivatives of 2,3-dihydro-lH-pyrrolizin moiety, preferably 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2, 3-dihydro-lH-pyrrolizin-5-yl-acetic acid, or their tautomeric forms, analogues, isomers, polymorphs, solvates, or pharmaceutically acceptable salts thereof.
It is yet another objective of the present invention to provide pharmaceutical composition comprising these novel polymorphic forms or its mixtures and optionally with pharmaceutically acceptable excipients.
The compositions of the present invention are useful as potent cyclooxygenase-2 and 5-lipoxygenase inhibitors.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel nitric oxide releasing derivatives of 2,3-dihydro-lH-pyrrolizin moiety. Preferably the present invention provides novel nitric oxide releasing derivatives of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1 H-pyrrolizin-5-yl-acetic acid of formula (1) as described herein, or their tautomeric forms, analogues, isomers, polymorphs, solvates, or pharmaceutically acceptable salts thereof. (Formula Removed)
where R' is as described herein earlier.
The nitrosated and/or nitrosylated compounds of Formula (1) of the present invention contains at least one - NO group or at least one - NO2 group, and wherein the at least one -NO group or the at least one - NO2 group is linked to the compounds of Formula (1) through an oxygen, carbon or a sulphur atom.
In a preferred embodiment, the compound according to the present invention have at least one -NO group or the at least one - NO2 group linked to the compounds of Formula (1) through an oxygen.
The novel compounds of the present invention donates, transfers or releases nitric oxide (NO), stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelim derived relaxing factor or is a substrate for nitric oxide synthase as non-steroidal anti-inflammatory compounds (NSAID), cyclooxygenase 2 (COX-2) inhibitors, 5 lipoxygenase (5-LO) inhibitors, including nitric oxide synthetase inhibitors, proton pump inhibitors and mixtures thereof.
In an embodiment, the present invention describes nitrosated and nitrosylated derivatives of 2,3-dihydro-lH-pyrrolizin of formula (2), more particularly of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-l H-pyrrolizin-5-yl-acetic acid. Such compounds are able to release nitric oxide and act as both cyclooxygenase-2 and 5-lipoxygenase enzyme inhibitors.
(Formula Removed)
In a further embodiment, Y and Z represent the following groups as shown in formula (2A). (Formula Removed)
where X is nitrogen atom, B is halogen atom preferably chlorine atom, and A represents -CH2COR' wherein R' is as described herein earlier.
In an embodiment of the present invention, the novel nitrosated and nitrosylated derivatives are as shown in the formula (2B).
(Formula Removed)
and where Z is Nitric oxide releasing moiety such as -NO2, -ONO, -ONO2, S-NO and C-NO and Y is halogen atom preferably a chlorine atom.
In an embodiment of the present invention, the novel nitrosated and nitrosylated derivatives of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2, 3-dihydro-lH-pyrrolizin-5-yl-acetic acid act as potent cyclooxygenase-2 and 5 - lipooxygenase inhibitors, and are able to release nitric oxide.
The compounds of the present invention are potent cyclooxygenase-2 and 5-lipoxygenase inhibitors at relatively lower doses and have better efficacy with lower toxicity.
In an embodiment of the present invention, processes are provided for preparing nitrosated and nitrosylated derivatives of 2,3-dihydro-lH-pyrrolizin moiety, preferably 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid.
In another embodiment, the compounds of the present invention act as potent nitric oxide releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs).
The examples of synthetic schemes for the preparation of nitrosated and nitrosylated derivatives of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid serve to illustrate embodiments of the present invention. However, they do not intend to limit the scope of invention.
In the following schemes, the compound "6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid" i.e. Licofelone (ML3000) has been represented as "R-COOH" and R is :
(Scheme Removed)

In the reaction sequences stated above, the compounds of this invention are prepared by the general reactions described in the art. [Advanced Organic Chemistry, Jerry March (fourth edition); and Organic Chemistry, Morrison and Boyd (sixth edition)]. In all the above reaction schemes, the compounds formed are the nitrosated and nitrosylated derivatives of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid.
In the reaction Scheme I, X denotes hydroxyl group and Y is halogen group such as -Br attached to corresponding C-atom coupled with stated 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid and then nitrosylated so as to provide the titled compound (IE), where Z denotes the corresponding nitrooxy moiety such as -ONO2.
In the reaction Scheme II, Y denotes halogen group such as -1 and Z denotes the corresponding nitrooxy group such as -ONO2, that leads to the coupled product (2C).
In the reaction Scheme III, the required nitrosylated derivative (3C) is obtained via coupling with 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid, where Z is the nitric oxide releasing moiety such as -ONO2.
In the reaction Scheme IV, Y denotes halogen group such as -I and Z denotes the corresponding nitrooxy group such as -ONO2, which when coupled with 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid, provides the required nitrate derivative (4C).
The reaction Scheme V leads to the coupled product (5D), which includes Z as the nitric oxide releasing moiety such as -ONO2.
The reaction Scheme VI, wherein Y denotes the halogen group such as -Cl, leads to (6E) via coupling with 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid, where Z denotes the nitric oxide releasing moiety such as -ONO2.
In the reaction Scheme VII, X denotes hydroxyl group, Y denotes halogen atom more particularly bromine atom and Z denotes the corresponding nitrooxy moiety such as -ONO2. Coupling with 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid provides the required nitrosylated derivative (7D) of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid.
The compounds of the present invention can be administered in the form of conventional pharmaceutical compositions. In an embodiment, the pharmaceutical compositions comprising compound of formula (1), optionally with pharmaceutically acceptable excipients can be administered by routes such as oral, parenteral, topical, nasal, pulmonary, vaginal, rectal and like.
For these purposes, the compounds of formula (1) may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous oily solutions, suspensions, emulsions, creams, ointments, gels, transdermal preparations, nasal sprays, suppositories, finely divided powders or aerosols for inhalation and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solution or suspension or sterile emulsions.
Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations.
The examples stated below describe the process of manufacture of compounds stated therein and their characterization. All experiments were run under an UHP grade nitrogen atmosphere. IR
spectras were recorded in KBr pellets and CCl4 (NaCl cells). 1H NMR spectras were recorded in CDC13 and DMSOd6 at 300 MHZ. Chemical shifts were reported as 8 values in ppm relative to internal tetramethylsilane. Analytical thin layer chromatography (TLC) was performed on Merck silica gel and neutral active aluminium oxide (Spectrochem). Solvents such as Dichloromethane, Diethyl ether, Ethyl acetate were distilled from CaH2.
Example-1: 3-trimethyl silyoxy benzyl aniline (1B)
To a mixture of 3-aminobenzylalcohol 1A (0.50 g, 4.07 mmol) in dry dichloromethane (10 ml) at room temperature was added triethylamine (0.822 g, 8.14 mmol). The resulting suspension was vigorously stirred for 10 minutes at room temperature. The reaction mixture was cooled 0°-5°C and trimethylsilyl chloride (0.883 g, 8.14 mmol) was added. The resulting suspension was stirred for 25 - 30 minutes at 5° - 10°C and warmed to room temperature. The reaction mixture was diluted with DM water (10 ml) and organic phase was separated. The organic phase was dried over anhydrous Na2SO4 and filtered. The solvent was removed in vacua and the residue was purified by column chromatography on silica gel (98/2 hexane/ethyl acetate) to furnish 1B as a light brown oil (0.40 g, 50.45% yield).
IR data: 3460, 3370, 3225, 3040, 2958, 2857, 1611, 1594, 1493, 1464, 1375, 1255, 1096, 777, 691 cm-1
Example-2: N-[3-trimethylsilyloxybenzyl]-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl] acetamide (1C)
To a solution of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin (5.83 g, 15.38 mmol) in diethyl ether (40 ml) was added n,n-dicyclohexylcarbodimide (3.17 g, 15.38 mmol) and stirred for 25 - 30 minutes at room temperature. To the resulting suspension was added IB (3.0 g, 15.38 mmol) alongwith n,n-dimethylaminopyridine in catalytic amount and the reaction mixture was stirred for 2.0 hours at 20° - 25°C. The resulting mixture was filtered through celite, which was washed with additional diethyl ether (10 ml). The filtrate was removed in vacuo and the residue was purified by column chromatography on silica gel (90/10 hexane/ethyl acetate) to furnish 1C as a colorless solid (2.33 g, 27.24% yield).
IRdata: 3300, 3052, 2956, 2929, 2856, 1663, 1599, 1552, 1488, 1440, 1369, 1256, 1100, 833, 778, 699 cm'1
'H NMR data: 5 1.25 (s, 6H), 2.79 (s, 2H), 3.36 (s, 9H), 3.56 (s, 2H), 3.74 (s, 2H), 4.66 (s, 2H), 7.00 - 7.50 (m, 13H), 9.55 (s, 1H)
ExampIe-3: N-[3-Bromomethylphenyl]-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-
dihydro-lH-pyrrolizin-5-yl] acetamide (1D)
To a solution of 1C (0.50 g, 0.898 mmol) in dry dichloromethane (7.0 ml) at room temperature was added phosphoroustribromide (0.162 g, 0.599 mmol). The resulting solution was vigorously stirred for 25 - 30 minutes at room temperature. The solvent was removed in vacua and the residue was purified by column chromatography on silica gel (90/10 hexane/ethyl acetate) to furnish ID as a colorless solid (0.20 g, 40.65% yield).
IR data: 3298, 3079, 2931, 2856, 1668, 1597, 1552, 1488, 1442, 1260, 1097, 833, 793, 765, 699, 545 cm'1
1H NMR data: 8 1.29 (s, 6H), 2.87 (s, 2H), 3.66 (s, 2H), 3.74 (s, 2H), 4.42 (s, 2H), 7.00 - 7.35 (m, 13H), 7.43 (s, 1H)
ExampIe-4: N-[3-Nitrooxymethylphenyl]-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-
dihydro-lH-pyrrolizin-5-yl] acetamide (1E)
To a solution of ID (0.20 g, 0.365 mmol) in acetonitrile (3.0 ml) was added silver nitrate (0.123 g, 0.73 mmol). The resulting suspension was stirred at room temperature for 1 hour and then refluxed for additional 1 hour. The reaction mixture was cooled to room temperature and filtered through a plug of celite, which was washed with additional acetonitrile (1.0 ml). The solvent was removed in vacua and the residue was purified by column chromatography on active neutral alumina (90/10 hexane/ethyl acetate) to furnish 1E as a light brown solid (0.06 g, 30.95% yield).
IR data: 3301, 3078, 2958, 2868, 1662, 1603, 1530, 1487, 1450, 1383, 1259, 1098, 833, 764, 699cm-1 (Figure 1)
!H NMR data: 8 1.29 (s, 6H), 2.87 (s, 2H), 3.66 (s, 2H), 3.73 (s, 2H), 5.36 (s, 2H), 7.00 - 7.31 (m, 13H), 7.47 (s, 1H) (Figure 2)
Example-5: 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid-2- bromo ethyl ester (2B)
To a mixture of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid (1.5 g, 3.95 mmol) in benzene (15 ml ) was added 1,8-diazabicyclo (5,4,0) undec -7-ene (0.648 ml, 4.35 mmol) and stirred at room temperature for 15-20 minutes. To the vigorously stirred mixture was added 1,2-dibromo ethane 2A (0.375 ml, 4.35 mmol). Reaction mixture was refluxed for 3 hours and then cooled to room temperature, diluted with water (15 ml) and organic phase was separated. The organic phase was dried over Na2SO4 and filtered. The solvent was
removed in vacua and the residue was purified by column chromatography on active neutral aluminium oxide (90/10 petroleum ether/ethyl acetate) to give 2B as light yellow colored oil (0.70 g, 36.5% yield).
IR data: 3039, 2961,2869, 1738, 1622, 1601, 1530, 1487, 1450, 1172, 838,768,701 cm-1
1H NMR data: 5 1.30 (s, 6H), 2.86 (s, 2H), 3.50 (t, 2H), 3.59 (s, 2H), 3.76 (s, 2H), 4.45 (t, 2H), 7.00 - 7.30 (m, 9H)
Example-6: 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid-2- nitrooxy ethyl ester (2C)
To a solution of 2B (1.2 g, 2.466 mmol) in acetonitrile (8 ml) was added silver nitrate (1.6 g, 9.523 mmol) at room temperature. The resulting reaction mixture was stirred for 1.0 hour at room temperature and heated to reflux. Reaction mass was re fluxed for 3.0 hours and then cooled to room temperature. The resulting mixture was then filtered through a bed of celite, which was washed with additional acetonitrile (5.0 ml). The filtrate was removed in vacua and the residue was purified by column chromatography on active neutral alumina (95/5 petroleum ether/ether) to give 2C as a colorless solid (0.5 g, 43.4% yield).
IR data: 3037, 2959, 2872, 1738, 1603, 1531, 1485, 1451, 1384, 1098, 837, 765, 699 cm-' (Figure 3)
'H NMR data: 5 1.30 (s, 6H), 2.85 (s, 2H), 3.57 (s, 2H), 3.73 (s, 2H), 4.42 (t, 2H), 4.68 (t, 2H), 7.00 - 7.30 (m, 9H) (Figure 4)
Example-7: 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid-3- iodopropyl ester (3B)
To a mixture of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid (2.0 g, 5.27 mmol) in benzene (15 ml) was added 1,8-diazabicyclo (5,4,0) undec-7-ene (0.865 ml, 5.79 mmol) and stirred at room temperature for 25-30 minutes. To the resulting solution was added 1,3-diiodopropane 3A (0.667 ml, 5.79 mmol) and reaction mass was heated to reflux. After reflux for 2.0 hours, reaction mixture was cooled to room temperature, diluted with water (20 ml) and organic layer was separated. The organic phase was dried over Na2SO4 and filtered. The solvent was removed in vacua and the residue was purified by column chromatography on active neutral aluminium oxide (90/10 hexane/ethyl acetate) to give 3B as a light yellow colored solid (1.0 g, 34.7% yield).
IR data: 3037, 3039, 2961, 2867, 1736, 1622, 1601, 1530, 1488, 1449, 1172, 1096, 834, 768, 701 cm-1
1H NMR data: 6 1.27 (s, 6H), 2.04 (m, 2H), 2.84 (s, 2H), 3.52 (t, 2H), 3.55 (s, 2H), 3.72 (s, 2H),
4.46 (t, 2H), 7.00 - 7.30 (m, 9H)
Example-8: 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid-3-nitrooxy propyl ester (3C)
To a solution of 3B (0.70 g, 1.28 mmol) in acetonitrile (10 ml) was added silver nitrate (0.324 g, 1.92 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 1.5 hours followed by 1.0 hour at 40°-45°C. Reaction mixture was cooled to room temperature and filtered through celite, which was washed with additional acetonitrile (5.0 ml). The solvent was removed in vacua and the residue was purified by column chromatography on active neutral aluminium oxide (95/5 hexane/ethyl acetate) to give 3C as colorless solid (0.40 g, 64.8% yield).
IR data: 3057, 3040, 2968, 2857, 1738, 1620, 1600, 1531, 1487, 1450, 1383, 1098, 836, 765, 700 cm-1 (Figure 5)
]H NMR data: 8 1.29 (s, 6H), 2.10 (m, 2H), 2.85 (s, 2H), 3.55 (s, 2H), 3.71 (s, 2H), 4.22 (t, 2H),
4.47 (t, 2H), 7.00 - 7.30 (m, 9H) (Figure 6)
Example-9: 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid-4- lodobutyl ester (4B)
To a mixture of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid (0.50 g, 1.32 mmol) in benzene (10 ml) was added 1,8-diazabicyclo (5,4,0) undec-7-ene (0.196 ml, 1.32 mmol) and stirred at 25°-30°C for 30 minutes. To the vigourously stirred mixture was added 1,4-diiodobutane 4A (0.173 ml, 1.32 mmol). Reaction mixture was heated to reflux. After reflux for 2.0 hours, the reaction mixture was cooled to 25°-30°C, diluted with water (40 ml) and organic layer was separated. The organic phase was dried over Na2SC>4 and filtered. The solvent was removed in vacua and the residue was purified by column chromatography on active aluminium oxide (neutral) (90/10 hexane/ethyl acetate) to give 4B as a light yellow colored oil (0.70 g, 94% yield).
IR data: 3049, 2958, 1727, 1620, 1603, 1531, 1487, 1449, 1281, 1173, 1026,837,767,701 cm-1'
'H NMR data: 5 1.28 (s, 6H), 1.76 (m, 4H), 2.85 (s, 2H), 3.19 (t, 2H), 3.54 (s, 2H), 3.74 (s, 2H), 4.16 (t,2H), 7.00 -7.30 (m, 9H)
Example-10: 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid-4-nitrooxy butyl ester (4C)
To a solution of 4B (0.30 g, 0.53 mmol) in acetonitrile (6.0 ml) was added silver nitrate (0.145 g, 0.85 mmol) at room temperature. The resulting reaction mixture was stirred for 2 hours at room temperature followed by 1.0 hour at 40°-45°C. The resulting mixture was filtered through a plug of celite at room temperature which was washed with additional acetonitrile (5.0 ml). The solvent was removed in vacua and the residue was purified by column chromatography on active aluminium neutral oxide (95/5 hexane/ethyl acetate) to give 4C as a colorless solid (0.20 g, 75.8% yield).
IR data: 3050, 2958, 1738, 1620, 1603, 1529, 1485, 1450, 1380, 1280, 1099, 837, 765, 700 cm"1 (Figure 7)
1H NMR data: 5 1.30 (s, 6H), 1.77 (m, 4H), 2.85 (s, 2H), 3.54 (s, 2H), 3.74 (s, 2H), 4.14 (t, 2H), 4.45 (t, 2H), 7.00 - 7.30 (m, 9H) (Figure 8)
Example-11: 2-Iodo-propan-l-ol (5B)
To a solution of allyl alcohol 5A (5.0 g, 86.21 mmol) was added hydroiodic acid (12.0 g, 93.75 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature overnight. After stirring at room temperature, the resulting solution was diluted with brine (25 ml) and extracted with carbon tetrachloride (2 x 25 ml). The organic phase was dried over MgSO4 and filtered. The solvent was removed in vacua and the residue was purified by column chromatography on silica gel (70/30 hexane/ethyl acetate) to furnish 5B as a dark brown oil (2.0 g, 12.5% yield).
IR data: 3467, 2925, 2868, 1451, 1377, 1092,486cm-1
Example-12: 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid-2-Iodopropyl ester (5C)
To a solution of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid (1.0 g, 2.63 mmol) in diethyl ether (10 ml) was added n,n-dicyclohexylcarbodimide (0.542 g, 2.63 mmol) and stirred at 25-30 minutes at room temperature. To the resulting suspension was added 5B (0.489 g, 2.63 mmol) alongwith 4-dimethyl amino pyridine in catalytic amount and the resulting mixture was stirred for 3.0 hours at 25° - 30°C. The resulting mixture was filtered through a plug of celite, which was washed with additional diethyl ether (10 ml). The solvent was removed in vacua and the residue was purified by column chromatography on

silica gel (90/10 hexane/ethyl acetate) to furnish 5C as a light yellow to green oil (0.60 g, 41.5% yield).
IR data: 3035, 2958, 2871, 1737, 1603, 1530, 1486, 1450, 1168, 1097,832,764,700cm-1
1H NMR data: 8 1.29 (s, 6H), 2.84 (s, 2H), 3.55 (s, 2H), 3.75 (s, 2H), 4.63 (d, 3H), 5.28 (d, 2H), 5.89 (m, 1H), 7.00 - 7.30 (m, 9H)
Example-13: 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid-2-nitrooxy propyl ester (5D)
To a solution of 5C (0.60 g, 1.095 mmol) in acetonitrile (4.0 ml) was added silver nitrate (0.368 g, 2.19 mmol). The resulting suspension was stirred at room temperature for 1 hour and then refluxed for additional 2.0 hours. The reaction mixture was cooled to room temperature and filtered through a plug of celite, which was washed with additional acetonitrile (3.0 ml). The solvent was removed in vacua and the residue was purified by column chromatography on active neutral alumina (95/5 hexane/ethyl acetate) to give 5D as a light yellow solid (0.20 g, 37.8% yield).
IR data: 3035, 2959, 2871, 1736, 1603, 1530, 1486, 1450, 1381, 1169, 1097, 832, 765, 700 cm'1 (Figure 9)
1H NMR data: 8 1.27 (s, 6H), 2.83 (s, 2H), 3.50 (s, 2H), 3.73 (s, 2H), 4.60 (d, 3H), 5.25 (d, 2H), 5.92 (m, 1H), 7.00 - 7.24 (m, 9H) (Figure 10)
Example-14: 4-chloro-3-nitrobenzylchloride (6B)
To a 100 ml three necked round bottom flask placed on ice bath, was added 10 ml nitric acid and cooled to 0° - 5°C. 10 ml of H2SO4 was added slowly to this solution at 0°C & then stirred for 30 minutes. 4-chlorobenzylchloride 6A (5.0 g, 0.031 mol) was charged to the resulting solution and was stirred vigorously at 0°C for 20 - 25 minutes followed by at room temperature for 30 minutes. The reaction mixture was poured into ice cooled water & stirred for 15 - 20 minutes. Compound was extracted in Ethyl acetate and the organic layer was dried over anhydrous Na2SO4. Solvent was recovered in vacua at 40 - 45°C. The crude oil was purified by column chromatography on silica gel (90/10 hexane/ ethyl acetate) to furnish 6B as a greenish oil (2.5 g, 39.12% yield).
IR data: 3040, 2966, 2875, 1608, 1569, 1533, 1479, 1446, 1355, 1134, 833, 721, 675 cm-1 'H NMR data: S 4.59 (s, 2H), 7.55 (m, 2H), 7.91 (s, 1H)
Example-15: 3-Amino-4-chlorobenzyl chloride (6C)
To a 100 ml three necked round bottom flask, was added ethyl alcohol (10 ml) 6B (1.0 g, 4.8 mmol) and the resulting mixture was stirred for 10 - 15 minutes. To this was followed by added iron powder (0.67 g, 12.1 mmol) & was stirred for 10 minutes. Then 2.0 ml of acetic acid was added. The reaction mixture was heated to 80 - 90°C followed by reflux for 3 hour. Then the reaction mass was cooled to room temperature & EtoH was distilled out completely under vacuum. To the resulting residue was added 20% NaOH solution (2 ml) to make the pH 8.0 -9.0. The residue was stirred for 10 minutes and was extracted with Ethyl acetate. The organic layer was washed with DM water & was dried over anhydrous Na2SO4. The solvent was removed in vacua, to get 6C as a brownish oil (0.60 g, 70.0% yield).
IR data: 3441, 3361, 3222, 3050,2965,2868, 1620, 1509, 1435, 1222, 1182, 832, 728 cm'1
Example-16: N-(2-chloro-5-chloromethylphenyl)-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl] acetamide (6D)
To a three neck 100 ml round bottom flask, charged Diethylether (10 ml) and 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl acetic acid (1.29 g, 3.4 mmol) was added and stirred for 10 to 15 minutes till it got dissolved. To this resulting solution N,N-dicyclohexylcarbodimide (0.7 g, 3.4 mmol) was added along with catalytic amount of 4-pyrrolidino pyridine and was stirred for 3 hours at room temperature. The resulting suspension was filtered through a bed of celite, which was washed with additional diethyl ether (5.0 ml). The filtrate was removed in vacua and the residue was purified by column chromatography on silica gel (90/10 Hexane/ethyl acetate) to furnish 6D as a yellowish solid (0.9 g, 50% yield).
IR data: 3300, 3079,2931,2856, 1650, 1602, 1559, 1536, 1488, 1227, 1177,830,764,699cm-1
'H NMR data: 5 1.29 (s, 6H), 2.87 (s, 2H), 3.66 (s, 2H), 3.74 (s, 2H), 4.38 (s, 2H), 7.00 - 7.30 (m, 12H), 7.45 (s, 1H)
Example-17: N-(2-chloro-5-nitrooxybenzyl)-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyI-2,3-dihydro-lH-pyrrolizin-5-yl] acetamide (6E)
100 ml round bottom flask was charged with acetonitrile (10 ml) and compound 6D (0.9 g, 1.67 mmol). The resulting solution was stirred for 10 minutes and silver nitrate (0.8 g, 5.02 mmol) was added. The reaction mixture was heated to 90-95°C and refluxed for 2 to 3 hours. The reaction mixture was cooled to room temperature and filtered through a plug of celite, which was washed with additional acetonitrile (5.0 ml). The solvent was removed in vacua and the residue
was purified by solumn chromatography on active neutral alumina (95/5 hexane/ Ethyl acetate) to furnish 6E as a yellowish solid (0.30 g, 33.3% yield).
IR data: 3279, 3038, 2957, 1668, 1633, 1602, 1581, 1527, 1487, 1427, 1380, 1278, 848, 763, 726,694cm-1 (Figure 11)
1H NMR data: 5 1.29 (s, 6H), 2.86 (s, 2H), 3.67 (s, 2H), 3.73 (s, 2H), 5.45 (s, 2H), 7.00 - 7.31 (m, 12H), 7.46 (s, 1H)
Example-18: 3-Hydroxybenzyl bromide (7B)
To a mixture of 3-hydroxybenzyl alcohol 7A (5.0 g, 40.32 mmol) in dry dichloromethane (30 ml) at room temperature was added phosphorous tribromide (1.22 ml, 13.44 mmol). The resulting suspension was vigorously stirred for 15 minutes at room temperature followed by 1 hour at reflux temperature. The solution was cooled to room temperature, diluted with DM water (35 ml) and organic phase was separated. The organic layer was dried over anhydrous Na2SO4 and filtered. The solvent was removed in vacua and the residue was purified by column chromatography on silica gel (85/15 hexane/ethyl acetate) to furnish 7B as a light brown crystalline solid (5.0 g, 66.32% yield).
IR data: 3327, (Broad), 3050, 2866, 1607, 1592, 1495, 1464, 1373, 1031,770,685cm"1
'H NMR data: 5 4.17 - 4.24 (s, IH(Bd)), 4.43 (s, 2H), 6.74 - 6.78 (dd, 1H), 6.86 - 6.88 (dd, 1H), 6.95 (d, 1H), 7.23 (t, 1H)
Example-19: 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl acetic acid-3-(bromo methyl) phenyl ester (7C)
To a solution of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl acetic acid (1.0 g, 2.63 mmol) in diethyl ether (10 ml) was added n,n-dicyclohexylcarbodimide (0.542 g, 2.63 mmol) and stirred for 25 - 30 minutes at room temperature. To the resulting suspension was added 7B (0.50 g, 2.63 mmol) alongwith 4-pyrrolidinopyridine in catalytic amount and the reaction mixture was stirred for 2.0 hours at 25° - 30°C. The resulting mixture was filtered through celite, which was washed with additional diethyl ether (5 ml). The filtrate was removed in vacua and the residue was purified by column chromatography on silica gel (90/10 hexane/ethyl acetate) to furnish 7C as a light green oil (0.342 g, 23.2% yield).
IR data: 3050, 2954, 1760, 1600, 1533, 1486, 1448, 1346, 1125, 1014, 829, 768, 703 cm-1
!H NMR data: 8 1.31 (s, 6H), 2.87 (s, 2H), 3.77 (s, 2H), 3.82 (s, 2H), 4.46 (s, 2H), 7.00 - 7.38 (m, 13H)
Example-20: 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl acetic acid-3-(nitrooxymethyl) phenyl ester (7D)
To a solution of 7C (0.32 g, 0.584 mmol) in acetonitrile (5 ml) was added silver nitrate (0.196 g, 1.17 mmol).The resulting suspension was stirred at room temperature for 1 hour and then refluxed for additional 2.0 hour. The reaction mixture was cooled to room temperature and filtered through a plug of celite, and washed with additional acetonitrile (5.0 ml). The solvent was removed in vacua and the residue was purified by column chromatography on active neutral alumina (95/5 hexane/ethyl acetate) to give 7D as a colorless solid (0.225 g, 72.70% yield).
IR data: 3060, 2957, 2858, 1756, 1626, 1601, 1587, 1535, 1488, 1450, 1432, 1392, 1348, 1088, 855,765,703cm-1 (Figure 12)
1H NMR data: 5 1.31 (s, 6H), 2.87 (s, 2H), 3.78 (s, 2H), 3.81 (s, 2H), 5.42 (s, 2H), 7.00 - 7.45 (m,13H) (Figure 13)
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 is a characteristic infrared spectrum (IR) of compound 1E.
Figure 2 is a characteristic nuclear magnetic resonance ( H NMR) of compound 1E.
Figure 3 is a characteristic infrared spectrum (IR) of compound 2C.
Figure 4 is a characteristic nuclear magnetic resonance (1H NMR) of compound 2C.
Figure 5 is a characteristic infrared spectrum (IR) of compound 3C.
Figure 6 is a characteristic nuclear magnetic resonance (1H NMR) of compound 3C.
Figure 7 is a characteristic infrared spectrum (IR) of compound 4C.
Figure 8 is a characteristic nuclear magnetic resonance (1H NMR) of compound 4C.
Figure 9 is a characteristic infrared spectrum (IR) of compound 5D.
Figure 10 is a characteristic nuclear magnetic resonance (1H NMR) of compound 5D.
Figure 11 is a characteristic infrared spectrum (IR) of compound 6E.
Figure 12 is a characteristic infrared spectrum (IR) of compound 7D.
Figure 13 is a characteristic nuclear magnetic resonance (1H NMR) of compound 7D.

We claim:
1. Compound of Formula (1):
(Formula Removed)

or tautomeric forms, analogues, isomers, polymorphs, solvates, or pharmaceutical ly acceptable salts thereof,
wherein R is selected from :
(Formula Removed)
and where Z is Nitric oxide releasing moiety such as -NO2, -ONO, -ONO2, S-NO and C-NO and Y is halogen atom preferably a chlorine atom
with the provision that the nitrosated and/or nitrosylated compounds of Formula (1) must contain at least one - NO group or at least one - NO2 group, and wherein the at least one - NO group or the at least one - NO2 group is linked to the compounds of Formula (1) through an oxygen, carbon or a sulphur atom.
2. Compound according to claim 1 wherein the at least one -NO group or the at least one - NO2
group is linked to the compound of Formula (1) through an oxygen.
3. A compound according to claim 2 characterized by
i) IR data: 3301, 3078, 2958, 2868, 1662, 1603, 1530, 1487, 1450, 1383, 1259, 1098, 833, 764,
699 cm"1 substantially in accordance with Figure 1.
ii) 'H NMR data: 5 1.29 (s, 6H), 2.87 (s, 2H), 3.66 (s, 2H), 3.73 (s, 2H), 5.36 (s, 2H), 7.00 -7.31 (m, 13H), 7.47 (s, 1H) substantially in accordance with Figure 2.
4. A compound according to claim 2 characterized by
i) IR data: 3037, 2959, 2872, 1738, 1603, 1531, 1485, 1451, 1384, 1098, 837, 765, 699 cm'1 substantially in accordance with Figure 3.
ii) 'H NMR data: 5 1.30 (s, 6H), 2.85 (s, 2H), 3.57 (s, 2H), 3.73 (s, 2H), 4.42 (t, 2H), 4.68 (t, 2H), 7.00 - 7.30 (m, 9H) substantially in accordance with Figure 4.
5. A compound according to claim 2 characterized by
i) IR data: 3057, 3040, 2968, 2857, 1738, 1620, 1600, 1531, 1487, 1450, 1383, 1098, 836, 765,
700 cm"' substantially in accordance with Figure 5.
ii) JH NMR data: 6 1.29 (s, 6H), 2.10 (m, 2H), 2.85 (s, 2H), 3.55 (s, 2H), 3.71 (s, 2H), 4.22 (t, 2H), 4.47 (t, 2H), 7.00 - 7.30 (m, 9H) substantially in accordance with Figure 6.
6. A compound according to claim 2 characterized by
i) IR data: 3050, 2958, 1738, 1620, 1603, 1529, 1485, 1450, 1380, 1280, 1099, 837, 765, 700 cm" 1 substantially in accordance with Figure 7.
ii) 'H NMR data: 6 1.30 (s, 6H), 1.77 (m, 4H), 2.85 (s, 2H), 3.54 (s, 2H), 3.74 (s, 2H), 4.14 (t, 2H), 4.45 (t, 2H), 7.00 - 7.30 (m, 9H) substantially in accordance with Figure 8.
7. A compound according to claim 2 characterized by
i)IR data: 3035, 2959, 2871, 1736, 1603, 1530, 1486, 1450, 1381, 1169, 1097,832,765,700cm" 1 substantially in accordance with Figure 9.
ii) 'H NMR data: 5 1.27 (s, 6H), 2.83 (s, 2H), 3.50 (s, 2H), 3.73 (s, 2H), 4.60 (d, 3H), 5.25 (d, 2H), 5.92 (m, 1H), 7.00 - 7.24 (m, 9H) substantially in accordance with Figure 10.
8. A compound according to claim 2 characterized by
i) IR data: 3279, 3038, 2957, 1668, 1633, 1602, 1581, 1527, 1487, 1427, 1380, 1278, 848, 763, 726, 694 cm"1 substantially in accordance with Figure 11.
ii) 'H NMR data: 5 1.29 (s, 6H), 2.86 (s, 2H), 3.67 (s, 2H), 3.73 (s, 2H), 5.45 (s, 2H), 7.00 - 7.31 (m, 12H), 7.46 (s, 1H).
9. A compound according to claim 2 characterized by
i) IR data: 3060, 2957, 2858, 1756, 1626, 1601, 1587, 1535, 1488, 1450, 1432, 1392, 1348, 1088, 855, 765, 703 cm-1 substantially in accordance with Figure 12.
ii) 'H NMR data: 5 1.31 (s, 6H), 2.87 (s, 2H), 3.78 (s, 2H), 3.81 (s, 2H), 5.42 (s, 2H), 7.00 - 7.45 (m, 13H) substantially in accordance with Figure 13.
10. A process for the preparation of the compound according to claim 3 characterized by
i) IRdata: 3301, 3078, 2958, 2868, 1662, 1603, 1530, 1487, 1450, 1383, 1259, 1098, 833, 764,
699 cm-1 substantially in accordance with Figure 1.
ii) 'H NMR data: 5 1.29 (s, 6H), 2.87 (s, 2H), 3.66 (s, 2H), 3.73 (s, 2H), 5.36 (s, 2H), 7.00 -7.31 (m, 13H), 7.47 (s, 1H) substantially in accordance with Figure 2.
11. A process for the preparation of the compound according to claim 4 characterized by
i) IR data: 3037, 2959, 2872, 1738, 1603, 1531, 1485, 1451, 1384, 1098, 837, 765, 699 cm-1 substantially in accordance with Figure 3.
ii) 'H NMR data: 5 1.30 (s, 6H), 2.85 (s, 2H), 3.57 (s, 2H), 3.73 (s, 2H), 4.42 (t, 2H), 4.68 (t, 2H), 7.00 - 7.30 (m, 9H) substantially in accordance with Figure 4.
12. A process for the preparation of the compound according to claim 5 characterized by
i) IR data: 3057, 3040, 2968, 2857, 1738, 1620, 1600, 1531, 1487, 1450, 1383, 1098, 836, 765,
700 cm"1 substantially in accordance with Figure 5.
ii) 'H NMR data: 5 1.29 (s, 6H), 2.10 (m, 2H), 2.85 (s, 2H), 3.55 (s, 2H), 3.71 (s, 2H), 4.22 (t, 2H), 4.47 (t, 2H), 7.00 - 7.30 (m, 9H) substantially in accordance with Figure 6.
13. A process for the preparation of the compound according to claim 6 characterized by
i) IR data: 3050, 2958, 1738, 1620, 1603, 1529, 1485, 1450, 1380, 1280, 1099, 837, 765, 700 cm-1 substantially in accordance with Figure 7.
ii) 1-H NMR data: 8 1.30 (s, 6H), 1.77 (m, 4H), 2.85 (s, 2H), 3.54 (s, 2H), 3.74 (s, 2H), 4.14 (t, 2H), 4.45 (t, 2H), 7.00 - 7.30 (m, 9H) substantially in accordance with Figure 8.
14. A process for the preparation of the compound according to claim 7 characterized by
i) IR data: 3035, 2959, 2871, 1736, 1603, 1530, 1486, 1450, 1381, 1169, 1097, 832, 765, 700 cm-1 substantially in accordance with Figure 9.
ii)1-H NMR data: 5 1.27 (s, 6H), 2.83 (s, 2H), 3.50 (s, 2H), 3.73 (s, 2H), 4.60 (d, 3H), 5.25 (d, 2H), 5.92 (m, 1H), 7.00 - 7.24 (m, 9H) substantially in accordance with Figure 10.
15. A process for the preparation of the compound according to claim 8 characterized by
i) IR data: 3279, 3038, 2957, 1668, 1633, 1602, 1581, 1527, 1487, 1427, 1380, 1278, 848, 763, 726, 694 cm-1 substantially in accordance with Figure 11.
ii) 1-H NMR data: 8 1.29 (s, 6H), 2.86 (s, 2H), 3.67 (s, 2H), 3.73 (s, 2H), 5.45 (s, 2H), 7.00 - 7.31 (m, 12H), 7.46 (s, 1H).
16. A process for the preparation of the compound according to claim 9
i) IR data: 3060, 2957, 2858, 1756, 1626, 1601, 1587, 1535, 1488, 1450, 1432, 1392, 1348, 1088, 855, 765, 703 cm-1 substantially in accordance with Figure 12.
ii) 'H NMR data: 8 1.31 (s, 6H), 2.87 (s, 2H), 3.78 (s, 2H), 3.81 (s, 2H), 5.42 (s, 2H), 7.00 - 7.45 (m, 13H) substantially in accordance with Figure 13.
17. A pharmaceutical composition comprising a compound according to any of the preceding
claims or mixture thereof in combination with pharmaceutically acceptable excipients.
18. Use of compositions comprising compound according to any of the preceding claims or
mixture thereof as potent cyclooxygenase-2 and 5-lipoxygenase inhibitors.
19. Compounds which are novel nitrosated and/or nitrosylated compounds of 6-(4-
chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid as herein
described and illustrated by the examples.
20. The process for the preparation of compounds which are novel nitrosated and/or nitrosylated
compounds of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic
acid, and their hydrates as herein described and illustrated by the examples.