Indian Patents. 270303:ASYMMETRIC SYNTHESIS FOR PREPARATION OF (S) ENANTIOMER OF 2-(ß)-HYDROXYPHENETHYLAMINO) PYRIDINE

Title of Invention	ASYMMETRIC SYNTHESIS FOR PREPARATION OF (S) ENANTIOMER OF 2-(ß)-HYDROXYPHENETHYLAMINO) PYRIDINE
Abstract	The present invention disclosed novel (R) and (S) Styrene Oxide based asymmetric synthesis for preparation of Phenyramidol enantiomers and to their pharmaceutically acceptable salts with high chiral purity. This invention further disclosed clinical evaluation of (R) and (S) enantiomers of Phenyramidol, their salts and composition thereof for enhanced/newer therapeutic benefits.

Full Text	FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 PROVISIONAL SPECIFICATION (See section 10 and rule 13) 1. TITLE OF THE INVENTION: "Optical enantiomers of Phenyramidol and process for chiral synthesis" 2. APPLICANT (S) (a) NAME: FERMENTA BIOTECH (UK) LIMITED (b) NATIONALITY: A British Company (Regn.No.3308303) (c) ADDRESS: Charter House, 8-10 Station Road, Manor Park, London, E12 5BT 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention. Technical Field of the Invention: The present invention relates to (R) and (S) Styrene Oxide based Asymmetric Synthesis for production of novel Phenyramidol isomers with high chiral purity. These R and S enantiomers of Phenyramidol have been synthesized and characterized for the first time. The present invention also provides for a process for isolation of 98% pure R-isomer of Phenyramidol. The present invention further relates to the (R) and (S)-Styrene Oxide based Asymmetric Synthesis Process providing the advantages of more effective use of starting material, less formation of unwanted product and requires milder conditions of operation with less energy consumption and lower pressure requirements. The present invention makes use of multi-step lab scale processes to ensure cost effective practical manufacturing models to transfer the technology from Lab scale to kilos and to tons of final product thereby providing therapeutic benefits as well as economic cost benefit. This invention further relates to clinical evaluation of R and S enantiomers of Phenyramidol for enhanced therapeutic benefits. The present invention still further relates to compositions containing the novel isomers of Phenyramidol. Background and prior art of the Invention: Formula I 2 Phenyramidol (also known as Fenyramidol or IN 511 or MJ 505) is a drug attributed for its analgesic and muscle relaxant property. Chemically, Phenyramidol of formula I is 2-((b-hydroxyphenethylamino)pyridine. The molecular formula for Phenyramidol is Ci3H14N20. Preparation of Phenyramidol was first described in 1959 in Journal of American Chemical society. Phenyramidol is indicated for treatment of several types of pain. Pain is often classified under various categories e.g. acute and chronic; nociceptive and neuropathic; pain accompanying inflammation (secondary to tissue injury); visceral (smooth muscle) pain and pain (body ache) associated with fever (Temperature) etc. Pain is defined by the 'International Association for the study of Pain' as an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage. Under normal circumstances pain is a result of stimulation of peripheral receptors which transmit impulses to the brain through pain pathway. Early treatment of pain is important as unrelieved pain can have profound psychological effect on the patient. Opium is one of the most ancient pain reliever known to man however both habituation propensity and the addiction potential of opium are well known. The search for safe, effective and non habituating analgesic has been everlasting and continues even today, in 21st Century. Many drugs pertaining to pure analgesic or analgesic with anti pyretic /anti inflammatory activity; analgesic and muscle relaxant activity etc have been invented with varied degree of claims on superiority and safety. This range includes NSAIDS, COX-2 inhibitors, Aspirin, Codeine and its derivatives, Morphine and its derivatives, Caffeine and even Corticosteroids to relieve head aches; etc. Serious Side effects, including fatal episodes with COX-2 inhibitors have raised some serious thoughts in medicinal research community regarding development of New Chemical Entities (NCEs) for analgesic, anti-inflammatory, muscle relaxant and antipyretic therapeutic segment. 3 For past few years, the attention is directed towards search for new therapeutic indications from existing products and/or to examine already existing old racemic molecules for their isomers for enhanced therapeutic activity. Phenyramidol (2- {beta-hydroxyphenethylamino}- pyridine) introduced originally as an analgesic has shown excellent skeletal muscle relaxant activity at very low doses when used parentally as well as orally. Phenyramidol is unique in its biological effects in that, it possesses measurable analgesic and muscle relaxant properties. Of equal importance is the fact that other central effects observed with other analgesics or muscle relaxant drugs (such as sedation, euphoria, and mental confusion) have not been apparent in pharmacological studies of Phenyramidol. The analgesic activity of Phenyramidol is of the order of Codeine and its muscle relaxant activity can abolish abnormal muscle tone without impairing normal neuromuscular function. Phenyramidol molecule has an asymmetric carbon (Chiral centre) centre and possesses optical activity. Presently this molecule is used as it is in form of a 'racemic' mixture and till date no effort has been made to resolve and subject its individual isomers to therapeutic evaluation for existing or new indications. Dosage forms like tablets, capsules and injections are manufactured using racemic Phenyramidol and they are actively promoted as safe and effective analgesic and muscle relaxant. Since its first introduction in 1959 Phenyramidol has been actively promoted in Turkey, Greece, Philippines, and EU markets by different Companies under different brand names and has not shown any untoward side effects, despite the use over past decades. US patent 4,168,308 discloses a composition for enhancing parenteral administration comprising a stable, oil-in-water emulsion containing a pharmacologically inert lipoid as a hydrophobic phase dispersed in a hydrophilic phase and an effective dose of a pharmacologically active, oil-soluble agent predominantly dissolved in said lipoid at a fraction ratio thereto in the hydrophobic phase. The oil-soluble pharmacological agent is a muscle relaxant from the compounds of Phenyramidol. 4 GB1229967 discloses pharmaceutical compositions for enteral, parenteral and intranasal application comprise an oil-soluble therapeutic and/or diagnostic agent dispersed in a diluent comprising an emulsion or dispersion of a pharmaceutically inert lipid and water, at least 50% by weight of the active material being in the lipid phase. Numerous types of medicaments are mentioned and examples relate to preparations comprising Phenyramidol, hexobarbital, hexyl ether, mecamylamine and quinidine. Chiral Chemisty of all kind from kinetic resolution to asymmetric synthesis, chiral chromatographic separation, racemisation and stereochemical inversion, to name a few -have formed the most dynamic subsection of the Research Activity involved in the development of New Chemical Entities. There are no prior Art relating to the L- or D- isomers of Phenyramidol or the process for their resolution or for their chiral synthesis in patent literature. Object of the Invention: Inspite of Phenyramidol being a 1959 molecule, no chiral synthesis or characterization and therapeutic evaluation of optical enantiomers of Phenyramidol have been reported or attempted till date. In this invention we have met this long felt need for patient benefit. The object of the present invention relates to (R) and (S) Styrene Oxide based Asymmetric Synthesis for production of novel Phenyramidol isomers. These R and S enantiomers of Phenyramidol have been synthesized and characterized for the first time. Another object of the present invention is the use of (R) and (S)-Styrene Oxide during Asymmetric Synthesis Process providing enantiomers of Phenyramidol with high chiral purity. In yet another object as per the present invention a process for isolation of 98% pure R-isomer of Phenyramidol is provided. 5 As per another object of the present invention, the (R) and (S)-Styrene Oxide based Asymmetric Synthesis Process provides huge advantages, including more effective use of starting material, less formation of unwanted product and requires milder conditions of operation with less energy consumption and lower pressure requirements. Further object of the invention is the use of multi-step lab scale processes to ensure cost effective practical manufacturing models to transfer the technology from Lab scale to kilos and to tons of final product have been carried out which provides therapeutic benefits as well as economic cost benefit. Still, further object of invention is clinical evaluation of R and S enantiomers of Phenyramidol for enhanced therapeutic benefits. Compositions' containing the novel isomers of Phenyramidol is another object of the present invention. Summary of the Invention: The present invention discloses (R) and (S)-Styrene Oxide based Asymmetric Synthesis for production of Phenyramidol isomers with high chiral purity. These R and S enantiomers of Phenyramidol have been synthesized and characterized for the first time. The present invention also discloses a process for isolation of 98% pure R-isomer of Phenyramidol and further discloses the advantages provided by the use of (R) and (S)-Styrene Oxide based Asymmetric Synthesis Process like more effective use of starting material, less formation of unwanted product and requirement of milder conditions of operation with less energy consumption and lower pressure. The present invention still further discloses the use of multi-step lab scale processes to ensure cost effective practical manufacturing models to transfer the technology from Lab scale to kilos and to tons of final product thereby providing therapeutic benefits as well as economic cost benefit. This invention further relates to clinical evaluation of R and S enantiomers of Phenyramidol for enhanced therapeutic benefits. 6 Also the present invention discloses compositions containing the novel isomers of Phenyramidol. Description of the Invention: The present invention describes an (R) and (S) Styrene Oxide based Asymmetric Synthesis for production of novel Phenyramidol isomers with high chiral purity. These R and S enantiomers of Phenyramidol have been synthesized and characterized for the first time. Phenyramidol molecule has an asymmetric carbon (Chiral centre) centre and possesses optical activity. This observation, lead the inventors of the present invention to arrive at a new important possibility of development of a molecule which can be explained as follows: i) The Greater part of therapeutic action of Phenyramidol is likely to be by the virtue of either of its Laevo- rotatory OR its Dextro- rotatory enantiomeric form since both being present in active pharmaceutical ingredient [API] of racemic Phenyramidol. ii) Segregation of the Laevo and Dextro enantiomers from Phenyramidol API and subjecting the same to in-vitro/in-vivo studies (Animal -Toxicological and Pharmacodynamic, Phased Clinical studies) to scientifically confirm that a particular laevo or dextro form shows better therapeutic activity. The inventors of the present invention employed (R) and (S) Styrene Oxide based Asymmetric Synthesis for production of Chiral Phenyramidol isomers. Use of (R) and (S)-Styrene Oxide during Asymmetric Synthesis Process provides with enantiomers of high chiral purity. The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention. 7 EXAMPLES Example 1 Process for synthesis of (-)-Phenyramidol:- 1 mole of 2-aminopyridine is dissolved in dimethylformamide at 0-30°C and added to 0.8-2.0 Moles of lithium amide, suspended in dimethylformamide at 0-50°C. The pH of the reaction mass is basic to very highly basic. After complete addition, the reaction mixture is stirred at 0-20°C for 10-60 minutes. Subsequently, the temperature is maintained between 25 to 80°C. Then, 1-1.5 moles of (R)-styreneoxide is added drop wise at 0-100°C. The Reaction mass is then stirred at 0-100°C for 1- 7 hr. After 1-7 hr dimethylformamide is distilled under reduced pressure. Water is added to the reaction mass at 0-90°C and is extracted with an organic solvent added at 0-90°C. The organic layer is separated, dried over anhydrous sodium sulphate and evaporated under vacuum to get red coloured viscous liquid, which solidifies with time. Specific Rotation: [&] = -40.29 (c=0.5, methanol) Yield: 45%-90% The above synthesis was performed in different solvents such as N-methyl -2-pyrollidone (NMP), tetrahydrofuran (THF), dimethyl sulphoxide (DMSO), methyl tert-butyl ether (MTBE), dimethylacetamide (DMA) instead of dimethylformamide. The above synthesis was also tried out with sodium amide in liquid ammonia. The crude product is crystallized from either toluene or benzene or xylene or aqueous methanol or ethanol. Chiral HPLC Purity :> 96% [&] = - 34.7 (c=0.5, methanol) [d] = -190.9 (c=0.8, chloroform) 8 The crude and the pure Phenyramidol base are converted to its hydrochloride, oxalates etc. Example 2 Process for synthesis of (+)-Phenyramidol:- 1 mole of 2-aminopyridine is dissolved in dimethylformamide at 0-30°C and added to 0.8-2.0 Moles of lithium amide, suspended in dimethylformamide at 0-50°C. After complete addition, the reaction mixture is stirred at 0-20°C for 10-60 minutes. Subsequently, the temperature is maintained between 25 to 80°C. Then, 1-1.5 moles of (S)-styrene oxide is added drop wise at 0-100°C. The Reaction mass is then stirred at 0-100°C for 1- 7 hr. After 1-7 hr dimethylformamide is distilled under reduced pressure. Water is added to the reaction mass and is extracted with an organic solvent. The organic layer is separated, dried over anhydrous sodium sulphate and evaporated under vacuum to get red coloured viscous liquid, which solidifies with time. Specific Rotation: [d] = +36.29 (c=0.5, methanol) Yield: 70%-90% The above synthesis was performed in different solvents such as N-methyl -2-pyrollidone (NMP), tetrahydrofuran (THF), dimethyl sulphoxide (DMSO), methyl tert-butyl ether (MTBE), dimethylacetamide (DMA) instead of dimethylformamide. The above synthesis was also tried out with sodium amide in liquid ammonia. The crude product is crystallized from either toluene or benzene or xylene or aqueous methanol or ethanol. Chiral HPLC Purity :> 96% [d] = +35.2 (c=0.5, methanol) [d] = +152.9 (c=0.5, chloroform) 9 The crude and the pure Phenyramidol base are converted to its hydrochloride, oxalates etc. The use of (R) and (S)-Styrene Oxide during Asymmetric Synthesis Process provided enantiomers with high chiral purity. The process as per present invention provided with isolation of 98% pure R-isomer of Phenyramidol, when studied on laboratory scale. The advantages of use of (R) and (S)-Styrene Oxide based Asymmetric Synthesis Process includes more effective use of starting material, less formation of unwanted product and requires milder conditions of operation with less energy consumption and lower pressure requirements. Also, multi-step lab scale processes were used to ensure cost effective practical manufacturing models to transfer the technology from Lab scale to kilos and to tons of final product providing therapeutic benefits as well as economic cost benefit. The R and S isomers are studied for enhanced therapeutic benefits. This invention further discloses the clinical evaluation of R and S enantiomers of Phenyramidol for enhanced therapeutic benefits. The new active Chiral Isomer/s of Phenyramidol has the following advantages; 1. Equipotent therapeutic results with lesser dosage schedule; 2. Lesser side effects because of equipotent therapeutic action in lesser dosage; 3. Better safety margin as muscle relaxant and hence becomes a preferred injectable in pre/post management of surgical patients, (in Gynecology, Cardiac, Orthopedic, CNS, Dental as well as general surgeries); 10 4. Sustained release preparation with chiral molecule is achievable with lesser mgs as compared to 600/800 or even 1200 mgs of conventional Phenyramidol, thereby providing a superior option to racemic Phenyramidol having better patient compliance. The present invention also provides compositions containing the novel isomers of Phenyramidol. Compositions of Phenyramidol as per the present invention have the following advantages; 1. Compositions containing Laevo / Dextro isomer are more potent (i.e. equipotent in smaller doses) when compared with formulations containing racemic Phenyramidol as an active ingredient. 2. Compositions containing Laevo / Dextro isomers cause lesser side effects as compared to formulations containing racemic Phenyramidol as an active ingredient. 3. Compositions containing Laevo / Dextro isomer offers better therapeutic and safety ratio as compared to conventional Phenyramidol. 4. Compositions containing Laevo / Dextro isomer offers additional therapeutic advantages in various indications by virtue of mixed actions on release /blockade of various neurotransmitters namely Ach, 5-HT, NE, Glutamet, Substance P - and by the virtue of its action on Receptor Agonist/Antagonist namely Nn, NMD A, D, Sigma, & Kappa. 5. Phenyramidol Chiral R/S offers extended Therapeutic potential as an analgesic without euphoria, respiratory depression, constipation, Pupillary constriction & corrects only abnormal Muscle tone/stretch without action at NMJ or without direct action on muscle fibers while exerting action against fever and inflammation. 11 6. The potential indications of Compositions containing Laevo / Dextro isomer of Phenyramidol are - blepharospasm, torticolis, anal fissures, post operative pain, mental depression, hyper acidity, vomiting of chemotherapy, muscular rigidity, Parkinsonism, motion sickness, reduction in cholesterol levels & allergy. It is highly effective in a dosage range of lmg to 1000mg daily in as single or multiple dosages as depending upon severity of indications. 7. Compositions containing Laevo / Dextro isomer of Phenyramidol when available in the Tablet, Capsules & Injection forms will make it an ideal analgesic for pediatric use (kid tabs /syrup). It will be an excellent Topical analgesic & muscle relaxant ideally suited for the treatment of muscle spasms, sport sprains and morning stiffness in geriatric patients. Analgesic ear and eye drops are another application of Laevo / Dextro isomer of Phenyramidol in pediatric & ophthalmic practice. It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. DESCRIPTION OF DRAWINGS: Figure 1 indicates the resolution of two optical isomers of racemic mixture of Phenyramidol Hydrochloride. 12 Figure 2 indicates the HPLC chromatogram; showing the peak obtained by (+) isomer of Phenyramidol hydrochloride (which is synthesized separately by Example 2). Figure 3 indicates the HPLC chromatogram; showing the peak obtained by (-) isomer of Phenyramidol hydrochloride (which is synthesized separately by Example 1). Figure 4 indicates the HPLC chromatogram; showing the peak obtained by a mixture of (+) and (-) [added separately] isomer of Phenyramidol hydrochloride. Figure 5 indicates the HPLC chromatogram; showing the peak obtained by a mixture of (+)isomer added to (-) isomer (added separately) of Phenyramidol hydrochloride. Figure 6 The resolution - optical isomers Phenyramidol hydrochloride by HPLC, observed in reported prior art reference www.chromtech.com. Ref: HPLC Guide by Chromtech's user Guide Second Edition Page 23. Column used: άi-acid glycoprotein 100 x 4.0 mm Mobile phase: 4% tetrahydrofuran in l0m/v sodium phosphate buffer pH:7 Detection: UV 225nm Sample concentration: 0.02mg/ml. (Used as reference for comparison and validation of our invention). Dated this 22nd day of May 2006 Dr. Gopakumar G. Nair Agent for the Applicant 13

Full Text

FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"Optical enantiomers of Phenyramidol and process for chiral synthesis"
2. APPLICANT (S)
(a) NAME: FERMENTA BIOTECH (UK) LIMITED
(b) NATIONALITY: A British Company (Regn.No.3308303)
(c) ADDRESS: Charter House, 8-10 Station Road, Manor Park, London, E12 5BT
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention.

Technical Field of the Invention:
The present invention relates to (R) and (S) Styrene Oxide based Asymmetric Synthesis for production of novel Phenyramidol isomers with high chiral purity. These R and S enantiomers of Phenyramidol have been synthesized and characterized for the first time. The present invention also provides for a process for isolation of 98% pure R-isomer of Phenyramidol. The present invention further relates to the (R) and (S)-Styrene Oxide based Asymmetric Synthesis Process providing the advantages of more effective use of starting material, less formation of unwanted product and requires milder conditions of operation with less energy consumption and lower pressure requirements.
The present invention makes use of multi-step lab scale processes to ensure cost effective practical manufacturing models to transfer the technology from Lab scale to kilos and to tons of final product thereby providing therapeutic benefits as well as economic cost benefit. This invention further relates to clinical evaluation of R and S enantiomers of Phenyramidol for enhanced therapeutic benefits.
The present invention still further relates to compositions containing the novel isomers of Phenyramidol.
Background and prior art of the Invention:
Formula I
2
Phenyramidol (also known as Fenyramidol or IN 511 or MJ 505) is a drug attributed for its analgesic and muscle relaxant property. Chemically, Phenyramidol of formula I is

2-((b-hydroxyphenethylamino)pyridine. The molecular formula for Phenyramidol is Ci3H14N20. Preparation of Phenyramidol was first described in 1959 in Journal of American Chemical society. Phenyramidol is indicated for treatment of several types of pain.
Pain is often classified under various categories e.g. acute and chronic; nociceptive and neuropathic; pain accompanying inflammation (secondary to tissue injury); visceral (smooth muscle) pain and pain (body ache) associated with fever (Temperature) etc.
Pain is defined by the 'International Association for the study of Pain' as an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage. Under normal circumstances pain is a result of stimulation of peripheral receptors which transmit impulses to the brain through pain pathway. Early treatment of pain is important as unrelieved pain can have profound psychological effect on the patient.
Opium is one of the most ancient pain reliever known to man however both habituation propensity and the addiction potential of opium are well known.
The search for safe, effective and non habituating analgesic has been everlasting and continues even today, in 21st Century. Many drugs pertaining to pure analgesic or analgesic with anti pyretic /anti inflammatory activity; analgesic and muscle relaxant activity etc have been invented with varied degree of claims on superiority and safety. This range includes NSAIDS, COX-2 inhibitors, Aspirin, Codeine and its derivatives, Morphine and its derivatives, Caffeine and even Corticosteroids to relieve head aches; etc.
Serious Side effects, including fatal episodes with COX-2 inhibitors have raised some serious thoughts in medicinal research community regarding development of New Chemical Entities (NCEs) for analgesic, anti-inflammatory, muscle relaxant and antipyretic therapeutic segment.
3

For past few years, the attention is directed towards search for new therapeutic indications from existing products and/or to examine already existing old racemic molecules for their isomers for enhanced therapeutic activity.
Phenyramidol (2- {beta-hydroxyphenethylamino}- pyridine) introduced originally as an analgesic has shown excellent skeletal muscle relaxant activity at very low doses when used parentally as well as orally. Phenyramidol is unique in its biological effects in that, it possesses measurable analgesic and muscle relaxant properties.
Of equal importance is the fact that other central effects observed with other analgesics or muscle relaxant drugs (such as sedation, euphoria, and mental confusion) have not been apparent in pharmacological studies of Phenyramidol. The analgesic activity of Phenyramidol is of the order of Codeine and its muscle relaxant activity can abolish abnormal muscle tone without impairing normal neuromuscular function.
Phenyramidol molecule has an asymmetric carbon (Chiral centre) centre and possesses optical activity. Presently this molecule is used as it is in form of a 'racemic' mixture and till date no effort has been made to resolve and subject its individual isomers to therapeutic evaluation for existing or new indications.
Dosage forms like tablets, capsules and injections are manufactured using racemic Phenyramidol and they are actively promoted as safe and effective analgesic and muscle relaxant. Since its first introduction in 1959 Phenyramidol has been actively promoted in Turkey, Greece, Philippines, and EU markets by different Companies under different brand names and has not shown any untoward side effects, despite the use over past decades.
US patent 4,168,308 discloses a composition for enhancing parenteral administration comprising a stable, oil-in-water emulsion containing a pharmacologically inert lipoid as a hydrophobic phase dispersed in a hydrophilic phase and an effective dose of a pharmacologically active, oil-soluble agent predominantly dissolved in said lipoid at a fraction ratio thereto in the hydrophobic phase. The oil-soluble pharmacological agent is a muscle relaxant from the compounds of Phenyramidol.
4

GB1229967 discloses pharmaceutical compositions for enteral, parenteral and intranasal application comprise an oil-soluble therapeutic and/or diagnostic agent dispersed in a diluent comprising an emulsion or dispersion of a pharmaceutically inert lipid and water, at least 50% by weight of the active material being in the lipid phase. Numerous types of medicaments are mentioned and examples relate to preparations comprising Phenyramidol, hexobarbital, hexyl ether, mecamylamine and quinidine.
Chiral Chemisty of all kind from kinetic resolution to asymmetric synthesis, chiral chromatographic separation, racemisation and stereochemical inversion, to name a few -have formed the most dynamic subsection of the Research Activity involved in the development of New Chemical Entities.
There are no prior Art relating to the L- or D- isomers of Phenyramidol or the process for their resolution or for their chiral synthesis in patent literature.
Object of the Invention:
Inspite of Phenyramidol being a 1959 molecule, no chiral synthesis or characterization and therapeutic evaluation of optical enantiomers of Phenyramidol have been reported or attempted till date. In this invention we have met this long felt need for patient benefit.
The object of the present invention relates to (R) and (S) Styrene Oxide based Asymmetric Synthesis for production of novel Phenyramidol isomers. These R and S enantiomers of Phenyramidol have been synthesized and characterized for the first time.
Another object of the present invention is the use of (R) and (S)-Styrene Oxide during Asymmetric Synthesis Process providing enantiomers of Phenyramidol with high chiral purity.
In yet another object as per the present invention a process for isolation of 98% pure R-isomer of Phenyramidol is provided.
5

As per another object of the present invention, the (R) and (S)-Styrene Oxide based Asymmetric Synthesis Process provides huge advantages, including more effective use of starting material, less formation of unwanted product and requires milder conditions of operation with less energy consumption and lower pressure requirements.
Further object of the invention is the use of multi-step lab scale processes to ensure cost effective practical manufacturing models to transfer the technology from Lab scale to kilos and to tons of final product have been carried out which provides therapeutic benefits as well as economic cost benefit.
Still, further object of invention is clinical evaluation of R and S enantiomers of Phenyramidol for enhanced therapeutic benefits.
Compositions' containing the novel isomers of Phenyramidol is another object of the present invention.
Summary of the Invention:
The present invention discloses (R) and (S)-Styrene Oxide based Asymmetric Synthesis for production of Phenyramidol isomers with high chiral purity. These R and S enantiomers of Phenyramidol have been synthesized and characterized for the first time. The present invention also discloses a process for isolation of 98% pure R-isomer of Phenyramidol and further discloses the advantages provided by the use of (R) and (S)-Styrene Oxide based Asymmetric Synthesis Process like more effective use of starting material, less formation of unwanted product and requirement of milder conditions of operation with less energy consumption and lower pressure.
The present invention still further discloses the use of multi-step lab scale processes to ensure cost effective practical manufacturing models to transfer the technology from Lab scale to kilos and to tons of final product thereby providing therapeutic benefits as well as economic cost benefit. This invention further relates to clinical evaluation of R and S enantiomers of Phenyramidol for enhanced therapeutic benefits.
6

Also the present invention discloses compositions containing the novel isomers of Phenyramidol.
Description of the Invention:
The present invention describes an (R) and (S) Styrene Oxide based Asymmetric Synthesis for production of novel Phenyramidol isomers with high chiral purity. These R and S enantiomers of Phenyramidol have been synthesized and characterized for the first time.
Phenyramidol molecule has an asymmetric carbon (Chiral centre) centre and possesses
optical activity. This observation, lead the inventors of the present invention to arrive at a
new important possibility of development of a molecule which can be explained as
follows:
i) The Greater part of therapeutic action of Phenyramidol is likely to be by the virtue of
either of its Laevo- rotatory OR its Dextro- rotatory enantiomeric form since both being
present in active pharmaceutical ingredient [API] of racemic Phenyramidol.
ii) Segregation of the Laevo and Dextro enantiomers from Phenyramidol API and
subjecting the same to in-vitro/in-vivo studies (Animal -Toxicological and
Pharmacodynamic, Phased Clinical studies) to scientifically confirm that a particular
laevo or dextro form shows better therapeutic activity.
The inventors of the present invention employed (R) and (S) Styrene Oxide based Asymmetric Synthesis for production of Chiral Phenyramidol isomers. Use of (R) and (S)-Styrene Oxide during Asymmetric Synthesis Process provides with enantiomers of high chiral purity.
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
7

EXAMPLES
Example 1
Process for synthesis of (-)-Phenyramidol:-
1 mole of 2-aminopyridine is dissolved in dimethylformamide at 0-30°C and added to
0.8-2.0 Moles of lithium amide, suspended in dimethylformamide at 0-50°C. The pH of
the reaction mass is basic to very highly basic.
After complete addition, the reaction mixture is stirred at 0-20°C for 10-60 minutes. Subsequently, the temperature is maintained between 25 to 80°C.
Then, 1-1.5 moles of (R)-styreneoxide is added drop wise at 0-100°C. The Reaction mass is then stirred at 0-100°C for 1- 7 hr. After 1-7 hr dimethylformamide is distilled under reduced pressure. Water is added to the reaction mass at 0-90°C and is extracted with an organic solvent added at 0-90°C. The organic layer is separated, dried over anhydrous sodium sulphate and evaporated under vacuum to get red coloured viscous liquid, which solidifies with time.
Specific Rotation: [&] = -40.29 (c=0.5, methanol) Yield: 45%-90%
The above synthesis was performed in different solvents such as N-methyl -2-pyrollidone (NMP), tetrahydrofuran (THF), dimethyl sulphoxide (DMSO), methyl tert-butyl ether (MTBE), dimethylacetamide (DMA) instead of dimethylformamide. The above synthesis was also tried out with sodium amide in liquid ammonia.
The crude product is crystallized from either toluene or benzene or xylene or aqueous methanol or ethanol.
Chiral HPLC Purity :> 96% [&] = - 34.7 (c=0.5, methanol) [d] = -190.9 (c=0.8, chloroform)
8

The crude and the pure Phenyramidol base are converted to its hydrochloride, oxalates etc.
Example 2
Process for synthesis of (+)-Phenyramidol:-
1 mole of 2-aminopyridine is dissolved in dimethylformamide at 0-30°C and added to
0.8-2.0 Moles of lithium amide, suspended in dimethylformamide at 0-50°C.
After complete addition, the reaction mixture is stirred at 0-20°C for 10-60 minutes. Subsequently, the temperature is maintained between 25 to 80°C.
Then, 1-1.5 moles of (S)-styrene oxide is added drop wise at 0-100°C. The Reaction mass is then stirred at 0-100°C for 1- 7 hr. After 1-7 hr dimethylformamide is distilled under reduced pressure. Water is added to the reaction mass and is extracted with an organic solvent. The organic layer is separated, dried over anhydrous sodium sulphate and evaporated under vacuum to get red coloured viscous liquid, which solidifies with time.
Specific Rotation: [d] = +36.29 (c=0.5, methanol) Yield: 70%-90%
The above synthesis was performed in different solvents such as N-methyl -2-pyrollidone (NMP), tetrahydrofuran (THF), dimethyl sulphoxide (DMSO), methyl tert-butyl ether (MTBE), dimethylacetamide (DMA) instead of dimethylformamide. The above synthesis was also tried out with sodium amide in liquid ammonia.
The crude product is crystallized from either toluene or benzene or xylene or aqueous methanol or ethanol.
Chiral HPLC Purity :> 96% [d] = +35.2 (c=0.5, methanol) [d] = +152.9 (c=0.5, chloroform)
9

The crude and the pure Phenyramidol base are converted to its hydrochloride, oxalates etc.
The use of (R) and (S)-Styrene Oxide during Asymmetric Synthesis Process provided enantiomers with high chiral purity. The process as per present invention provided with isolation of 98% pure R-isomer of Phenyramidol, when studied on laboratory scale.
The advantages of use of (R) and (S)-Styrene Oxide based Asymmetric Synthesis Process includes more effective use of starting material, less formation of unwanted product and requires milder conditions of operation with less energy consumption and lower pressure requirements.
Also, multi-step lab scale processes were used to ensure cost effective practical manufacturing models to transfer the technology from Lab scale to kilos and to tons of final product providing therapeutic benefits as well as economic cost benefit.
The R and S isomers are studied for enhanced therapeutic benefits. This invention further discloses the clinical evaluation of R and S enantiomers of Phenyramidol for enhanced therapeutic benefits.
The new active Chiral Isomer/s of Phenyramidol has the following advantages;
1. Equipotent therapeutic results with lesser dosage schedule;
2. Lesser side effects because of equipotent therapeutic action in lesser dosage;
3. Better safety margin as muscle relaxant and hence becomes a preferred injectable in pre/post management of surgical patients, (in Gynecology, Cardiac, Orthopedic, CNS, Dental as well as general surgeries);
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4. Sustained release preparation with chiral molecule is achievable with lesser mgs as compared to 600/800 or even 1200 mgs of conventional Phenyramidol, thereby providing a superior option to racemic Phenyramidol having better patient compliance.
The present invention also provides compositions containing the novel isomers of Phenyramidol.
Compositions of Phenyramidol as per the present invention have the following advantages;
1. Compositions containing Laevo / Dextro isomer are more potent (i.e. equipotent in smaller doses) when compared with formulations containing racemic Phenyramidol as an active ingredient.
2. Compositions containing Laevo / Dextro isomers cause lesser side effects as compared to formulations containing racemic Phenyramidol as an active ingredient.
3. Compositions containing Laevo / Dextro isomer offers better therapeutic and safety ratio as compared to conventional Phenyramidol.
4. Compositions containing Laevo / Dextro isomer offers additional therapeutic advantages in various indications by virtue of mixed actions on release /blockade of various neurotransmitters namely Ach, 5-HT, NE, Glutamet, Substance P - and by the virtue of its action on Receptor Agonist/Antagonist namely Nn, NMD A, D, Sigma, & Kappa.
5. Phenyramidol Chiral R/S offers extended Therapeutic potential as an analgesic
without euphoria, respiratory depression, constipation, Pupillary constriction &
corrects only abnormal Muscle tone/stretch without action at NMJ or without direct
action on muscle fibers while exerting action against fever and inflammation.
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6. The potential indications of Compositions containing Laevo / Dextro isomer of Phenyramidol are - blepharospasm, torticolis, anal fissures, post operative pain, mental depression, hyper acidity, vomiting of chemotherapy, muscular rigidity, Parkinsonism, motion sickness, reduction in cholesterol levels & allergy. It is highly effective in a dosage range of lmg to 1000mg daily in as single or multiple dosages as depending upon severity of indications.
7. Compositions containing Laevo / Dextro isomer of Phenyramidol when available in the Tablet, Capsules & Injection forms will make it an ideal analgesic for pediatric use (kid tabs /syrup). It will be an excellent Topical analgesic & muscle relaxant ideally suited for the treatment of muscle spasms, sport sprains and morning stiffness in geriatric patients. Analgesic ear and eye drops are another application of Laevo / Dextro isomer of Phenyramidol in pediatric & ophthalmic practice.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
DESCRIPTION OF DRAWINGS:
Figure 1 indicates the resolution of two optical isomers of racemic mixture of Phenyramidol Hydrochloride.
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Figure 2 indicates the HPLC chromatogram; showing the peak obtained by (+) isomer of Phenyramidol hydrochloride (which is synthesized separately by Example 2).
Figure 3 indicates the HPLC chromatogram; showing the peak obtained by (-) isomer of Phenyramidol hydrochloride (which is synthesized separately by Example 1).
Figure 4 indicates the HPLC chromatogram; showing the peak obtained by a mixture of (+) and (-) [added separately] isomer of Phenyramidol hydrochloride.
Figure 5 indicates the HPLC chromatogram; showing the peak obtained by a mixture of (+)isomer added to (-) isomer (added separately) of Phenyramidol hydrochloride.
Figure 6 The resolution - optical isomers Phenyramidol hydrochloride by HPLC,
observed in reported prior art reference www.chromtech.com.
Ref: HPLC Guide by Chromtech's user Guide Second Edition Page 23.
Column used: άi-acid glycoprotein 100 x 4.0 mm
Mobile phase: 4% tetrahydrofuran in l0m/v sodium phosphate buffer pH:7
Detection: UV 225nm
Sample concentration: 0.02mg/ml.
(Used as reference for comparison and validation of our invention).
Dated this 22nd day of May 2006
Dr. Gopakumar G. Nair Agent for the Applicant
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Documents:

http://ipindiaonline.gov.in/patentsearch/GrantedSearch/viewdoc.aspx?id=DxzOOClWM0E/1fDw5giraQ==&loc=vsnutRQWHdTHa1EUofPtPQ==

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Patent Number

270303

Indian Patent Application Number

778/MUM/2006

PG Journal Number

50/2015

Publication Date

11-Dec-2015

Grant Date

09-Dec-2015

Date of Filing

23-May-2006

Name of Patentee

FERMENTA BIOTECH (UK) LIMITED

Applicant Address

CHARTER HOUSE, 8-10 STATION ROAD, MANOR PARK, LONDON, E12 5BT,

Inventors:

#	Inventor's Name	Inventor's Address
1	DATLA, ANUPAMA	'dil' Complex, Ghodbuder Road, Majiwada, Thane (West) - 400 610, Maharashtra, India.
2	WALAVALKAR, PRAMOD ABAJI	'dil' Complex, Ghodbuder Road, Majiwada, Thane (West) - 400 610, Maharashtra, India.
3	KONDA, ASHOK	'dil' Complex, Ghodbuder Road, Majiwada, Thane (West) - 400 610, Maharashtra, India.
4	TRIVIKRAM, SREENATH BABUNATH	'dil' Complex, Ghodbuder Road, Majiwada, Thane (West) - 400 610, Maharashtra, India.

PCT International Classification Number

C07D213/74

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA