DESC:
FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patent Rules 2003
COMPLETE SPECIFICATION
(see sections 10 & rule 13)
1. TITLE OF THE INVENTION
“DEUTERATED ANALOGUE OF AMFEPRAMONE COMPOUND AND PROCESS FOR SYNTHESISING THE SAME”
2. APPLICANT (S)
NAME NATIONALITY ADDRESS
CLEARSYNTH LABS LIMITED INDIAN 17th Floor, Lotus Nilkamal Business Park, New Link Road, Andheri [West], Mumbai - 400053, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION

COMPLETE SPECIFICATION
The following specification particularly describes the invention and the manner in which it is to be performed

FIELD OF INVENTION
The present invention relates to novel deuterated analogues of amfepramone (diethylpropion), compound of formula I, and process for synthesising the same. More particularly, the invention relates to deuterium-substituted amfepramone compounds that exhibit improved pharmacokinetic and metabolic stability profiles for use in the treatment of obesity and related disorders.

BACKGROUND OF INVENTION
Amfepramone, also known as diethylpropion, is a stimulant drug of the phenethylamine, amphetamine, and cathinone classes that is used as an appetite suppressant. It is used in the short-term management of obesity. Amfepramone is chemically known as 2-(diethylamino)-1-phenylpropan-1-one. It was approved in August 1959 in USA. Amfepramone is represented by following formula

It, a stimulant, previously used as an appetite suppressant for weight management, carries a significant number of health risks and is no longer recommended for this purpose. Although it has been shown to be effective for the short-term treatment of obesity, its use is associated with risk such as cardiovascular issues, pulmonary arterial hypertension (PAH), psychiatric effects, addiction and dependence, potential for developing psychological and physical dependence, harm to unborn babies. It also has additional concerns such as limited efficacy, high risk of misuse, withdrawal symptoms. These safety concerns led the European Medicines Agency (EMA) to recommend the withdrawal of its marketing authorization in 2022.
Deuterated compounds are often used in pharmaceutical research because they can be used to study the metabolism and pharmacokinetics of drugs. Deuterium atoms are not radioactive, so they can be safely administered to humans. In addition, deuterated compounds can be easily distinguished from their non-deuterated counterparts using mass spectrometry.
Here are some of the potential benefits of using deuterated compounds in pharmaceutical research:
• Deuterated compounds can be used to track the movement and fate of drugs in the body.
• Deuterated compounds can be used to study the metabolism of drugs.
• Deuterated compounds can be used to develop new and more effective drugs.
The main problem with amfepramone is its metabolism, specifically its breakdown in the body. When amfepramone is metabolized, it can produce various metabolites, some of which may be responsible for unwanted side effects or have a different duration of action than the parent drug. In some cases, the metabolism of the drug can be too fast, requiring more frequent dosing.
The solution provided by deuterated amfepramone addresses this metabolic issue. Deuterium (D or 2H) is a stable, non-radioactive isotope of hydrogen (H or 1H) that contains an extra neutron. Replacing a hydrogen atom with a deuterium atom in a drug's chemical structure doesn't significantly change its size or shape, so it still binds to its target effectively. However, the carbon-deuterium bond (C-D) is stronger than the carbon-hydrogen bond (C-H) due to the heavier mass of deuterium. This stronger bond is more resistant to enzymatic cleavage, particularly by the cytochrome P-450 enzymes in the liver that are responsible for drug metabolism.
By selectively substituting hydrogen atoms with deuterium atoms at specific sites on the amfepramone molecule, a deuterated amfepramone can be created that has a different metabolic profile. This can lead to a slower rate of metabolism and a longer half-life, meaning the drug stays in the body longer. The potential benefits of this include: (a) Improved Pharmacokinetics (A longer half-life may allow for a reduced dose or less frequent dosing); (b) Reduced Side Effects (Slower metabolism can lead to a lower concentration of potentially harmful metabolites); (c) Enhanced Efficacy (A more stable concentration of the drug in the body can lead to a more consistent therapeutic effect).While consider above mentioned problems, there is a need to design stable and pharmaceutically acceptable deuterated analogues of amfepramone and its preparation that maintain its anorectic activity while offering better metabolic resistance and pharmacokinetics.
Thus, the present invention provides deuterated amfepramone compounds which can be used to study the drug's metabolism in humans. Deuterated amfepramone may be metabolized more slowly than regular amfepramone. As a result of this, deuterated amfepramone may have a longer duration of action than the non-deuterated drug.

OBJECTS OF INVENTION
The main object of the present invention is to design a novel deuterated analogue of amfepramone compound of formula I, specially compound I-D13 or amfepramone-d13 & compound I-D19 or amfepramone-d19.
Another object of the present invention is to provide process for synthesis of deuterated amfepramone analogues (compound I-D13 & compound I-D19) in high yield and purity.
Another object of the present invention is to provide characterisation of synthesised deuterated amfepramone compounds namely formula I-D13 & formula I-D19.
Another object of the present invention is to provide biological activity of deuterated amfepramone compounds, compound I-D13 & compound I-D19.
Another object of the present invention is to provide the mechanism of action of deuterated Amfepramone.
Another object of the present invention is to provide deuterated Amfepramone compounds with improved efficacy, reduced side effects, enhanced bioavailability, prolonged duration of action, less susceptible to certain types of drug interactions.
Yet another object of the present invention is to provide a pharmaceutical composition of deuterated analogues of Amfepramone (formula I-D13 or formula I-D19).
Yet still another embodiment of the present invention is to provide dosage form of the pharmaceutical composition of deuterated analogues of Amfepramone (formula I-D13 or formula I-D19).

SUMMARY OF THE INVENTION
One of the aspects of the present invention provides a compound of formula I represented by:

Wherein R1 to R19 are independently selected from hydrogen (H), deuterium (D), C1 to C5 alkyl, aryl group.
Another aspect of the present invention provides a process for synthesis of compound of formula I, the process comprising:
a) treating a compound of formula 1 with a compound of comula 2 in presence of metal (M), halogen (X) in a solvent to obtain a compound of formula 3;

b) reacting the compound of formula 3 with halogenating agent in presence of a base in a solvent to obtain a compound of formula 4;

c) contacting the compound of formula 4 with a compound of formula 5A or 5B in presence of metal halide (M-X) in presence of a base in a solvent to obtain a compound of formula I.

FIGURES OF THE INVENTION
Figure 1 shows Decay Curve of Atenolol- Mouse Liver Microsomes (MLM)
Figure 2 shows Decay Curve of Verapamil- Mouse Liver Microsomes (MLM)
Figure 3 depicts Decay Curve of Amfepramone - Mouse Liver Microsomes (MLM)
Figure 4 illustrates Decay Curve of Amfepramone-D13-Mouse Liver Microsomes (MLM)

DETAILED DESCRIPTION OF THE PRESENT INVENTION
For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are collected here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art.
The terms used herein have the meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred methods, and materials are now described.
Detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely exemplary of the invention, which may be embodied in various forms. Therefore, specific functional and structural details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present invention in virtually any appropriately detailed structure.
In the specification different terms are used for describing the invention. The definitions of the terms are provided below.
The term ‘compound’ or ‘deuterated Amfepramone or ‘compound of formula I’ or ‘compound I-D13’ or ‘compound I-D19’ used herein, is also intended to include any salts, solvates, or hydrates thereof. Thus, it is to be understood that when any compound is referred to herein by name and structure, salts, solvates, and hydrates thereof are included.
The terms ‘compound’ or ‘deuterated Amfepramone or ‘compound of formula I’ or ‘compound I-D13’ or ‘compound I-D19’ can be used interchangeably in the specification.
‘D’ and ‘d’ both used herein refer to deuterium. ‘D’ and ‘d’ can be used interchangeably in the specification.
The term ‘solvent’ used herein refers to a substance that can dissolve another substance, or in which another substance is dissolved, forming a solution. The solvent used in the present invention can be polar or nonpolar solvent. The said solvent may be used in anhydrous form. The solvent includes such as but not limit to water, alcohols, ethers, ketones, acids, esters, acetonitrile (ACN), halogenated solvent(s) and/or deuterated form of water, alcohols, ethers, ketones, acids, esters, and/or deuterated halogenated solvent(s).
The term ‘C1-C5 alkyl’ group used in the compound of formula I includes straight chain or branched chain carbon atoms. The ‘C1-C5 alkyl’ group may include such as but is not limited to methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, n-butyl and n-pentyl group.
One of the embodiments of the present invention provides a compound of formula I, which is represented by

Wherein R1 to R19 are independently selected from hydrogen (H), deuterium (D), C1 to C5 alkyl, aryl group.
Another embodiment of the present invention provides a compound of formula I, wherein R1 to R19 are deuterium (D).
Another embodiment of the present invention provides a compound of formula I, wherein compound of formula I is amfepramone-D13, wherein R1 to R5, R6 to R8, R9, R13 to R16 are deuterium (D); and R10 to R12 and R17 to R19 are hydrogen(s).
Another embodiment of the present invention provides a compound of formula I, wherein the compound of formula I may include such as but is not limited to compound I-D13 (Amfepramone-D13) or compound I-D19 (Amfepramone-D19).
Another embodiment of the present invention provides a compound of formula I, wherein the compound of formula I include the compound I-D13 which is represented by

Wherein R1, R2, R3, R4, R5, R6, R7, R8 or R9 is deuterium (D), and R13, R14, R15 or R16 is deuterium.
Another embodiment of the present invention provides a compound of formula I, wherein the compound of formula I include the compound I-D19 which is represented by

Wherein R1 to R19 are deuterium (D).
In another embodiment of the present invention provides a process for synthesising compound of formula I, the process comprising:
a) treating a compound of formula 1 with a compound of comula 2 in presence of metal (M), halogen (X) in a solvent to obtain a compound of formula 3;

b) reacting the compound of formula 3 with halogenating agent in presence of a base in a solvent to obtain a compound of formula 4;

c) contacting the compound of formula 4 with a compound of formula 5A or 5B in presence of metal halide (M-X) and a base in a solvent to obtain a compound of formula I.

In another embodiment of the present invention, there is provided a process for synthesising compound of formula I, wherein the intermediate compounds used in the said synthesis include such as but is not limited to



In another embodiment of the present invention there is provided a process for synthesising compound of formula I, wherein compound 1 is bromobenzene-D5, compound 2 is N-methoxy-N-methylpropionamide-D5, compound 3 is Propiophenone-D10, compound 4 is 2-bromopropiophenone-D9, compound 5A is diethylamine-D4, compound 5B is diethylamine-D6.
In another embodiment of the present invention provides a process for synthesising compound of formula I, wherein metal (M) include such as but is not limited to sodium (Na), magnesium (Mg), lithium (Li), magnesium (Mg), and aluminum (Al).
In an embodiment, metal is magnesium (Mg).
In another embodiment of the present invention provides a process for synthesising compound of formula I, wherein halogen (X) is selected from fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I).
In an embodiment, halogen is iodine (I).
In another embodiment of the present invention provides a process for synthesising compound of formula I, wherein halogenating agent, any one known in the art can be used. There are, for example, Br2, phosgene, oxalyl dichloride, thionyl chloride, phosphorus pentachloride, phosphorous trichloride, phosphorus oxychloride, carbonyl dibromide, oxalyl bromide, thionyl bromide, phosphorous bromide and phosphorus oxybromide.
In an embodiment, the halogenating agent is bromine (Br2).
In another embodiment of the present invention provides a process for synthesising compound of formula I, wherein base is selected from organic and/or inorganic base.
In another embodiment of the present invention there is provided a process for synthesis of compound of formula I, wherein an inorganic base includes such as but is not limited to sodium hydroxide, potassium hydroxide, strontium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, cesium hydroxide, sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, strontium carbonate, cesium carbonate, sodium sulfide, sodium hydride and combinations thereof; preferably sodium bicarbonate.
In another embodiment of the present invention there is provided a process for synthesising of compound of formula I, wherein organic base includes such as but is not limited sodium alkoxide, potassium alkoxide, butyl lithium, pyridine, quinoline, 4-dimethylaminopyridine or an organic amine like ethyl amine, triethyl amine, di-isopropyl ethyl amine (DIPEA); preferably DIPEA.
In another embodiment of the present invention provides a process for synthesising compound of formula I, wherein metal halide (M-X) includes such as but is not limited to Sodium iodide (NaI), Sodium chloride (NaCl), Potassium chloride (KCl), Potassium iodide (KI), Lithium chloride (LiCl), Copper(II) chloride (CuCl2), Silver chloride (AgCl), Calcium chloride (CaCl2), Chlorine fluoride (ClF); preferably sodium iodide (NaI).
In another embodiment of the present invention provides a process for synthesising compound of formula I, wherein solvent is polar and/or non-polar solvent.
In another embodiment of the present invention there is provided a process for synthesising compound of formula I, wherein the reaction is carried out in presence of a solvent. The solvents that can be used, includes such as but is not limited to water, ketone solvent such as acetone, methyl ethyl ketone, methylisobutylketone (MIBK) or the like; halogenated hydrocarbon solvent such as dichloromethane, ethylene dichloride, chloroform, hexane or the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile or the like; ethers such as diethyl ether, tetrahydrofuran, methyl tetrahydrofuran, or the like; alcohols such as methanol, ethanol, 2-propanol, 2-butanol and mixtures thereof. In an embodiment, solvent is dry solvent.
In another embodiment of the present invention there is provided a process for synthesising compound of formula I, wherein solvent is selected from water, acetone, methyl ethyl ketone, methylisobutylketone (MIBK), dichloromethane, ethylene dichloride, chloroform, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile, ethyl acetate hexane, diethyl ether, tetrahydrofuran, methyl tetrahydrofuran, methanol, ethanol, isopropanol, n-propanol, tert-butanol, n-butanol and combinations thereof.
In another embodiment of the present invention there is provided a process for synthesising compound of formula I, wherein metal include such as but is not limited to Pd, Pt, Ni, Rh, Cu, Li, Mg, Al, Na.
In an embodiment, the metal is Mg.
In another embodiment of the present invention there is provided a process for synthesisng compound of formula I, wherein halogen include such as but is not limited to fluorine (-F), chlorine (-Cl), bromine (-Br) and iodine (-I).
Another embodiment of the present invention provides a process for synthesising compound of formula I, wherein compound of formula I is purified by using known conventional techniques such as but is not limited to crystallisation, chromatography, precipitation etc.
Another embodiment of the present invention provides a process for synthesising compound of formula I, wherein compound of formula I is purified by using polar and non-polar solvents.
In another embodiment of the present invention provides a process for synthesising compound of formula I, wherein synthesis of compound I-D19 may be carried out as per following scheme.

In another embodiment of the present invention provides a process for synthesising compound of formula I, wherein synthesis of compound I-D13 may be carried out as per following scheme.

In another embodiment of the present invention there is provided a process for synthesising compound of formula I, wherein compound of formula I is optionally converted into its pharmaceutically acceptable salt at a desired reaction condition.
In another embodiment of the present invention there is provided compound of formula I or its pharmaceutically acceptable salts, wherein said salts can be prepared from acids or bases including inorganic or organic acids and inorganic or organic bases by conventional chemical methods using a compound of formula I.
In one embodiment of the present invention, the compound of formula I can be used in combinations of another active pharmaceutical ingredient or other drug.
In another embodiment of the present invention there is provided a pharmaceutical composition, wherein the said composition comprises of
i. compound of formula I or its pharmaceutically acceptable salt; and
ii. one or more pharmaceutically acceptable excipient.
The examples provided in the definitions present in this application are non-inclusive unless otherwise stated. They include but are not limited to the recited examples.
EXAMPLES:
A. SYNTHESIS OF COMPOUND OF FORMULA I:
I. Synthesis of Amfepramone-D19 (compound I-D19):
Synthesis of Amfepramone-D19 (compound I-D19) was carried out in following steps.
Step-1: Synthesis of propiophenone-D10 (compound 3):
Magnesium turnings (1.249 g, 51.39 mmol) were placed in an oven dried two-neck round-bottom flask. A crystal of iodine was added and the flask was heated under stirring to activate the magnesium. After cooling, 25 mL of dry tetrahydrofuran were added, followed by the dropwise addition of bromobenzene-D5 (7.989 g, 50.88 mmol) to maintain the reaction at reflux and stirred for a further hour at reflux. Thus, after cooling to room temperature, the Grignard reagent solution was dropwise added to a solution of N-methoxy-N-methylpropionamide-D5 (5.326 g, 33.92 mmol) in dry tetrahydrofuran (34 mL) at 0 ºC. The reaction mixture was let warm to room temperature and stirred for 16 hours before being quenched by the addition of a saturated solution of ammonium chloride. Upon separation and extraction of the aqueous phase with diethyl ether, the combined organic phases were washed with brine and dried over sodium sulfate. After removal of the solvents at reduced pressure the residue was purified by flash chromatography on silica gel (from 0 to 20% ethylacetate in hexanes) to obtain desired Propiophenone-D10 in 85% yields.
Step-2: Synthesis of 2-bromopropiophenone-D9 (compound 4):
To an ice-cooled solution of the corresponding Propiophenone-D10 (0.04 mol), bromine (0.04 mol, 2 mL) was added dropwise. The almost colourless solution was stirred at room temperature for another 20 min. After addition of aqueous sodium bicarbonate solution (100 mL) the organic layer was separated and dried over sodium sulfate. After removal of the solvents at reduced pressure to get the desired 2-bromopropiophenone-D9 in 90% yields.
Step-3: Synthesis of compound I-D19:
An acetonitrile solution (10 mL) of 2-bromopropiophenone-D9 (1.0 g, 4.7 mmol) was charged with sodium iodide (704 mg, 4.7 mmol), diethylamine-D10 (1.0 g, 1.5 mL, 14.1 mmol), and N, N-diisopropylethylamine (607 mg, 819 µL, 4.7 mmol) and allowed to stir at 40 °C for 16 hours. The reaction mixture was concentrated in vacuo to a slurry, partitioned between sat. sodium bicarbonate (15 mL) and dichloromethane (15 mL), and the aqueous layer extracted with dichloromethane three times. The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography eluting with 97:2:1 (CH2Cl2: MeOH :7N NH3 in MeOH) to get the Amfepramone-D19. Yield: 75%.
II. Synthesis of labelled reagents:
1. N-methoxy-N-methylpropionamide-D5 (compound 2):
To a mixture of the corresponding propionic-d5 acid (20.0 mmol), N, O-dimethylhydroxylamine hydrochloride (2.536 g, 26.0 mmol) and 4-Dimethylaminopyridine (244.4 mg, 2.0 mmol) in dichloromethane (100 mL) at 0oC were added triethylamine (3.7 mL, 26.6 mmol) and 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (4.984 g, 26.0 mmol) successively. The reaction mixture was stirred at 0oC for 1 hour, then allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (200 mL). The organic layer was washed with 1 N hydrochloric acid (3×20 mL), aqueous saturated sodium bicarbonate (3×20 mL), and brine (40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel using ethyl acetate and hexane as an eluent (EtOAc/hexane = 1:3) to get the desired N-methoxy-N-methylpropionamide-D5. Yield: 80%.
B. SYNTHESIS OF AMFEPRAMONE-D13 (COMPOUND I-D13):
Synthesis of Amfepramone-D13 (compound I-D13) was carried out in following steps.
Step-1: Synthesis of propiophenone-D10 (compound 3):
Magnesium turnings (1.249 g, 51.39 mmol) were placed in an oven dried two-neck round-bottom flask. A crystal of iodine was added and the flask was heated under stirring to activate the magnesium. After cooling, 25 mL of dry tetrahydrofuran were added, followed by the dropwise addition of bromobenzene-D5 (7.989 g, 50.88 mmol) to maintain the reaction at reflux and stirred for a further hour at reflux. Thus, after cooling to room temperature, the Grignard reagent solution was dropwise added to a solution of N-methoxy-N-methylpropionamide-D5 (5.326 g, 33.92 mmol) in dry tetrahydrofuran (34 mL) at 0 ºC. The reaction mixture was let warm to room temperature and stirred for 16 hours before being quenched by the addition of a saturated solution of ammonium chloride. Upon separation and extraction of the aqueous phase with diethyl ether, the combined organic phases were washed with brine and dried over sodium sulfate. After removal of the solvents at reduced pressure the residue was purified by flash chromatography on silica gel (from 0 to 20% ethylacetate in hexanes) to obtain desired Propiophenone-D10 in 85% yields.
Step 2- Synthesis of 2-bromopropiophenone-D9 (compound 4):
To an ice-cooled solution of the corresponding Propiophenone-D10 (0.04 mol), bromine (0.04 mol, 2 mL) was added dropwise. The almost colourless solution was stirred at room temperature for another 20 min. After addition of aqueous sodium bicarbonate solution (100 mL) the organic layer was separated and dried over sodium sulfate. After removal of the solvents at reduced pressure to get the desire 2-bromopropiophenone-D9 in 90% yields.
Step 3- Synthesis of Amfepramone-D13 (compound I-D13):
An acetonitrile solution (10 mL) of 2-bromopropiophenone-D9 (1.0 g, 4.7 mmol) was charged with sodium iodide (704 mg, 4.7 mmol), diethylamine-D4 (1.0 g, 1.5 mL, 14.1 mmol), and N,N-diisopropylethylamine (607 mg, 819 µL, 4.7 mmol) and allowed to stir at 40 °C for 16 hours. The reaction mixture was concentrated in vacuo to a slurry, partitioned between sat. sodium bicarbonate (15 mL) and dichloromethane (15 mL), and the aqueous layer extracted with dichloromethane three times. The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography eluting with 97:2:1 (CH2Cl2:MeOH : 7N NH3 in MeOH) to get the Amfepramone-D13. Yield: 75%.
I. Synthesis of labelled reagents:
N-methoxy-N-methylpropionamide-D5 (A) (compound 2):
To a mixture of the corresponding propionic-d5 acid (20.0 mmol), N, O-dimethylhydroxylamine hydrochloride (2.536 g, 26.0 mmol) and 4-Dimethylaminopyridine (244.4 mg, 2.0 mmol) in dichloromethane (100 mL) at 0oC were added triethylamine (3.7 mL, 26.6 mmol) and 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (4.984 g, 26.0 mmol) successively. The reaction mixture was stirred at 0oC for 1 hour, then allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (200 mL). The organic layer was washed with 1 N hydrochloric acid (3×20 mL), aqueous saturated sodium bicarbonate (3×20 mL), and brine (40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel using ethyl acetate and hexane as an eluent (EtOAc/hexane = 1:3) to get the desired N-methoxy-N-methylpropionamide-D5 in 80% yields.
Diethylamine-l,l,l' ,l'-d4 hydrochloride (compound 5B):
25 grams (0.25 mole) of sublimed diacetamide in ether were added dropwise (100 ml) to a suspension of lithium aluminum deuteride (10.0 g) in 450 ml of absolute ether and the reaction mixture was stirred for 10 hours. The complex salt and excess deuteride were decomposed by careful addition of 3 N hydrochloric acid until the reaction mixture was acidic. The ether was then evaporated, and the residue made alkaline by addition of 50% sodium hydroxide before distillation with steam. The distillate was collected in 20 ml concentrated hydrochloric acid diluted with 60 ml of water. The distillate was freed of water and excess acid in the rotary evaporator under reduced pressure. The residue was dissolved in 300 ml chloroform and distilled for azeotropic elimination of the residual solvent. Suspended ammonium chloride was removed by filtration and the residual chloroform evaporated to get the desired product diethylamine- l,l,l',l'-d4 hydrochloride. Yield: 70%.
Intrinsic Clearance Determination:
Intrinsic Clearance Determination of synthesised compounds and different drug compounds was carried out as the procedure described below.
Incubation Conditions:
Test compound concentration 1 µM
Microsomal protein concentration 0.5 mg/mL
NADPH concentration 1 mM
Buffer 100 mM Potassium Phosphate Buffer pH 7.4
Temperature 37oC
Preincubation 10 min
Actual incubation duration 45 min
Quenching solution Acetonitrile containing internal standard
Matrix Mouse
Procedure:
Buffer and microsomes were mixed and preincubated for 10 min. After preincubation compound and NADPH were added to the incubation mixture and the reaction is initiated. Incubations were carried out in duplicate. 50 µl of aliquot was collected at each time point of 0, 5, 10, 20, 30 and 45 min and quenched with 150 µl of Acetonitrile containing internal standard. Samples are then briefly vortexed and centrifuged at 4000 rpm for 10 min and supernatant transferred to 2ml vials for drying and further reconstituted and loaded for LC-MS /MS analysis.
Calculation:

Table 1: Intrinsic Clearance Determination of Atenolol in Mouse Liver Microsomes (MLM)
Intrinsic Clearance Determination-Mouse Liver Microsomes
Compound Name of the sample Drug Area IS Area Area Ratio %PCR Time Pointmin ln Slope Clint Avg. Clint Time
(min) ln %PCR
Atenolol 0
Min-1 26082 315808 0.0826 100.00 0 4.605 0.005 9.49 8.43 0 4.61
5
Min-1 26518 313681 0.0845 102.30 5 4.628 5 4.63
10
Min-1 26535 353027 0.0752 91.04 10 4.511 10 4.51
20
Min-1 29900 360674 0.0829 100.36 20 4.609 20 4.61
30 Min-1 25264 362510 0.0697 84.38 30 4.435 30 4.44
45
Min-1 22611 333946 0.0677 81.96 45 4.406 45 4.41
0
Min-2 25727 360686 0.0713 100.00 0 4.605 0.04 7.38 0 4.61
5
Min-2 26962 351229 0.0768 107.71 5 4.679 5 4.68
10
Min-2 27294 357017 0.0765 107.29 10 4.676 10 4.68
20
Min-2 27189 359076 0.0757 106.17 20 4.665 20 4.67
30
Min-2 23252 363364 0.0640 89.76 30 4.497 30 4.50
45
Min-2 21025 324279 0.0648 90.88 45 4.510 45 4.51
45 Min
(-NA DPH)-1 24890 360282 0.0691 83.66 45 % Stability in microsomes at 45 mins (Without NADPH)
45 Min (-NA DPH)-2 26188 359989 0.0727 101.96 45

Table 2: Intrinsic Clearance Determination of Verapamil in Mouse Liver Microsomes (MLM)
Intrinsic Clearance Determination-Mouse Liver Microsomes
Compound Name of the sample Drug Area IS Area Area Ratio %PCR Time Pointmin ln Slope Clint Avg. Clint Time
(min) ln %PCR

Verapamil

Verapamil

Verapamil 0
Min-1 261323 347553 0.7519 100.00 0 4.605 0.068 135.37 135.78 0 4.61
5
Min-1 119037 350180 0.3399 45.21 5 3.811 5 3.81
10
Min-1 66889 352704 0.1896 25.22 10 3.227 10 3.23
20
Min-1 40177 349775 0.1149 15.28 20 2.727 20 2.73
30
Min-1 28000 346689 0.0808 10.75 30 2.375 30 2.37
45
Min-1 8978 348344 0.0258 3.43 45 1.233 45 1.23
0 Min-2 264562 350120 0.7556 100.00 0 4.605
0.068
136.18 0 4.61
5
Min-2 119318 351079 0.3399 44.98 5 3.806 5 3.81
10
Min-2 65828 346754 0.1898 25.12 10 3.224 10 3.22
20 Min-2 39974 350549 0.1140 15.09 20 2.714 20 2.71
30 Min-2 27992 351258 0.0797 10.55 30 2.356 30 2.36
45 Min-2 8810 346086 0.0255 3.37 45 1.216 45 1.22
45 Min (-NA DPH)-1 267238 345602 0.7733 102.85 45 % Stability in microsomes at 45 mins (Without NADPH)
45 Min (-NA DPH)-2 260796 349040 0.7472 98.89 45
Table 3: Intrinsic Clearance Determination of Amfepramone in Mouse Liver Microsomes (MLM)
Intrinsic Clearance Determination-Mouse Liver Microsomes
Compound Name of the sample Drug Area IS Area Area Ratio %PCR Time Ptmin ln Slope Clint Avg. Clint Time
(min) ln %
PCR
Amfepramone 0
Min-1 20988 308632 0.0680 100.00 0 4.605 0.003 5.87 4.89 0 4.61
5
Min-1 21867 311558 0.0702 103.24 5 4.637 5 4.64
10
Min-1 21489 311401 0.0690 101.47 10 4.620 10 4.62
20 Min-1 20243 317709 0.0637 93.68 20 4.540 20 4.54
30 Min-1 19593 318816 0.0615 90.44 30 4.505 30 4.50
45 Min-1 19948 320929 0.0622 91.47 45 4.516 45 4.52
0
Min-2 21144 308558 0.0685 100.00 0 4.605 0.002 3.91 0 4.61
5
Min-2 20456 313602 0.0652 95.18 5 4.556 5 4.56
10
Min-2 20307 314020 0.0647 94.45 10 4.548 10 4.55
20 Min-2 20059 319209 0.0628 91.68 20 4.518 20 4.52
30 Min-2 19949 319941 0.0624 91.09 30 4.512 30 4.51
45 Min-2 19712 318280 0.0619 90.36 45 4.504 45 4.50
45 Min (-NA DPH)-1 22154 304661 0.0727 106.91 45 % Stability in microsomes at 45 mins (Without NADPH)
45 Min (-NA DPH)-2 21291 306679 0.0694 101.31 45

Table 4: Intrinsic Clearance Determination of Amfepramone-D13 in Mouse Liver Microsomes (MLM)
Intrinsic Clearance Determination-Mouse Liver Microsomes
Compound Name of the sample Drug Area IS Area Area Ratio %PCR Time Ptmin ln Slope Clint Avg. Clint Time
(min) ln %
PCR
Amfepramone_D13 0
Min-1 44306 376095 0.1178 100.00 0 4.605 0.001 1.25 2.21 0 4.61
5
Min-1 48043 379297 0.1267 107.56 5 4.678 5 4.68
10
Min-1 40301 380180 0.1060 89.98 10 4.500 10 4.50
20 Min-1 49287 388698 0.1268 107.64 20 4.679 20 4.68
30 Min-1 50521 379110 0.1333 113.16 30 4.729 30 4.73
45 Min-1 40152 372596 0.1078 91.51 45 4.516 45 4.52
0
Min-2 49811 369067 0.1350 100.00 0 4.605 0.002 3.18 0 4.61
5
Min-2 48146 376004 0.1280 94.81 5 4.552 5 4.55
10
Min-2 49248 376954 0.1306 96.74 10 4.572 10 4.57
20 Min-2 46551 378992 0.1228 90.96 20 4.510 20 4.51
30 Min-2 50926 386346 0.1318 97.63 30 4.581 30 4.58
45 Min-2 45537 375002 0.1214 89.95 45 4.499 45 4.50
45 Min (-NADPH)-1 49133 382129 0.1286 109.17 45 % Stability in microsomes at 45 mins (Without NADPH)
45 Min (-NADPH)-2 44002 372841 0.1180 87.41 45
Liver Microsomal Intrinsic Clearance data Summary:
Compound Name Intrinsic clearance (µL/min/mg protein)
Mouse Liver Microsomes
Atenolol 8.43
Verapamil 135.78
Amfepramone 4.89
Amfepramone D13 2.21

Analysis of Intrinsic Clearance (Clint):
Based on the intrinsic clearance values provided, here is a summary of the metabolic resistance and pharmacokinetics of Amfepramone-D13 and Amfepramone. A lower intrinsic clearance value generally indicates better metabolic resistance and more favorable pharmacokinetics, as the compound is metabolized more slowly.
Mouse Liver Microsomes:
Amfepramone-D13 shows better metabolic resistance with a clearance value of 2.21 µL/min/mg protein, compared to Amfepramone's 4.89 µL/min/mg protein. This suggests that in mice, Amfepramone D13 would likely have a longer half-life.

We claim
1. A compound of formula I represented by

Wherein R1 to R19 are independently selected from hydrogen (H), deuterium (D), C1 to C5 alkyl, aryl group.
2. The compound of formula I as claimed in claim 1, wherein R1 to R5, R6 to R8, R9, R15 to R16, R13 to R14 are deuterium (D); and R10 to R12 and R17 to R19 are hydrogen(s).
3. The compound of formula I as claimed in claim 1, wherein R1 to R19 are deuterium (D).
4. The compound of formula I as claimed in claim 1, wherein the compound of formula I is I-D13 (Amfepramone-D13) or I-D19 (Amfepramone-D19).
5. A process for synthesising the compound of formula I, the process comprising:
a) treating a compound of formula 1 with a compound of comula 2 in presence of metal (M), halogen (X) in a solvent to obtain a compound of formula 3;

b) reacting the compound of formula 3 with a halogenating agent in presence of a base in a solvent to obtain a compound of formula 4;

c) contacting the compound of formula 4 with a compound of formula 5A or 5B in presence of metal halide (M-X) in presence of a base in a solvent to obtain a compound of formula I.

6. The process as claimed in claim 5, wherein compound 1 is bromobenzene-D5, compound 2 is N-methoxy-N-methylpropionamide-D5, compound 3 is Propiophenone-D10, compound 4 is 2-bromopropiophenone-D9, compound 5A is diethylamine-D4, compound 5B is diethylamine-D6.
7. The process as claimed in claim 5, wherein metal is selected from Pd, Pt, Ni, Rh, Cu, Li, Mg, Al, Na; preferably Mg; and halogen (X) is selected from fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I); preferably iodine (-I).
8. The process as claimed in claim 5, wherein halogenating agent is selected from Br2, phosgene, oxalyl dichloride, thionyl chloride, phosphorus pentachloride, phosphorous trichloride, phosphorus oxychloride, carbonyl dibromide, oxalyl bromide, thionyl bromide, phosphorous bromide and phosphorus oxybromide; preferably Br2.
9. The process as claimed in claimed 5, wherein metal halide (M-X) is selected from Sodium iodide (NaI), Sodium chloride (NaCl), Potassium chloride (KCl), Potassium iodide (KI), Lithium chloride (LiCl), Copper (II) chloride (CuCl2), Silver chloride (AgCl), Calcium chloride (CaCl2), Chlorine fluoride (ClF); preferably sodium iodide (NaI).
10. The process as claimed in claim 5, wherein solvent is selected from water, acetone, methyl ethyl ketone, methylisobutylketone (MIBK), dichloromethane, ethylene dichloride, chloroform, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile, ethyl acetate hexane, diethyl ether, tetrahydrofuran, methyl tetrahydrofuran, methanol, ethanol, isopropanol, n-propanol, tert-butanol, n-butanol and combinations thereof.

Dated this: Aug 11, 2025
Vijaykumar Shivpuje
IN-PA/1096
Agent for the Applicant
To
The Controller of Patents
The Patent Office, Mumbai

ABSTRACT
“DEUTERATED ANALOGUE OF AMFEPRAMONE COMPOUND AND PROCESS FOR SYNTHESISING THE SAME”

The present invention provides deuterated analogues of Amfepramone. Most particularly, it relates to deuterated analogues of Amfepramone compound of formula I and process for synthesising the same. The compound of formula I is represented by

Wherein R1 to R19 are independently selected from hydrogen (H), deuterium (D), C1 to C5 alkyl, aryl group.

,CLAIMS:We claim
1. A compound of formula I represented by

Wherein R1 to R19 are independently selected from hydrogen (H), deuterium (D), C1 to C5 alkyl, aryl group.
2. The compound of formula I as claimed in claim 1, wherein R1 to R5, R6 to R8, R9, R15 to R16, R13 to R14 are deuterium (D); and R10 to R12 and R17 to R19 are hydrogen(s).
3. The compound of formula I as claimed in claim 1, wherein R1 to R19 are deuterium (D).
4. The compound of formula I as claimed in claim 1, wherein the compound of formula I is I-D13 (Amfepramone-D13) or I-D19 (Amfepramone-D19).
5. A process for synthesising the compound of formula I, the process comprising:
a) treating a compound of formula 1 with a compound of comula 2 in presence of metal (M), halogen (X) in a solvent to obtain a compound of formula 3;

b) reacting the compound of formula 3 with a halogenating agent in presence of a base in a solvent to obtain a compound of formula 4;

c) contacting the compound of formula 4 with a compound of formula 5A or 5B in presence of metal halide (M-X) in presence of a base in a solvent to obtain a compound of formula I.

6. The process as claimed in claim 5, wherein compound 1 is bromobenzene-D5, compound 2 is N-methoxy-N-methylpropionamide-D5, compound 3 is Propiophenone-D10, compound 4 is 2-bromopropiophenone-D9, compound 5A is diethylamine-D4, compound 5B is diethylamine-D6.
7. The process as claimed in claim 5, wherein metal is selected from Pd, Pt, Ni, Rh, Cu, Li, Mg, Al, Na; preferably Mg; and halogen (X) is selected from fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I); preferably iodine (-I).
8. The process as claimed in claim 5, wherein halogenating agent is selected from Br2, phosgene, oxalyl dichloride, thionyl chloride, phosphorus pentachloride, phosphorous trichloride, phosphorus oxychloride, carbonyl dibromide, oxalyl bromide, thionyl bromide, phosphorous bromide and phosphorus oxybromide; preferably Br2.
9. The process as claimed in claimed 5, wherein metal halide (M-X) is selected from Sodium iodide (NaI), Sodium chloride (NaCl), Potassium chloride (KCl), Potassium iodide (KI), Lithium chloride (LiCl), Copper (II) chloride (CuCl2), Silver chloride (AgCl), Calcium chloride (CaCl2), Chlorine fluoride (ClF); preferably sodium iodide (NaI).
10. The process as claimed in claim 5, wherein solvent is selected from water, acetone, methyl ethyl ketone, methylisobutylketone (MIBK), dichloromethane, ethylene dichloride, chloroform, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile, ethyl acetate hexane, diethyl ether, tetrahydrofuran, methyl tetrahydrofuran, methanol, ethanol, isopropanol, n-propanol, tert-butanol, n-butanol and combinations thereof.