Title of Invention	"A PROCESS FOR THE SYNTHESIS OF 4-(1-ADAMANTYL)-2-SUBSTITUTED QUINOLINES EFFECTIVE FOR THE TREATMENT OF TUBERCULOSIS"
Abstract	The present invention deals with a process for the synthesis of 4-(l-adamantyl)-2-substituted quinolines. More preferably, a simple process to produce a novel ring-substituted quinoline derivatives of general formula (i) for the treatment and prevention of tuberculosis. Some of these new derivatives have shown excellent in vitro anti-tuberculosis activity against M. tuberculosis H37Rv strain. The above results clearly established the discovery of 4-(l-adamantyl)-2-substitutedquinolines as a new class of anti-tuberculosis agents, and therefore, these molecules are very attractive for further chemical and biological optimization. Moreover, majority of these compounds are prepared in economical short steps, they have excellent scope for further development as anti-tuberculosis agents. Furthermore, all these compounds are structurally different from existing anti-tuberculosis drugs; thus making them attractive for further development. It is expected that development of these compounds as ideal anti-tuberculosis agents will add to already existing armament for the treatment of infection caused by M. tuberculosis.

Title of Invention

"A PROCESS FOR THE SYNTHESIS OF 4-(1-ADAMANTYL)-2-SUBSTITUTED QUINOLINES EFFECTIVE FOR THE TREATMENT OF TUBERCULOSIS"

Abstract

The present invention deals with a process for the synthesis of 4-(l-adamantyl)-2-substituted quinolines. More preferably, a simple process to produce a novel ring-substituted quinoline derivatives of general formula (i) for the treatment and prevention of tuberculosis. Some of these new derivatives have shown excellent in vitro anti-tuberculosis activity against M. tuberculosis H37Rv strain. The above results clearly established the discovery of 4-(l-adamantyl)-2-substitutedquinolines as a new class of anti-tuberculosis agents, and therefore, these molecules are very attractive for further chemical and biological optimization. Moreover, majority of these compounds are prepared in economical short steps, they have excellent scope for further development as anti-tuberculosis agents. Furthermore, all these compounds are structurally different from existing anti-tuberculosis drugs; thus making them attractive for further development. It is expected that development of these compounds as ideal anti-tuberculosis agents will add to already existing armament for the treatment of infection caused by M. tuberculosis.

Full Text	TITLE A process for the synthesis 4-(l-adamantyl)-2-substituted quinolines effective for the treatment of tuberculosis. FIELD OF THE INVENTION The present invention deals with a process for the synthesis of 4-(l-adamantyl)-2-substituted quinolines. More preferably, a simple process to produce a new structural class of anti-tuberculosis agents of general formula (i), which offer an improved and additional means for the treatment and prevention of tuberculosis. (Formula Removed) Wherein R represents side-chain present in all D/L amino acids, RI represents -H, CHs; C2Hs; C3H7; NHNH2; CO2C(CH3)3; CO2CH2C6H5; CO2CH3; CO2C2H5; CO3C2H7. The development of these compounds offers and adds one more line of drugs for the treatment and control of disease caused by Mycobacterium tuberculosis. BACKGROUND OF THE INVENTION Development of resistance to known drugs is a growing phenomenon and now has reached alarming levels for certain infectious diseases. Tuberculosis (TB) has staged a deadly comeback primarily because of resistance development by the causative organism, Mycobacterium tuberculosis against all major anti-TB drugs, and the rising incidence of immuno-compromised situations partly due to cancer chemotherapy, AIDS infection and transplantation. Approximately, 32% of the world's population is currently infected with TB. Each year, eight to nine million of infected people develop clinical pulmonary TB, leading to more than 2 million deaths around world. If this trend continues, TB is likely to claim more than 35 million lives within the next decade. Although regimens exist for treating tuberculosis, they are far from ideal. Treatment usually involves a combination of first line of TB drugs — Isoniazid (INH) and Rifampicin (RIF), which are given for at least 6 months, and pyrazinamide and ethambutol (or streptomycin), which are used only in the first 2 months of treatment. This complex and long treatment regimen was rarely followed strictly and patients usually stop taking medicine once common symptoms of TB disappear. To make this regimen workable a program of Directly Observed Treatment, Short course (DOTS) is recommended by World Health Organization (WHO). Statistics suggest that currently one-fourth of the world's TB patients were treated under DOTS. Inconsistent or partial treatment leads to the development and spread of drug-resistant strains. These strains have a much lower cure rate and can be up to 100-fold more expensive to treat. There is thus an urgent need for shorter, simpler therapeutic and prophylactic regimens to increase patient compliance. In addition, new drugs are needed to combat the increasing number of multi-drug-resistant strains (MDR-TB). Treatment for MDR-TB often requires the use of a second line of TB drugs, all of which can produce serious side effects. Therapy for 18 months to 2 years may be necessary, and patients should receive at least three drugs to which the bacteria are susceptible. The survival rate for patients with MDR-TB is approximately 50 percent. The inadequate armory of drugs in widespread use for the treatment, and development of drug-resistant forms of the disease against most commonly used mainstay drugs INH and RIF have severely curtailed fight against TB. Despite this it has been nearly forty years since a new structural class of drug was introduced specifically to treat this infectious disease. This underscores the continuing urgent need for the discovery of new structural classes of anti-tuberculosis agents to replace and/or to supplement the current drug regimens. OBJECT OF INVENTION The principal object of the present invention is to develop a simple process for the production of anti-tuberculosis agent [4-(l-adamantyl)-2-substituted quinolines] STATEMENT OF INVENTION Accordingly, the present invention is about a process for the producing 4-(l-adamantyl)-2-substituted quinolines derivatives for the treatment and prevention of tuberculosis comprising general formula (i) (Formula Removed) Wherein "X" is selected from formula (ii) or (iii) (Formula Removed) wherein, R represents side-chain present in all D and L amino acids, R1 represents -H, H3; C2H5; C3H7; NHNH2; CO2C(CH3)3; CO2CH2C6H5; CO2CH3; CO2C2H5; CO3C2H7. DETAILED DESCRIPTION OF THE INVENTION The present invention provides a process for producing 4-(l-adamantyl)-2-substituted quinolines derivatives of general formula (i) for the treatment and prevention of tuberculosis. Some of these new derivatives have shown excellent in vitro anti-tuberculosis activity against M. tuberculosis H37Rv strain. All these compounds are structurally different from so far existing anti-tuberculosis drugs; thus making it attractive for further development. It is expected that development of these compounds as ideal anti-tuberculosis agents will add to already existing armament for the suppression as well as radical cure of the tuberculosis infection. 4-(Adamantan-l-yl)-quinoline-2-carboxylic acid (4) was synthesized in three steps from commercially available quinoline-2-carboxylic acid (1). The latter compound 4 upon reaction with thionyl chloride in the presence of pyridine for one minute produced acid chloride derivative in situ, which upon subsequent reaction with commercially available suitably side-chain protected L/D-amino acid methyl esters in the presence of 4-(dimethylamino)pyridine (DMAP) in Dichloromethane (DCM) provided methyl esters 5-12 in good yields (Scheme 1). The methyl esters 5-12 upon reaction with hydrazine hydrate in presence of abs. ethanol for 48 h at ambient temperature produced 4-(adamantyl-l-yl)- quinoline-2-carboxylic acid (1-hydrazinocarbonylalkyl) amides 13-17. For some compounds (where side chain is protected i.e. Om, Lys with carbobenzyloxy and Tyr with benzyl) an additional deprotection step was performed. The deprotection at the side-chain was achieved by reaction with 33% HBr in acetic acid at ambient temperature for 30 min to produce 4-(adamantyl-l-yl)-quinoline-2-carboxylic acid (l-hydrazinocarbonyl-alkyl)amides 18-20 as their hydrobromide salts in excellent yields (Scheme 1). (Formula Removed) Scheme 7, (i) abs. EtOH, HCI gas, 4 °C, 2h; (ii) 1-adamantanecarboxylic acid, AgNO3, (NH4)2S208, CH3CN, 10% H2S04, 15 min; (iii) 6N HCI, 100 °C, 8 h; (iv) SOCI2, C5H5N, 1min, DMAP, H2N-AA-OMe, 20 min; (v) NH2NH2.H20, abs. EtOH, 48h, rt; 33% HBr-AcOH, 30 min, rt. (Formula Removed) 4-(Adamantan-l-yl)-quinoline-2-carbohydrazide (21) required for the synthesis of 22-31 was synthesized in three convenient steps from commercially available quinoline-2-carboxylic acid (1). The latter compound 21 upon reaction with suitably side-chain protected commercially available Boc/Cbz-L/D-amino acids in the presence of 1,3-dicyclohexylcarbodiimide (DCC) and DMAP in anhydrous DCM as solvent for 8 h afforded Boc/Cbz-group protected quinoline-amino acid conjugates (S)-{l-[N'-(4-adamantan-l-yl-quinoline-2-carbonyl)-hydrazinecarbonyl]alkyl carbamic acid tert-butyl esters 22-31 (Scheme 2). The latter compounds 22-31 upon reaction with 33% hydrogen bromide solution in acetic acid at ambient temperature for 30 min easily and cleanly produced 4-(adamantan-l-yl)quinoline-2-carboxylic ,N'-(2-aminoalkyl)hydrazides 32-40 as hydrobromide salt (Scheme 2). (Formula Removed) Scheme2. (i) NH2NH2.H2O, EtOH, 80 °C, 8 h; (ii) DCC, DMAP, Boc-AA-OH, 8h, DCM; (iii) 33% HBr-AcOH, 30 min, rt or HCI-MeOH, 8h, rt, Advantageously, this compound may be formulated so as to prepare tablets, pellets, pills or capsule, for which the binders are selected from glycol, ethyl cellulose, starch paste, poly viryl pyrrolidone. Lubricants are selected from vegetable oils, stearic acid, Magnesium stearate, Aluminium Stearate. Glidant is selected from Colloidal silicon dioxide, cab-o-sil, talc and Disintegrant is selected from crossed linked poly vinyl pyrrolidone, cross carmilose, sodium starch glycolate. The invention is illustrated by the following examples which are not to be construed as limitations on the inventive concept. The examples are meant only for illustration and all embodiments that may be apparent to a person skilled in the art are deemed to fall within the scope thereof. The following are non-limiting examples showing the composition, property, application and antimicrobial activity of the instant antimicrobial herbal composition. EXAMPLES EXPERIMENTAL Synthesis of quinoIine-2-carboxylic acid ethyl ester (2, Scheme 1) To a suspension of quinoline-2-carboxylic acid (1, 2 g, 12 mmol) in abs. ethyl alcohol (150 mL), dry hydrogen chloride gas was purged at 4 °C for 2 h. The reaction mixture was left overnight at ambient temperature and solvent evaporated under reduced pressure to afford quinolin-2-carboxylic acid ethyl ester hydrochloride salt. The hydrochloric salt of the quinoline-2-carboxylic acid ethyl ester was suspended in dichloromethane (250 mL) and heutralized by drop wise addition of 25% NH4OH solution. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure to produce quinoline-2-carboxylic acid ethyl ester (2). Yield: 78%; oil; 1H NMR (CDC13): δ 8.33 ( m, 2H, 4 & 8-Ar-H), 8.19 (d, 1H, 5-Ar-H, J= 8.5 Hz), 7.89 (d, 1H, 3-Ar-H, J= 6.6 Hz), 7.79 (m, 1H, 7-Ar-H), 7.65 (m, 1H, 6-Ar-H), 4.57 (q, 2H, CH2, J= 14.2 Hz), 1.49 (t, 3H, CH3, J= 7.1 Hz); ESIMS: m/z 202 (M+l); Analysis for C12H11N2O (201.2), calcd: C, 76.07; H, 6.38; N, 3.65; found: C, 76.03; H, 6.25; N, 3.59. Synthesis of 4-adamantan-l-yl-quinoline-2-carboxylic acid ethyl ester (3, Scheme 2) Quinoline-2-carboxylic acid ethyl ester (2, 2 g, 10 mmol), was added to a mixture of AgNO3 (0.9 g, 5.2 mmol) and 1-adamantane carboxylic acid (4.9 g, 32 mmol) in 10% H2SO4 (17 mL) and acetonitrile (8 mL). The reaction mixture was heated at 70-80°C. A freshly prepared solution of ammonium persulfate (6.67 g, 30 mmol) in water (10 mL) was added drop wise over 15 min. The heating source was then removed and reaction proceeded with the evolution of carbon dioxide. After 15 min, the reaction was terminated by pouring it on ice. The resulting mixture was made alkaline with 25% NH4OH solution and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with brine (2 x 25 mL) and dried (Na2SO4). The solvent was removed under reduced pressure to afford crude product, which upon chromatographic purification over silica gel (230-400 mesh) using ethyl acetate:hexanes (10:90) produced 4-adamantan-l-yl-quinoline-2-carboxylic acid ethyl ester 3. Yield: 48%; mp: 124-126 °C; 1HNMR (CDC13): δ 8.65 (d, 1H, 8-Ar-H, J= 8.80 Hz), 8.34 (d, 1H, 5-Ar-H, J= 8.60 Hz), 7.89 (s, 1H, 3-Ar-H), 7.79 (m, 1H, 7-Ar-H), 7.65 (m, 1H, 6-Ar-H), 4.57 (q, 2H, CH2, J= 14.1 Hz), 1.88 (m, 15H, adamantyl protons), 1.49 (t, 3H, CH3, J= 7.1 Hz); ESIMS: m/z 336 (M+l); Analysis for C22H25NO2 (335.4), calcd: C, 78.77; H, 7.51; N, 4.18; found: C, 78.77; H, 7.56; N, 4.28. Synthesis of 4-adamantan-l-yl-quinoline-2-carboxylic acid (4, Scheme 1) A solution of 4-adamantan-l-yl-quinoline-2-carboxylic acid ethyl ester (3, 2 g, 10 mmol) in 6N HC1 (20 mL) was heated at reflux temperature for 8 h. Mono hydrochloride salt of 4- adamantan-l-yl-quinoline-2-carboxylic acid (4) was obtained directly by evaporation of the acid hydrolysis solution. Yield: 95%; mp: 124-126 °C; 1HNMR (CD3OD): δ 8.47 ( d, 1H, 8-Ar-H, J= 8.5 Hz), 7.95 (d, 1H, 5-Ar-H, J= 7.1 Hz), 7.77 (s, 1H, 3-Ar-H), 7.54 (m, 1H, 7-Ar-H), 7.44 (m, 1H, 6-Ar-H), 1.88 (m, 15H, adamantyl protons); ESIMS: m/z 308 (M+l); Analysis for C20H22ClNO2 (343.8), calcd: C, 69.86; H, 6.45; N, 4.07; found: C, 69.92; H, 6.63; N, 4.32. Synthesis of 4-adamantan-l-yl-quinoline-2-carboxylic acid hydrazide (21, Scheme 2) To a solution of 4-adamantan-l-yl-quinoline-2-carboxylic acid ethyl ester (2, 1 g, 3 mmol) in 95% ethyl alcohol (15 mL), hydrazine hydrate (1 mL, 25 mmol) was added, and reaction mixture was heated at 80 °C for 8 h. 4-Adamantan-l-yl-quinoline-2-carboxylic acid hydrazide 21 was obtained directly after evaporation of the reaction solution. Yield: 98%; mp: 142-150 °C; 1H NMR (CDC13): 5 8.67 (d, 1H, 8-Ar-H, J= 8.4 Hz), 8.18 (s, 1H, 3-Ar-H), 8.12 (d, 1H, 5-Ar-H, J= 8.3 Hz), 7.69 (m, 1H, 7-Ar-H), 7.59 (m, 1H, 6-Ar-H), 1.88 (m, 15H, adamantyl protons); ESIMS: m/z 322 (M+l); Analysis for C20H23N3O (321.4), calcd: C, 74.74; H, 7.21; N, 13.07; found: C, 74.81; H, 7.31; N, 13.01. General procedure for the synthesis of methyl-2-[4-(l-adamantyl)-2-quinonylcarboxamido] alkanoate 5-12 (Scheme 1) To a mixture of 4-(adamantan-l-yl)-quinoline-2-carboxylic acid (4, 0.324 g, 0.94 mmol) and pyridine (112 µL, 148 mmol) in anhydrous DCM (15 mL), SOC12 (95 µL, 1.35 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 1 min. To intermediate acid chloride was added drop wise a solution of desired L/D-amino acid ester (0.82 mmol) and DMAP (0.81 mmol) in DCM (10 mL) via a syringe during 5 min. The reaction mixture was stirred for another 20 min at ambient temperature. The reaction mixture was diluted with DCM (50 mL) and washed with water (2 x 25 mL) and brine solution (25 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to produce crude product, which was purified by column chromatography on silica gel (60-120 mesh) using ethyl acetate:hexane (10:90) as eluant to provide methyl-2-[4-(l-adamantyl)-2-quinonylcarboxamido]alkanoate 5-12. Methyl (25)-2-[4-(l-adamantyl)-2-quinonyIcarboxamido]propanoate (5) Yield: 7%; oil; IR (neat): 3380 cm'1 (amine), 1741 (amide); 1H NMR (CDC13): δ 8.69 (bs, 1H, NH, exchangeable witn D2O), 8.66 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.20 (m, 2H, 5-Ar-H & 3-Ar-H), 7.69 (m, 1H, 7-Ar-H), 7.55 (m, 1H, 6-Ar-H), 4.21 (m, 1H, a-CH), 3.80 (s, 3H, OCH3), 1.88 (m, 15H, adamantyl protons), 1.60 (d, 3H, CH3, J= 6.8 Hz); ESIMS: m/s 393 (M+l); Analysis for C24H28N2O3 (392.4), calcd: C, 73.44; H, 7.19; N, 7.14; found: C, 73.32; H, 7.17; N, 12.19. Methyl (2S, 3S)-2-[4-(l-adamantyl)-2-quinonylcarboxamido]-3-methylpentanoate (6) Yield: 14%; oil; IR (neat): 3391 cm-1 (amine), 1701 (amide); 1H NMR (CDC13): δ 8.74 (bs, 1H, NH, exchangeable witn D2O), 8.66 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.21 (m, 2H, 5-Ar-H & 3-Ar-H), 7.70 (m, 1H, 7-Ar-H), 7.60 (m, 1H, 6-Ar-H), 4.83 (m, 1H, α-CH), 3.78 (s, 3H, OCH3), 1.88 (m, 15H, adamantyl protons), 1.33 (m, 1H, CH), 1.25 (m, 2H, CH2), 1.10 (m, 6H, 2 x CH3); ESIMS: m/z 435 (M+l); Analysis for C27H34N2O3 (434.5), calcd: C, 74.62: H, 7.89; N, 6.45; found: C, 74.64; H, 7.75: N, 6.38. Methyl (2S)2-[4-(l-adamantyl)-2-quinonylcarboxamido]-4-methyIpentanoate (7) Yield: 14%; oil; IR (neat): 3412 cm'1 (amine), 1720 (amide); 1H NMR (CDC13): δ 8.66 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.59 (bs, 1H, NH, exchangeable witn D2O), 8.24 (s, 1H, 3-Ar-H), 8.19 (d, 1H, 5-Ar-H, J= 7.6 Hz), 7.70 (m, 1H, 7-Ar-H), 7.57 (m, 1H, 6-Ar-H), 4.89 (m, 1H, α-CH), 3.78 (s, 3H, OCH3), 1.88 (m, 15H, adamantyl protons), 1.81 (m, 2H, CH2), 1.25 (m, 1H, CH), 1.10 (m, 6H, 2 x CH3); ESIMS: m/z 435 (M+l); Analysis for C27H34N2O3 (434.5), calcd: C, 74.62; H, 7.89; N, 6.45; found: C, 74.65; H, 7.83; N, 6.38. Methyl (2S)-2-[4-(l-adamantyl)-2-quinonylcarboxamido]-4-methylsulfanyIbutanoate (8) Yield: 24%; oil; IR (neat): 3379 cm-1 (amine), 1731 (amide); 1H NMR (CDC13): δ 8.78 (bs, 1H, NH, exchangeable witn D2O), 8.66 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.20 (m, 2H, 5-Ar-H & 3-Ar-H), 7.70 (m, 1H, 7-Ar-H), 7.57 (m, 1H, 6-Ar-H), 4.97 (m, 1H, a-CH), 3.82 (s, 3H, OCH3), 2.13 (s, 3H, SCH3), 1.88 (m, 15H, adamantyl protons), 1.59 (m, 2H, CH2), 1.25 (m, 2H, CH2); ESIMS: m/z 453 (M+l); Analysis for C26H32N2O3S (452.2), calcd: C, 68.99; H, 7.13; N, 6.19; found: C, 68.93; H, 7.07; N, 6.15. Methyl (2S)-2-[4-(l-adamantyl)-2-quinonylcarboxamido]-(lH-4-imidazolyl)propaonoate (9) Yield: 8%; oil; IR (neat): 3352 cm-1 (amine), 1703 (amide); 1H NMR (CDC13): δ 9.12 (bs, 1H, NH, exchangeable with D2O), 8.72 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.25 (d, 1H, 5-Ar-H, J= 9.8 Hz), 8.17 (s, 1H, 3-Ar-H), 7.90 (s, 1H, imid-Ar-H), 7.76 (m, 1H, 7-Ar-H), 7.67 (m, 1H, 6-Ar-H), 6.25 (s, 1H, imid-Ar-H), 4.20 (m, 1H, a-CH), 3.86 (s, 3H, OCH3), 2.28 (m, 2H, CH2), 1.88 (m, 15H, adamantyl protons); ESIMS: m/z 459 (M+l); Analysis for C24H30N4O3 (458.6), calcd: C, 70.72; H, 6.59; N, 12.22; found; C, 70.54; H, 5.47; N, 12.17. Methyl (2S)-2-l4-(l-adamantyl)-2-quinonylcarboxamido]-5-benzyloxycarbonylamino)-pentanoate (10) Yield: 29%; oil; IR (neat): 3400 cm-1 (amine), 1715 (amide); 1H NMR (CDC13): δ 8.72 (bs, 1H, NH, exchangeable witn D2O), 8.65 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.20 (m, 2H, 3-Ar-H & 5- Ar-H), 7.69 (m, 1H, 7-Ar-H), 7.57 (m, 1H, 6-Ar-H), 7.33 (m, 5H, phenyl), 5.08 (s, 2H, CH2), 4.84 (m, 1H, α-CH), 3.70 (s, 3H, OCH3), 3.26 (m, 2H, N-CH2), 1.88 (m, 15H, adamantyl protons), 1.24 (m, 4H, 2 x CH2); APCIMS: m/z 570 (M+l); Analysis for C34H39N3O5 (569.7), calcd: C, 71.68; H, 6.90; N, 7.38; found: C, 71.62; H, 6.55; N, 7.32. Methyl (2S)-2-[4-(l-adamantyl)-2-quinonylcarboxamido]-6-benzyIoxycarbonylamino)-hexanoate (11) Yield: 25%; oil; IR (neat): 3381 cm-1 (amine), 1728 (amide); 1H NMR (CDC13): δ 8.72 (bs, 1H, NH, exchangeable witn D2O), 8.65 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.20 (m, 2H, 3-Ar-H & 5-Ar-H), 7.69 (m, 1H, 7-Ar-H), 7.57 (m, 1H, 6-Ar-H), 7.30 (m, 5H, phenyl), 5.05 (s, 2H, CH2), 4.87 (m, 1H, α- CH), 3.79 (s, 3H, OCH3), 3.18 (m, 2H, N-CH2), 1.88 (m, 15H, adamantyl protons), 1.48 (m, 6H, 3 x CH2); ESIMS: m/z 584 (M+l); Analysis for C35H41N3O5 (583.7), calcd: C, 72.02; H, 7.08; N, 7.20; found: C, 72.09; H, 7.15; N, 7.25. Methyl (2S)-2-[4-(l-adamantyI)-2-quinonylcarboxamido]-3-(4-benzyloxyphenyl)prop-anoate (12) Yield: 8%; oil; IR (neat): 3344 cm-1 (amine), 1718 (amide); 1H NMR (CDC13): δ 8.78 (bs, 1H, NH, exchangeable witn D2O), 8.67 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.21 (s, 1H, 3-Ar-H), 8.13 (d, 1H, 5-Ar-H, .J= 8.3 Hz), 7.69 (m, 1H, 7-Ar-H), 7.57 (m, 1H, 6-Ar-H), 7.36 (m, 5H, Ar-H), 7.15 (d, 2H, Ar-H, J= 8.5 Hz), 6.91 (d, 2H, Ar-H, J= 8.6 Hz), 5.06 (s, 2H, CH2), 4.08 (m, 1H, a-CH), 3.74 (s, 3H, OCH3), 3.23 (m, 2H, CH2), 1.88 (m, 15H, adamantyl protons); ESIMS: m/z 575 (M+l); Analysis for C37H38N2O4 (574.7), calcd: C, 77.33; H, 6.66; N, 4.87; found: C, 77.18; H, 6.52; N, 4.80. General procedure for the synthesis of N2-[l-hydrazinocarbonylalkyl]-4-(l-adamantyl)-2-quinolinecarboxamides 13-20 (Scheme 1) To the solution of methyl-2-[4-(l-adamantyl)-2-quinonylcarboxamido]alkanoate (5-12, 0.1 mmol) in abs. ethyl alcohol (10 mL), hydrazine hydrate (0.5 mL, 12.5 mmol) was added and reaction mixture was stirred for 48 h at ambient temperature, solvent was removed under reduced pressure to afford N2-[l-hydrazinocarbonylalkyl]-4-(l-adamantyl)-2-qumolinecarboxamide (6a-e, i) in quantitative yields. In certain cases where side chain of amino acid ester were protected i.e. Orn, Lys with carbobenzyloxy, and Tyr with benzyl and additional deprotection step was carried out. A solution of 33% HBr in acetic acid (2 mL) was added to 5f-h (0.1 mmol) and reaction mixture was stirred at ambient temperature for 30 min. Solvent was removed under reduced pressure to afford compounds 6f-h as their hydrobromide salts in excellent yields. N2-[(1S)-l-hydrazinocarbonylethyl]-4-(l-adamantyl)-2-quinoline carboxamide (13) Yield: 95%; semi-solid; 1H NMR (CDC13): δ 8.66 (d, IH, 8-Ar-H, J= 8.7 Hz), 8.53 (bs, IH, NH, exchangeable with D2O), 8.18 (m, 2H, 5-Ar-H & 3-Ar-H), 7.73 (m, lH, 7-Ar-H), 7.58 (m, lH, 6-Ar-H), 4.71 (m, lH, a-CH), 1.88 (m, 15H, adamantyl protons), 1.60 (d, 3H, CH3, J = 6.8 Hz); ESIMS: m/z 393 (M+l); Analysis for C23H28N4O2 (392.4), calcd: C, 70.38; H, 7.19; N, 14.27; found: C, 70.42; H, 7.21; N, 14.31. N2-[(1S, 2S)-l-hydrazinocarbonyI-2-methylbutyl]-4-(l-adamantyl)-2-quinoline carbox-amide (14) Yield: 95%; semi-solid; 1H NMR (CDC13): 5 8.66 (d, lH, 8-Ar-H, J= 8.4 Hz), 8.49 (bs, lH, NH, exchangeable with D2O), 8.18 (m, 2H, 5-Ar-H & 3-Ar-H), 7.72 (m, lH, 7-Ar-H), 7.58 (m, lH, 6-Ar-H), 4.67 (m, lH, α-CH), 1.88 (m, 15H, adamantyl protons), 1.31 (m, lH, CH), 1.21 (m, 2H, CH2), 1.10 (m, 6H, 2 x CH3); ESIMS: m/z 435 (M+l); Analysis for C26H34N4O2 (434.5), calcd: C, 71.86; H, 7.89; N, 12.89; found: C, 71.89; H, 7.91; N, 12.85. N2-[(1S)-l-hydrazinocarbonyl-3-methylbutyl]-4-(l-adamantyI)-2-quinoIine carboxamide (15) Yield: 95%; semi-solid; 1H NMR (CDC13): δ 8.67 (d, lH, 8-Ar-H, J= 8.3 Hz), 8.18 (m, 2H, 5-Ar-H & 3-Ar-H), 7.71 (m, lH, 7-Ar-H), 7.59 (m, lH, 6-Ar-H), 7.47 (bs, lH, NH, exchangeable with D2O), 4.44 (m, lH, α-CH), 1.88 (m, 15H, adamantyl protons), 1.61 (m, 2H, CH2), 1.25 (m, lH, CH), 0.99 (m, 6H, 2 x CH3); ESIMS: m/z 435 (M+l); Analysis for C26H34N4O2 (434.5), calcd: C, 71.86; H, 7.89; N, 12.89; found: C, 71.92; H, 7.95; N, 12.87. N2-[(1S)-l-hydrazinocarbonyl-3-methylsulfanylpropyl]-4-(l-adamantyl)-2-quinoline-carboxamide (16) Yield: 95%; semi-solid; 1H NMR (CDC13): δ 8.72 (bs, lH, NH, exchangeable witn D2O), 8.66 (d, lH, 8-Ar-H, J= 7.9 Hz), 8.17 (m, 2H, 5-Ar-H & 3-Ar-H), 7.69 (m, lH, 7-Ar-H), 7.59 (m, lH, 6-Ar-H), 4.85 (m, lH, a-CH), 2.64 (m, 2H, CH2), 2.13 (s, 3H, SCH3), 1.88 (m, 15H, adamantyl protons), 1.25 (m, 2H, CH2); ESIMS: m/z 453 (M+l); Analysis for C25H32N4O2S (452.2), calcd: C, 66.34; H, 7.13; N, 12.38; found: C, 66.37; H, 7.14; N, 12.28. N2-[(1S)-l-hydrazinocarbonyl-2(lH-4-imidazolyl)ethyl]-4-(l-adamantyl)-2-quinoline-carboxamide (17) Yield: 95%; semi-solid; 1HNMR (CDC13): δ 8.71 (d, lH, 8-Ar-H, J= 8.6 Hz), 8.25 (d, IH, 5-Ar-H, J = 9.6 Hz), 8.17 (s, lH, 3-Ar-H), 7.91 (s, IH, imid-Ar-H), 7.75 (m, lH, 7-Ar-H), 7.65 (m, lH, 6-Ar-H), 6.23 (s, lH, imid-Ar-H), 4.19 (m, lH, a-CH), 232 (m, 2H, CH2), 1.88 (m, 15H, adamantyl protons); ESIMS: m/z 459 (M+l); Analysis for C26H3oN6O2 (458.6), calcd: C, 68.10; H, 6.59; N, 18.33; found; C, 68.08; H, 6.57; N, 18.32. N2-[(1S)-l-hydrazinocarbonylbutyl]-4-(l-adamantyl)-2-quinolinecarboxamide.3HBr (18) Yield: 95%; semi-solid; 1H NMR (CD3OD): δ 9.10 (d, 1H, 8-Ar-H, J= 8.9 Hz), 8.54 (m, 2H, 5-Ar-H & 3-Ar-H), 8.14 (m, 1H, 7-Ar-H), 8.00 (m, 1H, 6-Ar-H), 4.85 (m, 1H, a-CH), 3.10 (m, 2H, N-CH2), 2.17 (m, 2H, CH2), 1.88 (m, 15H, adamntyl protons), 1.30 (m, 2H, CH2); MALDIMS: m/z 436 (M+l); Analysis for C25H36Br3N5O2 (678.3), calcd: C, 44.27; H, 5.35; N, 10.32; found: C, 44.21; H, 5.28; N, 10.27. N2-[(1S)-l-hydrazinocarbonylpentyl]-4-(l-adamantyl)-2-quinolinecarboxamide.3HBr (19) Yield: 95%; semi-solid; 1H NMR (CD3OD): δ 9.00 (d, 1H, 8-Ar-H, J= 8.8 Hz), 8.41 (d, IH, 5-Ar-H, J= 8.4 Hz), 8.36 (s, 1H, 3-Ar-H), 7.99 (m, 1H, 7-Ar-H), 7.87 (m, 1H, 6-Ar-H), 4.77 (m, 1H, a-CH), 2.98 (m, 2H, N-CH2), 2.09 (m, 2H, CH2), 1.88 (m, 15H, adamantyl protons), 1.30 (m, 4H, 2 x CH2); ESIMS: m/z 450 (M+l); Analysis for C26H38Br3N5O2 (692.3), calcd: C, 45.11; H, 5.53; N, 10.12; found: C, 45.07; H, 5.49; N, 10.07. N2-[(1S)-l-hydrazinocarbonyl-2-(4-hydroxyphenyl)ethyl]-4-(l-adamantyl)-2-quinoline-carboxamide. 2HBr (20) Yield: 95%; semi-solid; 1H NMR (CD3OD): δ 8.98 (d, 1H, 8-Ar-H, J= 8.8 Hz), 8.37 (d, 1H, 5-Ar-H, J= 8.3 Hz), 8.20 (s, 1H, 3-Ar-H), 8.02 (m, 1H, 7-Ar-H), 7.88 (d, 2H, Ar-H, J= 8.1 Hz), 7.17 (d, 2H, Ar-H, J= 8.1 Hz), 6.74 (d, 2H, Ar-H, J= 7.7 Hz), 3.34 (s, 2H, CH2), 1.88 (m, 15H, adamantyl protons); ESIMS: m/z 485 (M+l); Analysis for C29H34 Br2N4O3 (646.4), calcd: C, 53.88; H, 5.30; N, 8.67; found: C, 53.78; H, 5.27; N, 8.63. General procedure for the synthesis of {l-[(S)-N'-(4-Adamantan-l-yl-quinoline-2-carbonyl)-hydrazinocarbonyl] alkyl-carbamic acid tert-batyl esters (22-31, Scheme 2) To a solution of 4-(adamantan-l-yl)-quinoline-2-carbohydrazide (21, 0.1 g, 0.31 mmol) in DCM (15 mL), Boc-L/D-AA-OH (0.08 g, 0.35 mmol), DCC (0.07 g, 0.35 mmol) and DMAP (0.02 mg, 0.16 mmol) were added. The reaction mixture was stirred for 8 h at ambient temperature. Solvent was removed under reduced pressure to afford semi-solid residue. The residue was dissolved in ethyl acetate (3 mL) and kept in the refrigerator for 8 h. The precipitated dicyclohexylurea was removed by filtration, and solvent was removed under reduced pressure to afford crude product, which upon column chromatographic purification over silica gel (230-400 mesh) using ethyl acetate:hexane (8:92) gave compounds 22-31 in moderate yields. {l-[(S)-N'-(4-Adamantan-l-yl-quinoline-2-carbonyl)hydrazinocarbonyl]-{4-(N,N'-bis-benzyloxycarbonylguanidinobutyl}carbamic acid tert-butyl ester (22) Yield: 27%; mp: 180-182 °C (dec.); 1H NMR (CDC13): δ 9.60 (bs, 1H, NH, exchangeable with D2O), 9.45 (bs, 1H, NH, exchangeable with D2O), 9.34 (bs, 1H, NH, exchangeable with D2O), 9.13 (bs, 1H, NH, exchangeable with D2O), 8.66 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.11 (m, 2H, 3-Ar-H & 5-Ar-H), 7.70 (m, 1H, 7-Ar-H), 7.58 (m, 1H, 6-Ar-H), 7.25 (m, 10H, phenyl protons), 5.25 (s, 2H, CH2), 5.23 (s, 2H, CH2), 4.45 (m, 1H, α-CH), 2.04 (m, 2H, CH2), 1.88 (m, 15H, adamantyl protons), 1.72 (m, 2H, CH2), 1.45 (s, 9H, 3 x CH3), 1.33 (m, 2H, CH2); MALDIMS: m/z 846 (M+l); Analysis for C47H55O8 (845.9), calcd: C, 66.73; H, 6.55; N, 11.59; found: C, 66.79; H, 6.49; N, 11.55. [2-[(S)-N'-(4-Adamantan-l-yl-quinoline-2-carbonyl)hydrazino]-l-(3H-imidazol-4-ylmethyl)-2-oxoethyI ]carbamic acid tert-butyl ester (23) Yield: 30%; mp: 182-184 °C (dec.); 1H NMR (CDC13): δ 8.67 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.20 (s, 1H, 3-Ar-H), 8.14 (d, 1H, 5-Ar-H, J= 8.1 Hz), 7.70 (m, 1H, 7-Ar-H), 7.58 (m, 2H, 6-Ar-H & imid-Ar-H), 6.90 (s, 1H, imid-Ar-H), 5.62 (bs, 1H, NH, exchangeable with D2O), 4.57 (m, 1H, a-CH), 3.10 (m, 2H, CH2), 1.88 (m, 15H, adamantyl protons), 1.47 (s, 9H, 3 x CH3); MALDIMS: m/z 559 (M+l); Analysis for C31H38N6O4 (558.6), calcd: C, 66.65; H, 6.86; N, 15.04; found: C, 66.69; H, 6.89; N, 15.09. {5-[(S)-N'-(4-Adamantan-l-yl-quinoline-2-carbonyl)hydrazino]-4-tert-butoxycarbonyl-amino-5-oxopentyl}carbamic acid tert-butyl ester (24) Yield: 35%; mp: 175-177 °C (dec.); 1H NMR (CDC13): δ 10.11 (bs, 1H, NH, exchangeable with D2O), 9.25 (bs, 1H, NH, exchangeable with D2O), 8.65 (d, 1H, 8-Ar-H, J= 8.6 Hz), 8.14 (m, 2H, 3-Ar-H & 5-Ar-H), 7.69 (m, 1H, 7-Ar-H), 7.57 (m, 1H, 6-Ar-H), 4.51 (m, 1H, a-CH), 3.14 (m, 2H, CH2), 1.88 (m, 15H, adamantyl protons), 1.44 (s, 18H, 6 x CH3), 1.28 (m, 4H, 2 x CH2); MALDIMS: m/z 636 (M+1); Analysis for C35H49N5O6 (635.7), calcd: C, 66.12; H, 7.77; N, 11.02; found: C, 66.18; H, 7.79; N, 11.05. {6-[(S)-N'-(4-Adamantan-l-yl-quinoline-2-carbonyl)hydrazino]-5-tert-butoxycarbonyI-amino-6-oxohexyl }carbamic acid benzyl ester (25) Yield: 37%; mp: 178-180 °C (dec.); 1H NMR (CDC13): δ 9.48 (bs, 1H, NH, exchangeable with D2O), 8.65 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.19 (m, 2H, 3-Ar-H & 5-Ar-H), 7.69 (m, 1H, 7-Ar-H), 7.58 (m, 1H, 6-Ar-H), 7.31 (m, 5H, phenyl protons), 5.08 (s, 2H, CH2), 4.35 (m, 1H, α-CH), 3.19 (m, 2H, CH2), 1.88 (m, 15H, adamantyl protons), 1.52 (m, 6H, 3 x CH2), 1.42 (s, 9H, 3 x CH3); MALDIMS: m/z 684 (M+1); Analysis for C39H49N5O6 (683.8), calcd: C, 68.50; H, 7.22; N, 10.24; found: C, 68.54; H, 7.25; N, 10.29. [2-[(S)-N'-(4-Adamantan-l-yl-quinoline-2-carbonyl)hydrazino]-l-(lH-indoI-2-yl-methyI)-2-oxoethyl]carbamic acid tert-butyl ester (26) Yield: 32%; mp: 176-178 °C (dec.); 1H NMR (CDC13): δ 10.19 (bs, 1H, NH, exchangeable wiui D2O), 8.65 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.22 (bs, 1H, NH, exchangeable with D2O), 8.14 (m, 2H, 3-Ar-H & 5-Ar-H), 7.69 (m, 2H, 7-Ar-H, Ar-H), 7.52 (m, 1H, 6-Ar-H), 7.50 (m, 3H, Ar-H), 7.37 (d, 1H, Ar-H, J= 7.7 Hz), 4.20 (m, 1H, a-CH), 2.20 (s, 2H, CH2), 1.88 (m, 15H, adamantyl protons), 1.43 (s, 9H, 3 x CH3); MALDIMS: m/z 608 (M+1); Analysis for C36H41N5O4 (607.7), calcd: C, 71.15; H, 6.80; N, 11.52; found: C, 71.18; H, 6.85; N, 11.55. {2-[(S)-N'-(4-Adamantan-l-yl-quinoIine-2-carbonyl)hydrazino]-l-benzyl-2-oxoethyl}-carbamic acid tert-butyl ester (27) Yield: 35%; mp: 167-169 °C (dec.); 1H NMR (CDC13): δ 10.27 (bs, 1H, NH, exchangeable with D2O), 9.03 (bs, 1H, NH, exchangeable with D2O), 8.63 (d, 1H, 8-Ar-H, J= 8.2 Hz), 8.13 (m, 2H, 3-Ar-H & 5-Ar-H), 7.67 (m, 1H, 7-Ar-H), 7.55 (m, 1H, 6-Ar-H), 7.22 (m, 5H, phenyl protons), 4.56 (m, 1H, a-CH), 3.18 (d, 2H, CH2, J = 6.4 Hz), 1.88 (m, 15H, adamantyl protons), 1.38 (s, 9H, 3 x CH3); MALDIMS: m/z 569 (M+l); Analysis for C34H40N4O4 "368.7), calcd: C, 71.81; H, 7.09; N, 9.85; found: C, 71.84; H, 7.05; N, 9.80. {2-[(S)-N'-(4-Adamantan-l-yl-quinoline-2-carbonyl)hydrazino]-l-methyI-2-oxoethyl}-carbamic acid tert-butyl ester (28) Yield: 30%; mp: 173-175 °C (dec.); 1H NMR (CDC13): δ 8.61 (d, 1H, 8-Ar-H, J = 8.6 Hz), 8.10 (m, 2H, 3-Ar-H & 5-Ar-H), 7.64 (m, 1H, 7-Ar-H), 7.54 (m, 1H, 6-Ar-H), 4.56 (m, 1H, a-CH), 1.88 (m, 15H, adamantyl protons), 1.51 (d, 3H, CH3, J= 6.7 Hz), 1.44 (s, 9H, 3 x CH3); MALDIMS: m/z 493 (M+l); Analysis for C28H36N4O4 (492.6), calcd: C, 68.27; H, 7.37; N, 11.37; found: C, 68.29; H, 7.39; N, 11.42. [2-[(S)-N'-(4-Adamantan-l-yl-quinoline-2-carbonyl)hydrazino]-l-(4-benzyloxybenzyl)-2-oxoethyl]carbamic acid tert-butyl ester (29) Yield: 38%; mp: 173-175 °C (dec.); 1H NMR (CDC13): δ 10.29 (bs, 1H, NH, exchangeable with D2O), 8.66 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.16 (m, 2H, 3-Ar-H & 5-Ar-H), 7.70 (m, 1H, 7-Ar-H), 7.58 (m, 1H, 6-Ar-H), 7.36 (m, 5H, phenyl protons), 7.23 (d, 2H, Ar-H, J= 8.5 Hz), 6.92 (d, 2H, Ar-H, J= 8.5 Hz), 5.02 (s, 2H, CH2), 4.55 (m, 1H, α-CH), 3.15 (d, 2H, CH2, J = 6.5 Hz), 1.88 (m, 15H, adamantyl protons), 1.42 (s, 9H, 3 x CH3); MALDIMS: m/z 675(M+1); Analysis for C41H46N4O5 (674.8), calcd: C, 72.97; H, 6.87; N, 8.30; found: C, 72.95; H, 6.82; N, 8.35. {l-[(S)-N'-(4-Adamantan-l-yl-quinoline-2-carbonyl)hydrazinocarbonyl]-3-methyl-sulfanylpropyl}carbamic acid tert-butyl ester (30) Yield: 25%; mp: 175-177 °C (dec.); 1H NMR (CDC13): δ 8.63 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.14 (m, 2H, 3-Ar-H & 5-Ar-H), 7.62 (m, 1H, 7-Ar-H), 7.51 (m, 1H, 6-Ar-H), 4.51 (m, 1H, α-CH), 2.62 (m, 2H, CH2), 2.21 (m, 2H, CH2), 2.15 (s, 3H, SCH3), 1.88 (m, 15H, adamantyl protons), 1.42 (s, 9H, 3 x CH3); MALDIMS: m/z 553 (M+l); Analysis for C30H40N4O4S (552.7), calcd: C, 65.19; H, 7.29; N, 10.14; found: C, 65.23; H, 7.33; N, 10.45. {l-[(S)-N'-(4-Adaraantan-l-yl-quinoline-l-carbonyl)hydrazinocarbonyl]-3-carbamoyl-tropyl}carbamic acid tert-butyl ester (31) Yield: 30%; mp: 173-175 °C (dec.); 1H NMR (CDC13): δ 9.88 (bs, 1H, NH, exchangeable with D2O) 8.67 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.15 (m, 2H, 3-Ar-H & 5-Ar-H), 7.70 (m, 1H, 7-Ar-H), 7.59 (m, 1H, 6-Ar-H), 4.56 (m, 1H, a-CH), 1.88 (m, 15H, adamantyl protons), 1.67 (m, 2H, CH2), 1.47 (s, 9H, 3 x CH3), 1.16 (m, 2H, CH2); MALDIMS: m/z 550 (M+1): Analysis for C30H39N5O5 (549.7), calcd: C, 65.55; H, 7.15; N, 12.74; found: C, 65.59; H, 7.12; N, 12.72. General method for the synthesis of (S)-4-adamantan-l-yl-quinoline-2-carboxylic acid N-(2-aminoalkyl) hydrazides (32-41, Scheme 2) A solution of 33% HBr in acetic acid (3 mL) was added to (S)-{l-[N'-(4-adamantan-l-yl-quinoline-2-carbonyl)hydrazinocarbonyl]alkylcarbamic acid tert-butyl ester (22-31, 0.1 mmol), and reaction mixture was stirred at ambient temperature for 30 min. Solvent was removed under reduced pressure to afford (S) 4-adamantan-l-yl-quinoline-2-carboxylic acid N'-(2-aminoalkyl)-hydrazides 32-41 as their hydrobromide salts. (S)-{5-[N'-(4-Adamantan-l-yl-2-carbonyl) hydrazino]-4-amino-5-oxopentyl}guanidine .3HBr (32) Yield: 95%; mp: 140-142 °C (dec.); 1H NMR (CD3OD): δ 9.15 (bs, 1H, NH, exchangeable with D2O), 8.88 (d, 1H, 8-Ar-H, J= 7.9 Hz), 8.57 (bs, 1H, NH, exchangeable with D2O), 8.33 (m, 1H, 5-Ar-H, J= 8.4 Hz), 8.23 (s, 1H, 3-Ar-H), 7.90 (m, 1H, 7-Ar-H), 7.80 (m, 1H, 6-Ar-H), 4.20 (m, 1H, α-CH), 2.04 (m, 2H, CH2), 1.88 (m, 15H, adamantyl protons), 1.72 (m, 2H, CH2), 1.33 (m, 2H, CH2); MALDIMS: m/z 478 (M+1); Analysis for C26H3SBr3N7O2 (720.3), calcd: C, 43.35; H, 5.32; N, 13.61; found: C, 43.32; H, 5.35; N, 13.64. (S}-4-Adamantan-l-yl-qumoline-2-carboxylic acid N'-[2-amino-3-(3H-imidazoI-4-yl)-propionyl]hydrazide.3HBr (33) Yield: 95%; mp: 165-167 °C (dec.); 1H NMR (CD3OD): δ 8.77 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.34 (d, 1H, 5-Ar-H, J= 8.1 Hz), 8.25 (s, 1H, 3-Ar-H), 7.75 (m, 1H, 7-Ar-H), 7.62 (m, 2H, 6-Ar-H & imid/-Ar-H), 6.92 (s, 1H, imid-Ar-H), 4.37 (m, 1H, a-CH), 2.91 (m, 2H, CH2), 1.88 (m, 15H, adamantyl protons); MALDIMS: m/z 459 (M+1); Analysis for C26H33 Br3N6O2 (701.2), calcd: C, 44.53; H, 4.74; N, 1 1.98; found: C, 44.56; H, 4.78; N, 1 1.97. (S)-4-Adamantan-l-yl-quinoIine-2-carboxyIic acid N'-(2,5-diaminopentanoyl)hydrazide 3HBr (34) Yield: 90%; semi-solid; 1H NMR (CD3OD): δ 8.76 (d, 1H, 8-Ar-H, J= 8.6 Hz), 8.25 (d, 1H, 5-Ar-H, J= 8.3 Hz), 8.14 (s, 1H, 3-Ar-H), 7.77 (m, 1H, 7-Ar-H), 7.71 (m, 1H, 6-Ar-H), 4.11 (m, 1H, a-CH), 3.07 (m, 2H, CH2), 2.10 (m, 2H, CH2), 1.88 (m, 15H, adamantyl protons), 1.28 (m, 2H, CH2); MALDIMS: m/z 436 (M+l); Analysis for C25H36Br3N5O6 (678.3), calcd: C, 44.27; H, 5.35; N, 10.32; found: C, 44.23; H, 5.31; N, 10.28. (S)-4-Adamantan-l-yl-quinoline-2-carboxylic acid N-(2,6-diaminohexanoyl)hydrazide .3HBr (35) Yield: 92%; mp: 172-174 °C (dec.); 1H NMR (CD3OD): 8.99 (d, 1H, 8-Ar-H, J = 8.7 Hz), 8.33 (d, 1H, 5-Ar-H, J= 8.7 Hz), 8.23 (s, 1H, 3-Ar-H), 7.90 (m, 1H, 7-Ar-H), 7.79 (m, 1H, 6-Ar-H), 4.13 (m, 1H, a-CH), 3.04 (m, 2H, CH2), 2.07 (m, 2H, CH2), 1.88 (m, 15H, adamantyl protons), 1.30 (m, 4H, 2 x CH2); MALDIMS: m/z 450 (M+l); Analysis for C26H38Br3N5O2 (692.3), calcd: C, 45.11; H, 5.53; N, 10.12; found: C, 45.07; H, 5.49; N, 10.09. (S)-4-Adamantan-l-yl-quinoline-2-carboxylic acid N-[2-amino-3-(lH-indol-2-yl)-propionyl]hydrazide.2HBr (36) Yield: 94%; mp: 176-178 °C (dec.); 1H NMR (CD3OD): δ 8.78 (d, 1H, 8-Ar-H, J= 8.6 Hz), 8.24 (d, 1H, 5-Ar-H, J= 8.3 Hz), 8.16 (s, 1H, 3-Ar-H), 7.78 (m, 3H, 7-Ar-H & Ar-H), 7.42 (m, 1H, 6-Ar-H), 7.34 (s, 1H, Ar-H), 7.11 (m, 2H, Ar-H), 4.30 (m, 1H, a-CH), 2.30 (s, 2H, CH2), 1.88 (m, 15H, adamantyl protons); MALDIMS: m/z 507 (M+l); Analysis for C31H35Br2N5O2 (749.4), calcd: C, 49.69; H, 4.71; N, 9.35; found: C, 49.63; H, 4.67; N, 9.33. (S)-4-Adamantan-l-yl-quinoline-2-carboxylic acid N'-(2-amino-3-phenylpropionyl)- hydrazide.2HBr (37) Yield: 90%; mp: 172-174 °C (dec.); 1H NMR (CD3OD): δ 8.78 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.25 (d, 1H, 5-Ar-H, J = 8.2 Hz), 8.14 (s, 1H, 3-Ar-H), 7.81 (m, 1H, 7-Ar-H), 7.71 (m, 1H, 6- Ar-H), 7.44 (m, 5H, phenyl protons), 4.32 (m, 1H, a-CH), 3.18 (d, 2H, CH2, J= 6.4 Hz), 1.88 (m, 15H, adamantyl protons); MALDIMS: m/z 469 (M+l); Analysis for C29H34Br2N4O2 (630.4), calcd: C, 55.25; H, 5.44; N, 8.89; found: C, 55.21; H, 5,44; N, 8.93. (S)-4-Adamantan-l-yl-quinoline-2-carboxylic acid N-(2-aminopropionyl)hydrazide .2HBr (38) Yield: 91%; mp: 175-177 °C (dec.); 1H NMR (CD3OD): δ 8.89 (d, 1H, 8-Ar-H, J= 8.6 Hz), 8.37 (d, 1H, 5-Ar-H, J= 8.4 Hz), 8.25 (s, 1H, 3-Ar-H), 7.93 (m, 1H, 7-Ar-H), 7.83 (m, 1H, 6-Ar-H), 4.14 (m, 1H, α-CH), 1.88 (m, 15H, adamantyl protons), 1.57 (d, 3H, CH3, J= 6.8 Hz); MALDIMS: m/z 393 (M+l); Analysis for C23H30Br2N4O2 (554.3), calcd: C, 49.84; H, 5.46; N, 10.11; found: C, 49.87; H, 5.49; N, 10.15. (S)-4-Adamantan-l-yl-quinoline-2-carboxylic acid N'-[2-amino-3-(4-hydroxyphenyl)-propionyl]hydrazide.2HBr (39) Yield: 90%; mp: 173-175 °C (dec.); 1H NMR (CD3OD): δ 8.89 (d, 1H, 8-Ar-H, J= 8.8 Hz), 8.33 (d, 1H, 7-Ar-H, J= 8.5 Hz), 8.24 (s, 1H, 3-Ar-H), 7.90 (m, 1H, 7-Ar-H), 7.79 (m, 1H, 6-Ar-H), 7.22 (d, 2H, Ar-H, J= 8.1 Hz), 6.82 (d, 2H, Ar-H, J= 8.2 Hz), 4.20 (m, 1H, a-CH), 1.96 (d, 2H, CH2, J= 6.5 Hz), 1.88 (m, 15H, adamantyl protons); MALDIMS: m/z 575 (M+l); Analysis for C29H34Br2N4O3 (646.4), calcd: C, 53.88; H, 5.30; N, 8.67; found: C, 53.84; H, 5.32; N, 8.69. (S)-4-Adamantan-l-yl-quinoline-2-carboxylic acid N'-(2-amino-4-methylsuIfanyl-butyryl)hydrazide.2HBr (40) Yield: 93%; mp: 173-175 °C (dec.); 1H NMR (CD3OD): δ 8.76 (d, 1H, 8-Ar-H, J= 8.3 Hz), 8.33 (d, 1H, 5-Ar-H, J= 8.3 Hz), 8.14 (s, 1H, 3-Ar-H), 7.77 (m, 1H, 7-Ar-H), 7.70 (m, 1H, 6-Ar-H), 4.20 (m, 1H, a-CH), 2.60 (m, 2H, CH2), 2.25 (m, 2H, CH2), 2.15 (s, 3H, SCH3), 1.88 (m, 15H, adamantyl protons); MALDIMS: m/z 453 (M+l); Analysis for C25H34Br2N4O2S (614.4), calcd: C, 48.87; H, 5.58; N, 9.12; found: C, 48.93; H, 5.61; N, 9.14. BIOLOGICAL ACTIVITIES In vitro activity of the 4-(1-adamantyl)-2-substituted quinolines for tuberculosis inhibition against M. tuberculosis H37Rv strain (ATCC 27294, susceptible both to rifatnpicin and isoniazid) was initially carried out using the Microplate Alamar Blue Assay (MABA). As a result a concentration of 6.25 µg/mL is finalized as standard dose. Compounds exhibiting fluorescence at the standard concentration (6.25 µg/mL) were then tested in the BACTEC 460 radiometric system for activities expressed as Minimum Inhibitory Concentration (MIC, µg/mL). The obtained results are summarized in Tables 1-2. Compounds demonstrating >90% inhibition at a concentration of 6.25 µg/mL in the initial screen were then pretested to determine the actual MIC value that is defined as the lowest concentration exhibiting >90% inhibition. Synthetic modifications of 4-l-adamantyl-quinoline-2-carboxilic acid is done by coupling it with various D/L-amino acids was achieved (I). For modification, the selection of the amino acid was carried out in such a way so as to determine the effect of the following; 1. Hydrophobicity -by incorporating alanine (Ala), leucine (Leu), isoleucine (Ileu) 2. Hydrophilicity - by incorporating tyrosine (Tyr), methionine (Met), lysine (Lys) and 3. Unnatural amino acid ornithine (Orn). In general, all ester derivatives of the amino acid conjugates were found more effective than their hydrazide counterparts; with ala analogue 13 being the sole aberration. Analogue 13 displayed 82% inhibition at the test concentration of 6.25 µg/mL; whereas, its methyl ester counterpart 5 only produced 73% inhibition at same test concentration. The most effective compound from the series was the methionine analogue 8 (R1 = CH3), which produced 86% inhibition at MIC of 6.25 )µg/mL. Interestingly, conversion of the methyl ester of methionine analogue 8 to corresponding hydrazide derivative 16 (R1 = NHNH2) resulted in marked reduction in the biological activity (68% inhibition, MIC = 6.25 µg/mL). In case of leu amino acid, both ester and hydarzide analogues 7 and 15 exhibited 83% inhibition at the test concentration of 6.25µg/mL. Cationic amino acid derivatives 18 and 19 displayed 48% and 36% inhibition respectively at 6.25 µg/mL (Table 1). Table 1. In vitro antimycobacterial activity evaluation of methyl 2-[4-(l-adamantyl)-2-quinonylcarboxamido]alkanoate and N2-[1 -hydrazino-carbonylalkyl]-4-( 1 -adamantyl)-2-quinoline-carboxamides 5-20 derivatives against drug-sensitive M tuberculosis H37Rv strain. (Table Removed) The most effective tryptophan-quinoline conjugated analogue 26 [R1 = CO2C(CH3)3] of the series (II) exhibited 95% inhibition at the preliminary test concentration of 6.25 µg/mL. Similarly, histidine-ring-substituted quinoline conjugated analogue 23 [R1 = CO2C(CH3)3] displayed promising 92% inhibition at the preliminary test concentration of 6.25 µg/mL (Table 2). Table 2. In vitro antimycobacterial activity evaluation of (S)-{l-[N'-(4-Adamantan-l-yl-quinoline-2-carbonyl)hydrazinocarbonyl]alkyl carbamic acid tert-butyl esters and (S)-4-adamantan-l-yl-quinoline-2-carboxylic acid N'-(2-aminoalkyl)hydrazides 22-40 derivatives against drug-sensitive M. tuberculosis H37Rv strain. (Table Removed) At the same time, hydrophobic side chain containing amino acid conjugates have shown moderate antimycobacterial activity with inhibition in the range of 42-88% at the concentration 6.25 µg/mL. Of these analogues, the most effective was the ala-quinoline conjugated analogue 28 [R1 = CO2C(CH3)3] which displayed 88% inhibition at the test concentration of 6.25 µg/mL. To our surprise, when the t-Boc protection of the amino group in 28 was removed, resulting compound 38 displayed marked reduction in the antimycobacteraial activity. A general observation of the already acquired results in this series predicts that heteroaromatic side-chain containing amino acid conjugates of 4-(l-adamantyl)-2- substitutedquinolines are better anti-tuberculosis agents compared to their non-heteroaromatic side-chain containing counterparts. We claim: 1. A process for producing a compound of 4-(l-adamantyl)-2-substituted quinoline derivatives, as new structural class of anti-tuberculosis agents comprising general (Formula Removed) formula (i) 2. The process as claimed in claim 1,Wherein the said compound 'X" is selected from formula (ii) or (iii) (Formula Removed) wherein, R represents side-chain present in all D and L amino acids, R1 represents -H, H3; C2H5; C3H7; NHNH2; CO2C(CH3)3; CO2CH2C6H5; CO2CH3; CO2C2H5; CO3C2H7. 3. The process as claimed in claim 1 is carried out in two schemes 1 and 2 a) Scheme 1- Synthesizing 4-(Adamantan-l-yl)-quinoline-2-carboxylic acid from commercially available quinoline-2-carboxylic acid (1). i. Acid chloride derivatives are obtained by adding thionyl chloride to 4- (Adamantan-1 -yl)-quinoline-2-carboxylic acid, ii. Step (i) is carried out in the presence of pyridine for one minute, iii. Acid chloride derivative obtained in step b reacts with commercially available suitably side-chain protected L/D-amino acid methyl esters produce iv. Step (iii) is performed in the presence of 4-(dimethylamino) pyridine (DMAP) in Dichloromethane (DCM), v. 4-(adamantyl-l-yl)- quinoline-2-carboxylic acid (1-hydrazinocarbonylalkyl) amides (13-17) is produced by the reaction of methyl esters (5-12) with hydrazine hydrate in presence of abs. ethanol for 48 h at ambient temperature. vi. Deprotection step is performed for side chain protected compounds by reaction with 33% HBr in acetic acid at ambient temperature for 30 min to produce 4-(adamantyl-l-yl)-quinoline-2-carboxylic acid (1-hydrazinocarbonyl-alkyl) amides 18-20 as their hydrobromide salts. vii. The deprotection step (vi) is carried out for side chain protected compounds selected from a group comprising Orn, Lys with carbobenzyloxy and Tyr with benzyl, b) Scheme 2- synthesizing 4-(Adamantan-l-yl)- quinoline-2-carbohydrazide (21) from commercially available quinoline-2-carboxylic acid (1). i. Reaction of 4-(Adamantan-l-yl)-quinoline-2-carbohydrazide with side-chain protected commercially available Boc/Cbz-L/D-amino acids ii. Step (i) is carried out in the presence of 1,3-dicyclohexylcarbodiimide (DCC) and DMAP in anhydrous DCM as solvent for 8 h afforded Boc/Cbz-group protected quinoline-amino acid conjugates (S)-{l-[N'-(4-adamantan-l-yl-quinoline-2-carbonyl)-hydrazine carbonyl] alkyl carbamic acid tert-bulyl esters 22-31. iii. (S)-{l-[N'-(4-adamantan-l-yl-quinoline-2-carbonyl)-hydrazine carbonyl] alkyl carbamic acid tert-butyl esters reacts with 33% hydrogen bromide solution in acetic acid at ambient temperature for 30 min to produce 4-(adamantan-l-yl)quinoline-2-carboxylic N'-(2-aminoalkyl) hydrazides 32-40 as hydrobromide salt. A process for producing a compound of 4-(l-adamantyl)-2-substituted quinoline derivatives substantially described herewith foregoing description and examples.

Full Text

TITLE
A process for the synthesis 4-(l-adamantyl)-2-substituted quinolines effective for the treatment of tuberculosis. FIELD OF THE INVENTION
The present invention deals with a process for the synthesis of 4-(l-adamantyl)-2-substituted quinolines. More preferably, a simple process to produce a new structural class of anti-tuberculosis agents of general formula (i), which offer an improved and additional means for the treatment and prevention of tuberculosis.
(Formula Removed)
Wherein R represents side-chain present in all D/L amino acids, RI represents -H, CHs; C2Hs; C3H7; NHNH2; CO2C(CH3)3; CO2CH2C6H5; CO2CH3; CO2C2H5; CO3C2H7. The development of these compounds offers and adds one more line of drugs for the treatment and control of disease caused by Mycobacterium tuberculosis.
BACKGROUND OF THE INVENTION
Development of resistance to known drugs is a growing phenomenon and now has reached alarming levels for certain infectious diseases. Tuberculosis (TB) has staged a deadly comeback primarily because of resistance development by the causative organism, Mycobacterium tuberculosis against all major anti-TB drugs, and the rising incidence of immuno-compromised situations partly due to cancer chemotherapy, AIDS infection and transplantation. Approximately, 32% of the world's population is currently infected with TB. Each year, eight to nine million of infected people develop clinical pulmonary TB, leading to more than 2 million deaths around world. If this trend continues, TB is likely to claim more than 35 million lives within the next decade.
Although regimens exist for treating tuberculosis, they are far from ideal. Treatment usually involves a combination of first line of TB drugs — Isoniazid (INH) and Rifampicin (RIF),
which are given for at least 6 months, and pyrazinamide and ethambutol (or streptomycin), which are used only in the first 2 months of treatment. This complex and long treatment regimen was rarely followed strictly and patients usually stop taking medicine once common symptoms of TB disappear. To make this regimen workable a program of Directly Observed Treatment, Short course (DOTS) is recommended by World Health Organization (WHO). Statistics suggest that currently one-fourth of the world's TB patients were treated under DOTS. Inconsistent or partial treatment leads to the development and spread of drug-resistant strains. These strains have a much lower cure rate and can be up to 100-fold more expensive to treat. There is thus an urgent need for shorter, simpler therapeutic and prophylactic regimens to increase patient compliance. In addition, new drugs are needed to combat the increasing number of multi-drug-resistant strains (MDR-TB). Treatment for MDR-TB often requires the use of a second line of TB drugs, all of which can produce serious side effects. Therapy for 18 months to 2 years may be necessary, and patients should receive at least three drugs to which the bacteria are susceptible. The survival rate for patients with MDR-TB is approximately 50 percent. The inadequate armory of drugs in widespread use for the treatment, and development of drug-resistant forms of the disease against most commonly used mainstay drugs INH and RIF have severely curtailed fight against TB. Despite this it has been nearly forty years since a new structural class of drug was introduced specifically to treat this infectious disease. This underscores the continuing urgent need for the discovery of new structural classes of anti-tuberculosis agents to replace and/or to supplement the current drug regimens.
OBJECT OF INVENTION
The principal object of the present invention is to develop a simple process for the production of anti-tuberculosis agent [4-(l-adamantyl)-2-substituted quinolines]
STATEMENT OF INVENTION
Accordingly, the present invention is about a process for the producing 4-(l-adamantyl)-2-substituted quinolines derivatives for the treatment and prevention of tuberculosis comprising general formula (i)
(Formula Removed)
Wherein "X" is selected from formula (ii) or (iii)
(Formula Removed)
wherein, R represents side-chain present in all D and L amino acids, R1 represents -H, H3; C2H5; C3H7; NHNH2; CO2C(CH3)3; CO2CH2C6H5; CO2CH3; CO2C2H5; CO3C2H7.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for producing 4-(l-adamantyl)-2-substituted quinolines derivatives of general formula (i) for the treatment and prevention of tuberculosis. Some of these new derivatives have shown excellent in vitro anti-tuberculosis activity against M. tuberculosis H37Rv strain. All these compounds are structurally different from so far existing anti-tuberculosis drugs; thus making it attractive for further development. It is expected that development of these compounds as ideal anti-tuberculosis agents will add to already existing armament for the suppression as well as radical cure of the tuberculosis infection.
4-(Adamantan-l-yl)-quinoline-2-carboxylic acid (4) was synthesized in three steps from commercially available quinoline-2-carboxylic acid (1). The latter compound 4 upon reaction with thionyl chloride in the presence of pyridine for one minute produced acid chloride derivative in situ, which upon subsequent reaction with commercially available suitably side-chain protected L/D-amino acid methyl esters in the presence of 4-(dimethylamino)pyridine (DMAP) in Dichloromethane (DCM) provided methyl esters 5-12 in good yields (Scheme 1).
The methyl esters 5-12 upon reaction with hydrazine hydrate in presence of abs. ethanol for 48 h at ambient temperature produced 4-(adamantyl-l-yl)- quinoline-2-carboxylic acid (1-hydrazinocarbonylalkyl) amides 13-17. For some compounds (where side chain is protected i.e. Om, Lys with carbobenzyloxy and Tyr with benzyl) an additional deprotection step was performed. The deprotection at the side-chain was achieved by reaction with 33% HBr in acetic acid at ambient temperature for 30 min to produce 4-(adamantyl-l-yl)-quinoline-2-carboxylic acid (l-hydrazinocarbonyl-alkyl)amides 18-20 as their hydrobromide salts in excellent yields (Scheme 1).
(Formula Removed)
Scheme 7, (i) abs. EtOH, HCI gas, 4 °C, 2h; (ii) 1-adamantanecarboxylic acid, AgNO3, (NH4)2S208, CH3CN, 10% H2S04, 15 min; (iii) 6N HCI, 100 °C, 8 h; (iv) SOCI2, C5H5N, 1min, DMAP, H2N-AA-OMe, 20 min; (v) NH2NH2.H20, abs. EtOH, 48h, rt; 33% HBr-AcOH, 30 min, rt. (Formula Removed)

4-(Adamantan-l-yl)-quinoline-2-carbohydrazide (21) required for the synthesis of 22-31 was synthesized in three convenient steps from commercially available quinoline-2-carboxylic acid (1). The latter compound 21 upon reaction with suitably side-chain protected commercially available Boc/Cbz-L/D-amino acids in the presence of 1,3-dicyclohexylcarbodiimide (DCC) and DMAP in anhydrous DCM as solvent for 8 h afforded Boc/Cbz-group protected quinoline-amino acid conjugates (S)-{l-[N'-(4-adamantan-l-yl-quinoline-2-carbonyl)-hydrazinecarbonyl]alkyl carbamic acid tert-butyl esters 22-31 (Scheme 2).
The latter compounds 22-31 upon reaction with 33% hydrogen bromide solution in acetic acid at ambient temperature for 30 min easily and cleanly produced 4-(adamantan-l-yl)quinoline-2-carboxylic ,N'-(2-aminoalkyl)hydrazides 32-40 as hydrobromide salt (Scheme 2).
(Formula Removed)
Scheme2. (i) NH2NH2.H2O, EtOH, 80 °C, 8 h; (ii) DCC, DMAP, Boc-AA-OH, 8h, DCM; (iii) 33% HBr-AcOH, 30 min, rt or HCI-MeOH, 8h, rt,
Advantageously, this compound may be formulated so as to prepare tablets, pellets, pills or capsule, for which the binders are selected from glycol, ethyl cellulose, starch paste, poly viryl pyrrolidone. Lubricants are selected from vegetable oils, stearic acid, Magnesium stearate, Aluminium Stearate. Glidant is selected from Colloidal silicon dioxide, cab-o-sil, talc and Disintegrant is selected from crossed linked poly vinyl pyrrolidone, cross carmilose, sodium starch glycolate.
The invention is illustrated by the following examples which are not to be construed as limitations on the inventive concept. The examples are meant only for illustration and all embodiments that may be apparent to a person skilled in the art are deemed to fall within the scope thereof. The following are non-limiting examples showing the composition, property, application and antimicrobial activity of the instant antimicrobial herbal composition.
EXAMPLES EXPERIMENTAL
Synthesis of quinoIine-2-carboxylic acid ethyl ester (2, Scheme 1)
To a suspension of quinoline-2-carboxylic acid (1, 2 g, 12 mmol) in abs. ethyl alcohol (150 mL), dry hydrogen chloride gas was purged at 4 °C for 2 h. The reaction mixture was left overnight at ambient temperature and solvent evaporated under reduced pressure to afford quinolin-2-carboxylic acid ethyl ester hydrochloride salt. The hydrochloric salt of the
quinoline-2-carboxylic acid ethyl ester was suspended in dichloromethane (250 mL) and heutralized by drop wise addition of 25% NH4OH solution. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure to produce quinoline-2-carboxylic acid ethyl ester (2).
Yield: 78%; oil; 1H NMR (CDC13): δ 8.33 ( m, 2H, 4 & 8-Ar-H), 8.19 (d, 1H, 5-Ar-H, J= 8.5 Hz), 7.89 (d, 1H, 3-Ar-H, J= 6.6 Hz), 7.79 (m, 1H, 7-Ar-H), 7.65 (m, 1H, 6-Ar-H), 4.57 (q, 2H, CH2, J= 14.2 Hz), 1.49 (t, 3H, CH3, J= 7.1 Hz); ESIMS: m/z 202 (M+l); Analysis for C12H11N2O (201.2), calcd: C, 76.07; H, 6.38; N, 3.65; found: C, 76.03; H, 6.25; N, 3.59.
Synthesis of 4-adamantan-l-yl-quinoline-2-carboxylic acid ethyl ester (3, Scheme 2) Quinoline-2-carboxylic acid ethyl ester (2, 2 g, 10 mmol), was added to a mixture of AgNO3 (0.9 g, 5.2 mmol) and 1-adamantane carboxylic acid (4.9 g, 32 mmol) in 10% H2SO4 (17 mL) and acetonitrile (8 mL). The reaction mixture was heated at 70-80°C. A freshly prepared solution of ammonium persulfate (6.67 g, 30 mmol) in water (10 mL) was added drop wise over 15 min. The heating source was then removed and reaction proceeded with the evolution of carbon dioxide. After 15 min, the reaction was terminated by pouring it on ice. The resulting mixture was made alkaline with 25% NH4OH solution and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with brine (2 x 25 mL) and dried (Na2SO4). The solvent was removed under reduced pressure to afford crude product, which upon chromatographic purification over silica gel (230-400 mesh) using ethyl acetate:hexanes (10:90) produced 4-adamantan-l-yl-quinoline-2-carboxylic acid ethyl ester 3.
Yield: 48%; mp: 124-126 °C; 1HNMR (CDC13): δ 8.65 (d, 1H, 8-Ar-H, J= 8.80 Hz), 8.34 (d, 1H, 5-Ar-H, J= 8.60 Hz), 7.89 (s, 1H, 3-Ar-H), 7.79 (m, 1H, 7-Ar-H), 7.65 (m, 1H, 6-Ar-H), 4.57 (q, 2H, CH2, J= 14.1 Hz), 1.88 (m, 15H, adamantyl protons), 1.49 (t, 3H, CH3, J= 7.1 Hz); ESIMS: m/z 336 (M+l); Analysis for C22H25NO2 (335.4), calcd: C, 78.77; H, 7.51; N, 4.18; found: C, 78.77; H, 7.56; N, 4.28.
Synthesis of 4-adamantan-l-yl-quinoline-2-carboxylic acid (4, Scheme 1)
A solution of 4-adamantan-l-yl-quinoline-2-carboxylic acid ethyl ester (3, 2 g, 10 mmol) in
6N HC1 (20 mL) was heated at reflux temperature for 8 h. Mono hydrochloride salt of 4-
adamantan-l-yl-quinoline-2-carboxylic acid (4) was obtained directly by evaporation of the
acid hydrolysis solution.
Yield: 95%; mp: 124-126 °C; 1HNMR (CD3OD): δ 8.47 ( d, 1H, 8-Ar-H, J= 8.5 Hz), 7.95 (d,
1H, 5-Ar-H, J= 7.1 Hz), 7.77 (s, 1H, 3-Ar-H), 7.54 (m, 1H, 7-Ar-H), 7.44 (m, 1H, 6-Ar-H),
1.88 (m, 15H, adamantyl protons); ESIMS: m/z 308 (M+l); Analysis for C20H22ClNO2 (343.8), calcd: C, 69.86; H, 6.45; N, 4.07; found: C, 69.92; H, 6.63; N, 4.32.
Synthesis of 4-adamantan-l-yl-quinoline-2-carboxylic acid hydrazide (21, Scheme 2) To a solution of 4-adamantan-l-yl-quinoline-2-carboxylic acid ethyl ester (2, 1 g, 3 mmol) in 95% ethyl alcohol (15 mL), hydrazine hydrate (1 mL, 25 mmol) was added, and reaction mixture was heated at 80 °C for 8 h. 4-Adamantan-l-yl-quinoline-2-carboxylic acid hydrazide 21 was obtained directly after evaporation of the reaction solution.
Yield: 98%; mp: 142-150 °C; 1H NMR (CDC13): 5 8.67 (d, 1H, 8-Ar-H, J= 8.4 Hz), 8.18 (s, 1H, 3-Ar-H), 8.12 (d, 1H, 5-Ar-H, J= 8.3 Hz), 7.69 (m, 1H, 7-Ar-H), 7.59 (m, 1H, 6-Ar-H), 1.88 (m, 15H, adamantyl protons); ESIMS: m/z 322 (M+l); Analysis for C20H23N3O (321.4), calcd: C, 74.74; H, 7.21; N, 13.07; found: C, 74.81; H, 7.31; N, 13.01.
General procedure for the synthesis of methyl-2-[4-(l-adamantyl)-2-quinonylcarboxamido] alkanoate 5-12 (Scheme 1)
To a mixture of 4-(adamantan-l-yl)-quinoline-2-carboxylic acid (4, 0.324 g, 0.94 mmol) and pyridine (112 µL, 148 mmol) in anhydrous DCM (15 mL), SOC12 (95 µL, 1.35 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 1 min. To intermediate acid chloride was added drop wise a solution of desired L/D-amino acid ester (0.82 mmol) and DMAP (0.81 mmol) in DCM (10 mL) via a syringe during 5 min. The reaction mixture was stirred for another 20 min at ambient temperature. The reaction mixture was diluted with DCM (50 mL) and washed with water (2 x 25 mL) and brine solution (25 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to produce crude product, which was purified by column chromatography on silica gel (60-120 mesh) using ethyl acetate:hexane (10:90) as eluant to provide methyl-2-[4-(l-adamantyl)-2-quinonylcarboxamido]alkanoate 5-12.
Methyl (25)-2-[4-(l-adamantyl)-2-quinonyIcarboxamido]propanoate (5)
Yield: 7%; oil; IR (neat): 3380 cm'1 (amine), 1741 (amide); 1H NMR (CDC13): δ 8.69 (bs, 1H, NH, exchangeable witn D2O), 8.66 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.20 (m, 2H, 5-Ar-H & 3-Ar-H), 7.69 (m, 1H, 7-Ar-H), 7.55 (m, 1H, 6-Ar-H), 4.21 (m, 1H, a-CH), 3.80 (s, 3H, OCH3), 1.88 (m, 15H, adamantyl protons), 1.60 (d, 3H, CH3, J= 6.8 Hz); ESIMS: m/s 393 (M+l); Analysis for C24H28N2O3 (392.4), calcd: C, 73.44; H, 7.19; N, 7.14; found: C, 73.32; H, 7.17; N, 12.19.
Methyl (2S, 3S)-2-[4-(l-adamantyl)-2-quinonylcarboxamido]-3-methylpentanoate (6)
Yield: 14%; oil; IR (neat): 3391 cm-1 (amine), 1701 (amide); 1H NMR (CDC13): δ 8.74 (bs, 1H, NH, exchangeable witn D2O), 8.66 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.21 (m, 2H, 5-Ar-H & 3-Ar-H), 7.70 (m, 1H, 7-Ar-H), 7.60 (m, 1H, 6-Ar-H), 4.83 (m, 1H, α-CH), 3.78 (s, 3H, OCH3), 1.88 (m, 15H, adamantyl protons), 1.33 (m, 1H, CH), 1.25 (m, 2H, CH2), 1.10 (m, 6H, 2 x CH3); ESIMS: m/z 435 (M+l); Analysis for C27H34N2O3 (434.5), calcd: C, 74.62: H, 7.89; N, 6.45; found: C, 74.64; H, 7.75: N, 6.38.
Methyl (2S)2-[4-(l-adamantyl)-2-quinonylcarboxamido]-4-methyIpentanoate (7)
Yield: 14%; oil; IR (neat): 3412 cm'1 (amine), 1720 (amide); 1H NMR (CDC13): δ 8.66 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.59 (bs, 1H, NH, exchangeable witn D2O), 8.24 (s, 1H, 3-Ar-H), 8.19 (d, 1H, 5-Ar-H, J= 7.6 Hz), 7.70 (m, 1H, 7-Ar-H), 7.57 (m, 1H, 6-Ar-H), 4.89 (m, 1H, α-CH), 3.78 (s, 3H, OCH3), 1.88 (m, 15H, adamantyl protons), 1.81 (m, 2H, CH2), 1.25 (m, 1H, CH), 1.10 (m, 6H, 2 x CH3); ESIMS: m/z 435 (M+l); Analysis for C27H34N2O3 (434.5), calcd: C, 74.62; H, 7.89; N, 6.45; found: C, 74.65; H, 7.83; N, 6.38.
Methyl (2S)-2-[4-(l-adamantyl)-2-quinonylcarboxamido]-4-methylsulfanyIbutanoate (8)
Yield: 24%; oil; IR (neat): 3379 cm-1 (amine), 1731 (amide); 1H NMR (CDC13): δ 8.78 (bs, 1H, NH, exchangeable witn D2O), 8.66 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.20 (m, 2H, 5-Ar-H & 3-Ar-H), 7.70 (m, 1H, 7-Ar-H), 7.57 (m, 1H, 6-Ar-H), 4.97 (m, 1H, a-CH), 3.82 (s, 3H, OCH3), 2.13 (s, 3H, SCH3), 1.88 (m, 15H, adamantyl protons), 1.59 (m, 2H, CH2), 1.25 (m, 2H, CH2); ESIMS: m/z 453 (M+l); Analysis for C26H32N2O3S (452.2), calcd: C, 68.99; H, 7.13; N, 6.19; found: C, 68.93; H, 7.07; N, 6.15.
Methyl (2S)-2-[4-(l-adamantyl)-2-quinonylcarboxamido]-(lH-4-imidazolyl)propaonoate (9)
Yield: 8%; oil; IR (neat): 3352 cm-1 (amine), 1703 (amide); 1H NMR (CDC13): δ 9.12 (bs, 1H, NH, exchangeable with D2O), 8.72 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.25 (d, 1H, 5-Ar-H, J= 9.8 Hz), 8.17 (s, 1H, 3-Ar-H), 7.90 (s, 1H, imid-Ar-H), 7.76 (m, 1H, 7-Ar-H), 7.67 (m, 1H, 6-Ar-H), 6.25 (s, 1H, imid-Ar-H), 4.20 (m, 1H, a-CH), 3.86 (s, 3H, OCH3), 2.28 (m, 2H, CH2), 1.88 (m, 15H, adamantyl protons); ESIMS: m/z 459 (M+l); Analysis for C24H30N4O3 (458.6), calcd: C, 70.72; H, 6.59; N, 12.22; found; C, 70.54; H, 5.47; N, 12.17.
Methyl (2S)-2-l4-(l-adamantyl)-2-quinonylcarboxamido]-5-benzyloxycarbonylamino)-pentanoate (10)
Yield: 29%; oil; IR (neat): 3400 cm-1 (amine), 1715 (amide); 1H NMR (CDC13): δ 8.72 (bs, 1H, NH, exchangeable witn D2O), 8.65 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.20 (m, 2H, 3-Ar-H & 5-

Ar-H), 7.69 (m, 1H, 7-Ar-H), 7.57 (m, 1H, 6-Ar-H), 7.33 (m, 5H, phenyl), 5.08 (s, 2H, CH2), 4.84 (m, 1H, α-CH), 3.70 (s, 3H, OCH3), 3.26 (m, 2H, N-CH2), 1.88 (m, 15H, adamantyl protons), 1.24 (m, 4H, 2 x CH2); APCIMS: m/z 570 (M+l); Analysis for C34H39N3O5 (569.7), calcd: C, 71.68; H, 6.90; N, 7.38; found: C, 71.62; H, 6.55; N, 7.32.
Methyl (2S)-2-[4-(l-adamantyl)-2-quinonylcarboxamido]-6-benzyIoxycarbonylamino)-hexanoate (11)
Yield: 25%; oil; IR (neat): 3381 cm-1 (amine), 1728 (amide); 1H NMR (CDC13): δ 8.72 (bs, 1H, NH, exchangeable witn D2O), 8.65 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.20 (m, 2H, 3-Ar-H & 5-Ar-H), 7.69 (m, 1H, 7-Ar-H), 7.57 (m, 1H, 6-Ar-H), 7.30 (m, 5H, phenyl), 5.05 (s, 2H, CH2), 4.87 (m, 1H, α- CH), 3.79 (s, 3H, OCH3), 3.18 (m, 2H, N-CH2), 1.88 (m, 15H, adamantyl protons), 1.48 (m, 6H, 3 x CH2); ESIMS: m/z 584 (M+l); Analysis for C35H41N3O5 (583.7), calcd: C, 72.02; H, 7.08; N, 7.20; found: C, 72.09; H, 7.15; N, 7.25.
Methyl (2S)-2-[4-(l-adamantyI)-2-quinonylcarboxamido]-3-(4-benzyloxyphenyl)prop-anoate (12)
Yield: 8%; oil; IR (neat): 3344 cm-1 (amine), 1718 (amide); 1H NMR (CDC13): δ 8.78 (bs, 1H, NH, exchangeable witn D2O), 8.67 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.21 (s, 1H, 3-Ar-H), 8.13 (d, 1H, 5-Ar-H, .J= 8.3 Hz), 7.69 (m, 1H, 7-Ar-H), 7.57 (m, 1H, 6-Ar-H), 7.36 (m, 5H, Ar-H), 7.15 (d, 2H, Ar-H, J= 8.5 Hz), 6.91 (d, 2H, Ar-H, J= 8.6 Hz), 5.06 (s, 2H, CH2), 4.08 (m, 1H, a-CH), 3.74 (s, 3H, OCH3), 3.23 (m, 2H, CH2), 1.88 (m, 15H, adamantyl protons); ESIMS: m/z 575 (M+l); Analysis for C37H38N2O4 (574.7), calcd: C, 77.33; H, 6.66; N, 4.87; found: C, 77.18; H, 6.52; N, 4.80.
General procedure for the synthesis of N2-[l-hydrazinocarbonylalkyl]-4-(l-adamantyl)-2-quinolinecarboxamides 13-20 (Scheme 1)
To the solution of methyl-2-[4-(l-adamantyl)-2-quinonylcarboxamido]alkanoate (5-12, 0.1 mmol) in abs. ethyl alcohol (10 mL), hydrazine hydrate (0.5 mL, 12.5 mmol) was added and reaction mixture was stirred for 48 h at ambient temperature, solvent was removed under reduced pressure to afford N2-[l-hydrazinocarbonylalkyl]-4-(l-adamantyl)-2-qumolinecarboxamide (6a-e, i) in quantitative yields.
In certain cases where side chain of amino acid ester were protected i.e. Orn, Lys with carbobenzyloxy, and Tyr with benzyl and additional deprotection step was carried out. A solution of 33% HBr in acetic acid (2 mL) was added to 5f-h (0.1 mmol) and reaction mixture
was stirred at ambient temperature for 30 min. Solvent was removed under reduced pressure to afford compounds 6f-h as their hydrobromide salts in excellent yields.
N2-[(1S)-l-hydrazinocarbonylethyl]-4-(l-adamantyl)-2-quinoline carboxamide (13)
Yield: 95%; semi-solid; 1H NMR (CDC13): δ 8.66 (d, IH, 8-Ar-H, J= 8.7 Hz), 8.53 (bs, IH, NH, exchangeable with D2O), 8.18 (m, 2H, 5-Ar-H & 3-Ar-H), 7.73 (m, lH, 7-Ar-H), 7.58 (m, lH, 6-Ar-H), 4.71 (m, lH, a-CH), 1.88 (m, 15H, adamantyl protons), 1.60 (d, 3H, CH3, J = 6.8 Hz); ESIMS: m/z 393 (M+l); Analysis for C23H28N4O2 (392.4), calcd: C, 70.38; H, 7.19; N, 14.27; found: C, 70.42; H, 7.21; N, 14.31.
N2-[(1S, 2S)-l-hydrazinocarbonyI-2-methylbutyl]-4-(l-adamantyl)-2-quinoline carbox-amide (14)
Yield: 95%; semi-solid; 1H NMR (CDC13): 5 8.66 (d, lH, 8-Ar-H, J= 8.4 Hz), 8.49 (bs, lH, NH, exchangeable with D2O), 8.18 (m, 2H, 5-Ar-H & 3-Ar-H), 7.72 (m, lH, 7-Ar-H), 7.58 (m, lH, 6-Ar-H), 4.67 (m, lH, α-CH), 1.88 (m, 15H, adamantyl protons), 1.31 (m, lH, CH), 1.21 (m, 2H, CH2), 1.10 (m, 6H, 2 x CH3); ESIMS: m/z 435 (M+l); Analysis for C26H34N4O2 (434.5), calcd: C, 71.86; H, 7.89; N, 12.89; found: C, 71.89; H, 7.91; N, 12.85.
N2-[(1S)-l-hydrazinocarbonyl-3-methylbutyl]-4-(l-adamantyI)-2-quinoIine carboxamide (15)
Yield: 95%; semi-solid; 1H NMR (CDC13): δ 8.67 (d, lH, 8-Ar-H, J= 8.3 Hz), 8.18 (m, 2H, 5-Ar-H & 3-Ar-H), 7.71 (m, lH, 7-Ar-H), 7.59 (m, lH, 6-Ar-H), 7.47 (bs, lH, NH, exchangeable with D2O), 4.44 (m, lH, α-CH), 1.88 (m, 15H, adamantyl protons), 1.61 (m, 2H, CH2), 1.25 (m, lH, CH), 0.99 (m, 6H, 2 x CH3); ESIMS: m/z 435 (M+l); Analysis for C26H34N4O2 (434.5), calcd: C, 71.86; H, 7.89; N, 12.89; found: C, 71.92; H, 7.95; N, 12.87.
N2-[(1S)-l-hydrazinocarbonyl-3-methylsulfanylpropyl]-4-(l-adamantyl)-2-quinoline-carboxamide (16)
Yield: 95%; semi-solid; 1H NMR (CDC13): δ 8.72 (bs, lH, NH, exchangeable witn D2O), 8.66 (d, lH, 8-Ar-H, J= 7.9 Hz), 8.17 (m, 2H, 5-Ar-H & 3-Ar-H), 7.69 (m, lH, 7-Ar-H), 7.59 (m, lH, 6-Ar-H), 4.85 (m, lH, a-CH), 2.64 (m, 2H, CH2), 2.13 (s, 3H, SCH3), 1.88 (m, 15H, adamantyl protons), 1.25 (m, 2H, CH2); ESIMS: m/z 453 (M+l); Analysis for C25H32N4O2S (452.2), calcd: C, 66.34; H, 7.13; N, 12.38; found: C, 66.37; H, 7.14; N, 12.28.
N2-[(1S)-l-hydrazinocarbonyl-2(lH-4-imidazolyl)ethyl]-4-(l-adamantyl)-2-quinoline-carboxamide (17)
Yield: 95%; semi-solid; 1HNMR (CDC13): δ 8.71 (d, lH, 8-Ar-H, J= 8.6 Hz), 8.25 (d, IH, 5-Ar-H, J = 9.6 Hz), 8.17 (s, lH, 3-Ar-H), 7.91 (s, IH, imid-Ar-H), 7.75 (m, lH, 7-Ar-H), 7.65 (m, lH, 6-Ar-H), 6.23 (s, lH, imid-Ar-H), 4.19 (m, lH, a-CH), 232 (m, 2H, CH2), 1.88 (m, 15H, adamantyl protons); ESIMS: m/z 459 (M+l); Analysis for C26H3oN6O2 (458.6), calcd: C, 68.10; H, 6.59; N, 18.33; found; C, 68.08; H, 6.57; N, 18.32.
N2-[(1S)-l-hydrazinocarbonylbutyl]-4-(l-adamantyl)-2-quinolinecarboxamide.3HBr (18)
Yield: 95%; semi-solid; 1H NMR (CD3OD): δ 9.10 (d, 1H, 8-Ar-H, J= 8.9 Hz), 8.54 (m, 2H, 5-Ar-H & 3-Ar-H), 8.14 (m, 1H, 7-Ar-H), 8.00 (m, 1H, 6-Ar-H), 4.85 (m, 1H, a-CH), 3.10 (m, 2H, N-CH2), 2.17 (m, 2H, CH2), 1.88 (m, 15H, adamntyl protons), 1.30 (m, 2H, CH2); MALDIMS: m/z 436 (M+l); Analysis for C25H36Br3N5O2 (678.3), calcd: C, 44.27; H, 5.35; N, 10.32; found: C, 44.21; H, 5.28; N, 10.27.
N2-[(1S)-l-hydrazinocarbonylpentyl]-4-(l-adamantyl)-2-quinolinecarboxamide.3HBr (19)
Yield: 95%; semi-solid; 1H NMR (CD3OD): δ 9.00 (d, 1H, 8-Ar-H, J= 8.8 Hz), 8.41 (d, IH, 5-Ar-H, J= 8.4 Hz), 8.36 (s, 1H, 3-Ar-H), 7.99 (m, 1H, 7-Ar-H), 7.87 (m, 1H, 6-Ar-H), 4.77 (m, 1H, a-CH), 2.98 (m, 2H, N-CH2), 2.09 (m, 2H, CH2), 1.88 (m, 15H, adamantyl protons), 1.30 (m, 4H, 2 x CH2); ESIMS: m/z 450 (M+l); Analysis for C26H38Br3N5O2 (692.3), calcd: C, 45.11; H, 5.53; N, 10.12; found: C, 45.07; H, 5.49; N, 10.07.
N2-[(1S)-l-hydrazinocarbonyl-2-(4-hydroxyphenyl)ethyl]-4-(l-adamantyl)-2-quinoline-carboxamide. 2HBr (20)
Yield: 95%; semi-solid; 1H NMR (CD3OD): δ 8.98 (d, 1H, 8-Ar-H, J= 8.8 Hz), 8.37 (d, 1H, 5-Ar-H, J= 8.3 Hz), 8.20 (s, 1H, 3-Ar-H), 8.02 (m, 1H, 7-Ar-H), 7.88 (d, 2H, Ar-H, J= 8.1 Hz), 7.17 (d, 2H, Ar-H, J= 8.1 Hz), 6.74 (d, 2H, Ar-H, J= 7.7 Hz), 3.34 (s, 2H, CH2), 1.88 (m, 15H, adamantyl protons); ESIMS: m/z 485 (M+l); Analysis for C29H34 Br2N4O3 (646.4), calcd: C, 53.88; H, 5.30; N, 8.67; found: C, 53.78; H, 5.27; N, 8.63.
General procedure for the synthesis of {l-[(S)-N'-(4-Adamantan-l-yl-quinoline-2-carbonyl)-hydrazinocarbonyl] alkyl-carbamic acid tert-batyl esters (22-31, Scheme 2) To a solution of 4-(adamantan-l-yl)-quinoline-2-carbohydrazide (21, 0.1 g, 0.31 mmol) in DCM (15 mL), Boc-L/D-AA-OH (0.08 g, 0.35 mmol), DCC (0.07 g, 0.35 mmol) and DMAP (0.02 mg, 0.16 mmol) were added. The reaction mixture was stirred for 8 h at ambient temperature. Solvent was removed under reduced pressure to afford semi-solid residue. The residue was dissolved in ethyl acetate (3 mL) and kept in the refrigerator for 8 h. The precipitated dicyclohexylurea was removed by filtration, and solvent was removed under reduced pressure to afford crude product, which upon column chromatographic purification over silica gel (230-400 mesh) using ethyl acetate:hexane (8:92) gave compounds 22-31 in moderate yields.
{l-[(S)-N'-(4-Adamantan-l-yl-quinoline-2-carbonyl)hydrazinocarbonyl]-{4-(N,N'-bis-benzyloxycarbonylguanidinobutyl}carbamic acid tert-butyl ester (22)
Yield: 27%; mp: 180-182 °C (dec.); 1H NMR (CDC13): δ 9.60 (bs, 1H, NH, exchangeable with D2O), 9.45 (bs, 1H, NH, exchangeable with D2O), 9.34 (bs, 1H, NH, exchangeable with D2O), 9.13 (bs, 1H, NH, exchangeable with D2O), 8.66 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.11 (m, 2H, 3-Ar-H & 5-Ar-H), 7.70 (m, 1H, 7-Ar-H), 7.58 (m, 1H, 6-Ar-H), 7.25 (m, 10H, phenyl protons), 5.25 (s, 2H, CH2), 5.23 (s, 2H, CH2), 4.45 (m, 1H, α-CH), 2.04 (m, 2H, CH2), 1.88 (m, 15H, adamantyl protons), 1.72 (m, 2H, CH2), 1.45 (s, 9H, 3 x CH3), 1.33 (m, 2H, CH2); MALDIMS: m/z 846 (M+l); Analysis for C47H55O8 (845.9), calcd: C, 66.73; H, 6.55; N, 11.59; found: C, 66.79; H, 6.49; N, 11.55.
[2-[(S)-N'-(4-Adamantan-l-yl-quinoline-2-carbonyl)hydrazino]-l-(3H-imidazol-4-ylmethyl)-2-oxoethyI ]carbamic acid tert-butyl ester (23)
Yield: 30%; mp: 182-184 °C (dec.); 1H NMR (CDC13): δ 8.67 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.20 (s, 1H, 3-Ar-H), 8.14 (d, 1H, 5-Ar-H, J= 8.1 Hz), 7.70 (m, 1H, 7-Ar-H), 7.58 (m, 2H, 6-Ar-H & imid-Ar-H), 6.90 (s, 1H, imid-Ar-H), 5.62 (bs, 1H, NH, exchangeable with D2O), 4.57 (m, 1H, a-CH), 3.10 (m, 2H, CH2), 1.88 (m, 15H, adamantyl protons), 1.47 (s, 9H, 3 x CH3); MALDIMS: m/z 559 (M+l); Analysis for C31H38N6O4 (558.6), calcd: C, 66.65; H, 6.86; N, 15.04; found: C, 66.69; H, 6.89; N, 15.09.
{5-[(S)-N'-(4-Adamantan-l-yl-quinoline-2-carbonyl)hydrazino]-4-tert-butoxycarbonyl-amino-5-oxopentyl}carbamic acid tert-butyl ester (24)
Yield: 35%; mp: 175-177 °C (dec.); 1H NMR (CDC13): δ 10.11 (bs, 1H, NH, exchangeable with D2O), 9.25 (bs, 1H, NH, exchangeable with D2O), 8.65 (d, 1H, 8-Ar-H, J= 8.6 Hz), 8.14 (m, 2H, 3-Ar-H & 5-Ar-H), 7.69 (m, 1H, 7-Ar-H), 7.57 (m, 1H, 6-Ar-H), 4.51 (m, 1H, a-CH), 3.14 (m, 2H, CH2), 1.88 (m, 15H, adamantyl protons), 1.44 (s, 18H, 6 x CH3), 1.28 (m, 4H, 2 x CH2); MALDIMS: m/z 636 (M+1); Analysis for C35H49N5O6 (635.7), calcd: C, 66.12; H, 7.77; N, 11.02; found: C, 66.18; H, 7.79; N, 11.05.
{6-[(S)-N'-(4-Adamantan-l-yl-quinoline-2-carbonyl)hydrazino]-5-tert-butoxycarbonyI-amino-6-oxohexyl }carbamic acid benzyl ester (25)
Yield: 37%; mp: 178-180 °C (dec.); 1H NMR (CDC13): δ 9.48 (bs, 1H, NH, exchangeable with D2O), 8.65 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.19 (m, 2H, 3-Ar-H & 5-Ar-H), 7.69 (m, 1H, 7-Ar-H), 7.58 (m, 1H, 6-Ar-H), 7.31 (m, 5H, phenyl protons), 5.08 (s, 2H, CH2), 4.35 (m, 1H, α-CH), 3.19 (m, 2H, CH2), 1.88 (m, 15H, adamantyl protons), 1.52 (m, 6H, 3 x CH2), 1.42 (s, 9H, 3 x CH3); MALDIMS: m/z 684 (M+1); Analysis for C39H49N5O6 (683.8), calcd: C, 68.50; H, 7.22; N, 10.24; found: C, 68.54; H, 7.25; N, 10.29.
[2-[(S)-N'-(4-Adamantan-l-yl-quinoline-2-carbonyl)hydrazino]-l-(lH-indoI-2-yl-methyI)-2-oxoethyl]carbamic acid tert-butyl ester (26)
Yield: 32%; mp: 176-178 °C (dec.); 1H NMR (CDC13): δ 10.19 (bs, 1H, NH, exchangeable wiui D2O), 8.65 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.22 (bs, 1H, NH, exchangeable with D2O), 8.14 (m, 2H, 3-Ar-H & 5-Ar-H), 7.69 (m, 2H, 7-Ar-H, Ar-H), 7.52 (m, 1H, 6-Ar-H), 7.50 (m, 3H, Ar-H), 7.37 (d, 1H, Ar-H, J= 7.7 Hz), 4.20 (m, 1H, a-CH), 2.20 (s, 2H, CH2), 1.88 (m, 15H, adamantyl protons), 1.43 (s, 9H, 3 x CH3); MALDIMS: m/z 608 (M+1); Analysis for C36H41N5O4 (607.7), calcd: C, 71.15; H, 6.80; N, 11.52; found: C, 71.18; H, 6.85; N, 11.55.
{2-[(S)-N'-(4-Adamantan-l-yl-quinoIine-2-carbonyl)hydrazino]-l-benzyl-2-oxoethyl}-carbamic acid tert-butyl ester (27)
Yield: 35%; mp: 167-169 °C (dec.); 1H NMR (CDC13): δ 10.27 (bs, 1H, NH, exchangeable with D2O), 9.03 (bs, 1H, NH, exchangeable with D2O), 8.63 (d, 1H, 8-Ar-H, J= 8.2 Hz), 8.13 (m, 2H, 3-Ar-H & 5-Ar-H), 7.67 (m, 1H, 7-Ar-H), 7.55 (m, 1H, 6-Ar-H), 7.22 (m, 5H, phenyl protons), 4.56 (m, 1H, a-CH), 3.18 (d, 2H, CH2, J = 6.4 Hz), 1.88 (m, 15H, adamantyl
protons), 1.38 (s, 9H, 3 x CH3); MALDIMS: m/z 569 (M+l); Analysis for C34H40N4O4 "368.7), calcd: C, 71.81; H, 7.09; N, 9.85; found: C, 71.84; H, 7.05; N, 9.80.
{2-[(S)-N'-(4-Adamantan-l-yl-quinoline-2-carbonyl)hydrazino]-l-methyI-2-oxoethyl}-carbamic acid tert-butyl ester (28)
Yield: 30%; mp: 173-175 °C (dec.); 1H NMR (CDC13): δ 8.61 (d, 1H, 8-Ar-H, J = 8.6 Hz), 8.10 (m, 2H, 3-Ar-H & 5-Ar-H), 7.64 (m, 1H, 7-Ar-H), 7.54 (m, 1H, 6-Ar-H), 4.56 (m, 1H, a-CH), 1.88 (m, 15H, adamantyl protons), 1.51 (d, 3H, CH3, J= 6.7 Hz), 1.44 (s, 9H, 3 x CH3); MALDIMS: m/z 493 (M+l); Analysis for C28H36N4O4 (492.6), calcd: C, 68.27; H, 7.37; N, 11.37; found: C, 68.29; H, 7.39; N, 11.42.
[2-[(S)-N'-(4-Adamantan-l-yl-quinoline-2-carbonyl)hydrazino]-l-(4-benzyloxybenzyl)-2-oxoethyl]carbamic acid tert-butyl ester (29)
Yield: 38%; mp: 173-175 °C (dec.); 1H NMR (CDC13): δ 10.29 (bs, 1H, NH, exchangeable with D2O), 8.66 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.16 (m, 2H, 3-Ar-H & 5-Ar-H), 7.70 (m, 1H, 7-Ar-H), 7.58 (m, 1H, 6-Ar-H), 7.36 (m, 5H, phenyl protons), 7.23 (d, 2H, Ar-H, J= 8.5 Hz), 6.92 (d, 2H, Ar-H, J= 8.5 Hz), 5.02 (s, 2H, CH2), 4.55 (m, 1H, α-CH), 3.15 (d, 2H, CH2, J = 6.5 Hz), 1.88 (m, 15H, adamantyl protons), 1.42 (s, 9H, 3 x CH3); MALDIMS: m/z 675(M+1); Analysis for C41H46N4O5 (674.8), calcd: C, 72.97; H, 6.87; N, 8.30; found: C, 72.95; H, 6.82; N, 8.35.
{l-[(S)-N'-(4-Adamantan-l-yl-quinoline-2-carbonyl)hydrazinocarbonyl]-3-methyl-sulfanylpropyl}carbamic acid tert-butyl ester (30)
Yield: 25%; mp: 175-177 °C (dec.); 1H NMR (CDC13): δ 8.63 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.14 (m, 2H, 3-Ar-H & 5-Ar-H), 7.62 (m, 1H, 7-Ar-H), 7.51 (m, 1H, 6-Ar-H), 4.51 (m, 1H, α-CH), 2.62 (m, 2H, CH2), 2.21 (m, 2H, CH2), 2.15 (s, 3H, SCH3), 1.88 (m, 15H, adamantyl protons), 1.42 (s, 9H, 3 x CH3); MALDIMS: m/z 553 (M+l); Analysis for C30H40N4O4S (552.7), calcd: C, 65.19; H, 7.29; N, 10.14; found: C, 65.23; H, 7.33; N, 10.45.
{l-[(S)-N'-(4-Adaraantan-l-yl-quinoline-l-carbonyl)hydrazinocarbonyl]-3-carbamoyl-tropyl}carbamic acid tert-butyl ester (31)
Yield: 30%; mp: 173-175 °C (dec.); 1H NMR (CDC13): δ 9.88 (bs, 1H, NH, exchangeable with D2O) 8.67 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.15 (m, 2H, 3-Ar-H & 5-Ar-H), 7.70 (m, 1H, 7-Ar-H), 7.59 (m, 1H, 6-Ar-H), 4.56 (m, 1H, a-CH), 1.88 (m, 15H, adamantyl protons), 1.67 (m, 2H, CH2), 1.47 (s, 9H, 3 x CH3), 1.16 (m, 2H, CH2); MALDIMS: m/z 550 (M+1): Analysis for C30H39N5O5 (549.7), calcd: C, 65.55; H, 7.15; N, 12.74; found: C, 65.59; H, 7.12; N, 12.72.
General method for the synthesis of (S)-4-adamantan-l-yl-quinoline-2-carboxylic acid N-(2-aminoalkyl) hydrazides (32-41, Scheme 2)
A solution of 33% HBr in acetic acid (3 mL) was added to (S)-{l-[N'-(4-adamantan-l-yl-quinoline-2-carbonyl)hydrazinocarbonyl]alkylcarbamic acid tert-butyl ester (22-31, 0.1 mmol), and reaction mixture was stirred at ambient temperature for 30 min. Solvent was removed under reduced pressure to afford (S) 4-adamantan-l-yl-quinoline-2-carboxylic acid N'-(2-aminoalkyl)-hydrazides 32-41 as their hydrobromide salts.
(S)-{5-[N'-(4-Adamantan-l-yl-2-carbonyl) hydrazino]-4-amino-5-oxopentyl}guanidine .3HBr (32)
Yield: 95%; mp: 140-142 °C (dec.); 1H NMR (CD3OD): δ 9.15 (bs, 1H, NH, exchangeable with D2O), 8.88 (d, 1H, 8-Ar-H, J= 7.9 Hz), 8.57 (bs, 1H, NH, exchangeable with D2O), 8.33 (m, 1H, 5-Ar-H, J= 8.4 Hz), 8.23 (s, 1H, 3-Ar-H), 7.90 (m, 1H, 7-Ar-H), 7.80 (m, 1H, 6-Ar-H), 4.20 (m, 1H, α-CH), 2.04 (m, 2H, CH2), 1.88 (m, 15H, adamantyl protons), 1.72 (m, 2H, CH2), 1.33 (m, 2H, CH2); MALDIMS: m/z 478 (M+1); Analysis for C26H3SBr3N7O2 (720.3), calcd: C, 43.35; H, 5.32; N, 13.61; found: C, 43.32; H, 5.35; N, 13.64.
(S}-4-Adamantan-l-yl-qumoline-2-carboxylic acid N'-[2-amino-3-(3H-imidazoI-4-yl)-propionyl]hydrazide.3HBr (33)
Yield: 95%; mp: 165-167 °C (dec.); 1H NMR (CD3OD): δ 8.77 (d, 1H, 8-Ar-H, J= 8.7 Hz), 8.34 (d, 1H, 5-Ar-H, J= 8.1 Hz), 8.25 (s, 1H, 3-Ar-H), 7.75 (m, 1H, 7-Ar-H), 7.62 (m, 2H, 6-Ar-H & imid/-Ar-H), 6.92 (s, 1H, imid-Ar-H), 4.37 (m, 1H, a-CH), 2.91 (m, 2H, CH2), 1.88 (m, 15H, adamantyl protons); MALDIMS: m/z 459 (M+1); Analysis for C26H33 Br3N6O2 (701.2), calcd: C, 44.53; H, 4.74; N, 1 1.98; found: C, 44.56; H, 4.78; N, 1 1.97.
(S)-4-Adamantan-l-yl-quinoIine-2-carboxyIic acid N'-(2,5-diaminopentanoyl)hydrazide 3HBr (34)
Yield: 90%; semi-solid; 1H NMR (CD3OD): δ 8.76 (d, 1H, 8-Ar-H, J= 8.6 Hz), 8.25 (d, 1H, 5-Ar-H, J= 8.3 Hz), 8.14 (s, 1H, 3-Ar-H), 7.77 (m, 1H, 7-Ar-H), 7.71 (m, 1H, 6-Ar-H), 4.11 (m, 1H, a-CH), 3.07 (m, 2H, CH2), 2.10 (m, 2H, CH2), 1.88 (m, 15H, adamantyl protons), 1.28 (m, 2H, CH2); MALDIMS: m/z 436 (M+l); Analysis for C25H36Br3N5O6 (678.3), calcd: C, 44.27; H, 5.35; N, 10.32; found: C, 44.23; H, 5.31; N, 10.28.
(S)-4-Adamantan-l-yl-quinoline-2-carboxylic acid N-(2,6-diaminohexanoyl)hydrazide .3HBr (35)
Yield: 92%; mp: 172-174 °C (dec.); 1H NMR (CD3OD): 8.99 (d, 1H, 8-Ar-H, J = 8.7 Hz), 8.33 (d, 1H, 5-Ar-H, J= 8.7 Hz), 8.23 (s, 1H, 3-Ar-H), 7.90 (m, 1H, 7-Ar-H), 7.79 (m, 1H, 6-Ar-H), 4.13 (m, 1H, a-CH), 3.04 (m, 2H, CH2), 2.07 (m, 2H, CH2), 1.88 (m, 15H, adamantyl protons), 1.30 (m, 4H, 2 x CH2); MALDIMS: m/z 450 (M+l); Analysis for C26H38Br3N5O2 (692.3), calcd: C, 45.11; H, 5.53; N, 10.12; found: C, 45.07; H, 5.49; N, 10.09.
(S)-4-Adamantan-l-yl-quinoline-2-carboxylic acid N-[2-amino-3-(lH-indol-2-yl)-propionyl]hydrazide.2HBr (36)
Yield: 94%; mp: 176-178 °C (dec.); 1H NMR (CD3OD): δ 8.78 (d, 1H, 8-Ar-H, J= 8.6 Hz),
8.24 (d, 1H, 5-Ar-H, J= 8.3 Hz), 8.16 (s, 1H, 3-Ar-H), 7.78 (m, 3H, 7-Ar-H & Ar-H), 7.42
(m, 1H, 6-Ar-H), 7.34 (s, 1H, Ar-H), 7.11 (m, 2H, Ar-H), 4.30 (m, 1H, a-CH), 2.30 (s, 2H,
CH2), 1.88 (m, 15H, adamantyl protons); MALDIMS: m/z 507 (M+l); Analysis for
C31H35Br2N5O2 (749.4), calcd: C, 49.69; H, 4.71; N, 9.35; found: C, 49.63; H, 4.67; N, 9.33.
(S)-4-Adamantan-l-yl-quinoline-2-carboxylic acid N'-(2-amino-3-phenylpropionyl)-
hydrazide.2HBr (37)
Yield: 90%; mp: 172-174 °C (dec.); 1H NMR (CD3OD): δ 8.78 (d, 1H, 8-Ar-H, J= 8.7 Hz),
8.25 (d, 1H, 5-Ar-H, J = 8.2 Hz), 8.14 (s, 1H, 3-Ar-H), 7.81 (m, 1H, 7-Ar-H), 7.71 (m, 1H, 6-
Ar-H), 7.44 (m, 5H, phenyl protons), 4.32 (m, 1H, a-CH), 3.18 (d, 2H, CH2, J= 6.4 Hz), 1.88
(m, 15H, adamantyl protons); MALDIMS: m/z 469 (M+l); Analysis for C29H34Br2N4O2
(630.4), calcd: C, 55.25; H, 5.44; N, 8.89; found: C, 55.21; H, 5,44; N, 8.93.
(S)-4-Adamantan-l-yl-quinoline-2-carboxylic acid N-(2-aminopropionyl)hydrazide .2HBr (38)
Yield: 91%; mp: 175-177 °C (dec.); 1H NMR (CD3OD): δ 8.89 (d, 1H, 8-Ar-H, J= 8.6 Hz), 8.37 (d, 1H, 5-Ar-H, J= 8.4 Hz), 8.25 (s, 1H, 3-Ar-H), 7.93 (m, 1H, 7-Ar-H), 7.83 (m, 1H, 6-Ar-H), 4.14 (m, 1H, α-CH), 1.88 (m, 15H, adamantyl protons), 1.57 (d, 3H, CH3, J= 6.8 Hz); MALDIMS: m/z 393 (M+l); Analysis for C23H30Br2N4O2 (554.3), calcd: C, 49.84; H, 5.46; N, 10.11; found: C, 49.87; H, 5.49; N, 10.15.
(S)-4-Adamantan-l-yl-quinoline-2-carboxylic acid N'-[2-amino-3-(4-hydroxyphenyl)-propionyl]hydrazide.2HBr (39)
Yield: 90%; mp: 173-175 °C (dec.); 1H NMR (CD3OD): δ 8.89 (d, 1H, 8-Ar-H, J= 8.8 Hz), 8.33 (d, 1H, 7-Ar-H, J= 8.5 Hz), 8.24 (s, 1H, 3-Ar-H), 7.90 (m, 1H, 7-Ar-H), 7.79 (m, 1H, 6-Ar-H), 7.22 (d, 2H, Ar-H, J= 8.1 Hz), 6.82 (d, 2H, Ar-H, J= 8.2 Hz), 4.20 (m, 1H, a-CH), 1.96 (d, 2H, CH2, J= 6.5 Hz), 1.88 (m, 15H, adamantyl protons); MALDIMS: m/z 575 (M+l); Analysis for C29H34Br2N4O3 (646.4), calcd: C, 53.88; H, 5.30; N, 8.67; found: C, 53.84; H, 5.32; N, 8.69.
(S)-4-Adamantan-l-yl-quinoline-2-carboxylic acid N'-(2-amino-4-methylsuIfanyl-butyryl)hydrazide.2HBr (40)
Yield: 93%; mp: 173-175 °C (dec.); 1H NMR (CD3OD): δ 8.76 (d, 1H, 8-Ar-H, J= 8.3 Hz), 8.33 (d, 1H, 5-Ar-H, J= 8.3 Hz), 8.14 (s, 1H, 3-Ar-H), 7.77 (m, 1H, 7-Ar-H), 7.70 (m, 1H, 6-Ar-H), 4.20 (m, 1H, a-CH), 2.60 (m, 2H, CH2), 2.25 (m, 2H, CH2), 2.15 (s, 3H, SCH3), 1.88 (m, 15H, adamantyl protons); MALDIMS: m/z 453 (M+l); Analysis for C25H34Br2N4O2S (614.4), calcd: C, 48.87; H, 5.58; N, 9.12; found: C, 48.93; H, 5.61; N, 9.14.
BIOLOGICAL ACTIVITIES
In vitro activity of the 4-(1-adamantyl)-2-substituted quinolines for tuberculosis inhibition against M. tuberculosis H37Rv strain (ATCC 27294, susceptible both to rifatnpicin and isoniazid) was initially carried out using the Microplate Alamar Blue Assay (MABA). As a result a concentration of 6.25 µg/mL is finalized as standard dose.
Compounds exhibiting fluorescence at the standard concentration (6.25 µg/mL) were then tested in the BACTEC 460 radiometric system for activities expressed as Minimum Inhibitory Concentration (MIC, µg/mL). The obtained results are summarized in Tables 1-2. Compounds
demonstrating >90% inhibition at a concentration of 6.25 µg/mL in the initial screen were then pretested to determine the actual MIC value that is defined as the lowest concentration exhibiting >90% inhibition.
Synthetic modifications of 4-l-adamantyl-quinoline-2-carboxilic acid is done by coupling it with various D/L-amino acids was achieved (I). For modification, the selection of the amino acid was carried out in such a way so as to determine the effect of the following;
1. Hydrophobicity -by incorporating alanine (Ala), leucine (Leu), isoleucine (Ileu)
2. Hydrophilicity - by incorporating tyrosine (Tyr), methionine (Met), lysine (Lys) and
3. Unnatural amino acid ornithine (Orn).
In general, all ester derivatives of the amino acid conjugates were found more effective than their hydrazide counterparts; with ala analogue 13 being the sole aberration. Analogue 13 displayed 82% inhibition at the test concentration of 6.25 µg/mL; whereas, its methyl ester counterpart 5 only produced 73% inhibition at same test concentration. The most effective compound from the series was the methionine analogue 8 (R1 = CH3), which produced 86% inhibition at MIC of 6.25 )µg/mL. Interestingly, conversion of the methyl ester of methionine analogue 8 to corresponding hydrazide derivative 16 (R1 = NHNH2) resulted in marked reduction in the biological activity (68% inhibition, MIC = 6.25 µg/mL). In case of leu amino acid, both ester and hydarzide analogues 7 and 15 exhibited 83% inhibition at the test concentration of 6.25µg/mL. Cationic amino acid derivatives 18 and 19 displayed 48% and 36% inhibition respectively at 6.25 µg/mL (Table 1).
Table 1. In vitro antimycobacterial activity evaluation of methyl 2-[4-(l-adamantyl)-2-quinonylcarboxamido]alkanoate and N2-[1 -hydrazino-carbonylalkyl]-4-( 1 -adamantyl)-2-quinoline-carboxamides 5-20 derivatives against drug-sensitive M tuberculosis H37Rv strain.
(Table Removed)
The most effective tryptophan-quinoline conjugated analogue 26 [R1 = CO2C(CH3)3] of the series (II) exhibited 95% inhibition at the preliminary test concentration of 6.25 µg/mL. Similarly, histidine-ring-substituted quinoline conjugated analogue 23 [R1 = CO2C(CH3)3] displayed promising 92% inhibition at the preliminary test concentration of 6.25 µg/mL (Table
2).
Table 2. In vitro antimycobacterial activity evaluation of (S)-{l-[N'-(4-Adamantan-l-yl-quinoline-2-carbonyl)hydrazinocarbonyl]alkyl carbamic acid tert-butyl esters and (S)-4-adamantan-l-yl-quinoline-2-carboxylic acid N'-(2-aminoalkyl)hydrazides 22-40 derivatives against drug-sensitive M. tuberculosis H37Rv strain.
(Table Removed)
At the same time, hydrophobic side chain containing amino acid conjugates have shown moderate antimycobacterial activity with inhibition in the range of 42-88% at the concentration 6.25 µg/mL. Of these analogues, the most effective was the ala-quinoline conjugated analogue 28 [R1 = CO2C(CH3)3] which displayed 88% inhibition at the test concentration of 6.25 µg/mL. To our surprise, when the t-Boc protection of the amino group in 28 was removed, resulting compound 38 displayed marked reduction in the antimycobacteraial activity. A general observation of the already acquired results in this series predicts that heteroaromatic side-chain containing amino acid conjugates of 4-(l-adamantyl)-2-
substitutedquinolines are better anti-tuberculosis agents compared to their non-heteroaromatic side-chain containing counterparts.

We claim:
1. A process for producing a compound of 4-(l-adamantyl)-2-substituted quinoline derivatives, as new structural class of anti-tuberculosis agents comprising general
(Formula Removed)
formula (i)
2. The process as claimed in claim 1,Wherein the said compound 'X" is selected from formula (ii) or (iii)
(Formula Removed)
wherein,
R represents side-chain present in all D and L amino acids, R1 represents -H, H3; C2H5; C3H7; NHNH2; CO2C(CH3)3; CO2CH2C6H5; CO2CH3; CO2C2H5; CO3C2H7. 3. The process as claimed in claim 1 is carried out in two schemes 1 and 2
a) Scheme 1- Synthesizing 4-(Adamantan-l-yl)-quinoline-2-carboxylic acid from commercially available quinoline-2-carboxylic acid (1). i. Acid chloride derivatives are obtained by adding thionyl chloride to 4-
(Adamantan-1 -yl)-quinoline-2-carboxylic acid, ii. Step (i) is carried out in the presence of pyridine for one minute, iii. Acid chloride derivative obtained in step b reacts with commercially
available suitably side-chain protected L/D-amino acid methyl esters produce
iv. Step (iii) is performed in the presence of 4-(dimethylamino) pyridine
(DMAP) in Dichloromethane (DCM),
v. 4-(adamantyl-l-yl)- quinoline-2-carboxylic acid (1-hydrazinocarbonylalkyl) amides (13-17) is produced by the reaction of methyl esters (5-12) with hydrazine hydrate in presence of abs. ethanol for 48 h at ambient temperature.
vi. Deprotection step is performed for side chain protected compounds by reaction with 33% HBr in acetic acid at ambient temperature for 30 min to produce 4-(adamantyl-l-yl)-quinoline-2-carboxylic acid (1-hydrazinocarbonyl-alkyl) amides 18-20 as their hydrobromide salts. vii. The deprotection step (vi) is carried out for side chain protected compounds selected from a group comprising Orn, Lys with carbobenzyloxy and Tyr with benzyl, b) Scheme 2- synthesizing 4-(Adamantan-l-yl)- quinoline-2-carbohydrazide (21)
from commercially available quinoline-2-carboxylic acid (1). i. Reaction of 4-(Adamantan-l-yl)-quinoline-2-carbohydrazide with side-chain protected commercially available Boc/Cbz-L/D-amino acids ii. Step (i) is carried out in the presence of 1,3-dicyclohexylcarbodiimide
(DCC) and DMAP in anhydrous DCM as solvent for 8 h afforded Boc/Cbz-group protected quinoline-amino acid conjugates (S)-{l-[N'-(4-adamantan-l-yl-quinoline-2-carbonyl)-hydrazine carbonyl] alkyl carbamic acid tert-bulyl esters 22-31.
iii. (S)-{l-[N'-(4-adamantan-l-yl-quinoline-2-carbonyl)-hydrazine carbonyl] alkyl carbamic acid tert-butyl esters reacts with 33% hydrogen bromide solution in acetic acid at ambient temperature for 30 min to produce 4-(adamantan-l-yl)quinoline-2-carboxylic N'-(2-aminoalkyl) hydrazides 32-40 as hydrobromide salt.
A process for producing a compound of 4-(l-adamantyl)-2-substituted quinoline derivatives substantially described herewith foregoing description and examples.

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Patent Number

268314

Indian Patent Application Number

1024/DEL/2006

PG Journal Number

35/2015

Publication Date

28-Aug-2015

Grant Date

25-Aug-2015

Date of Filing

20-Apr-2006

Name of Patentee

NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH

Applicant Address

SECTOR 67, S.A.S.NAGAR, PUNJAB 160062,INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	RAHUL JAIN	DEPARTMENT OF MEDICINAL CHEMISTRY, NIPER, SECTOR 67, S.A.S.NAGAR, PUNJAB - 160062, INDIA.
2	AMIT NAYYAR	DEPARTMENT OF MEDICINAL CHEMISTRY, NIPER, SECTOR 67, S.A.S.NAGAR, PUNJAB - 160062, INDIA.

PCT International Classification Number

A61K 35/78

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA