Title of Invention

"NOVEL 4-ETHYL-5ALKOXYPRIMAQUINE COMPOUNDS"

Abstract The present invention relates to the synthesis and biological activities 4-ethyl-alkoxy primaquine analogues represented by general formula (I), used in the treatment and prevention of malaria, also having a unique blend of broad spectrum activity against the blood as well as tissue stages and resistant strains of the human malaria parasites thereby providing improved means for the chemotherapy of malaria.
Full Text Quinoline analogues with broad-spectrum anti-malarial
activities.
FIELD OF THE INVENTION
The present invention relates to 4-ethyl-5-alkoxy-pnmaquine analogues having a general formula 1 and its pharmaceutically acceptable salts thereof, their process of preparation and their biological activities of, which also offers an improved means for the chemotherapy of malaria.
(Formula Removed)
Wherein R1 represents 1 to 10 carbon atom containing straight-chain alkyl groups, R2 represents hydrogen or all (R)- and (S)-enantiomers of proteiogenic amino acids or L-unnatural amino acids or pro-prodrug anchors of the formula 2 and 3,
BACKGROUND OF THE INVENTION
An infectious disease crisis of global proportion is today threatening health care system of many countries. Malana, caused by protozoan belonging to the genus Plasmodium, is one of the most severe parasitic diseases. According to the World Health Organization (WHO) estimates, nearly four billion people, mostly in the tropical/impoverished countries, are at the risk of malana. Each year 2-3 million people, mostly youngsters, in more than one hundred countries die from malana, and its associated
complications Most malana deaths occur in sub-Saharan Africa, where malana accounts for one in five of all childhood deaths Women are especially vulnerable dunng pregnancy They are more likely to die from the disease, suffer miscarnages or give birth to premature, low-weight babies (Kevin, B J Drugs, 59, p 719, 2000) In India alone, 2 5-2 8 million clinical cases of malaria are reported annually Civil conflicts, large-scale human migrations, climatic and environmental changes, inadequate and detenorating health systems, growing insecticide and drug resistance have all combined to bnng about the resurgence of malana. Hence, malana remains a major burden to human health in tropical and subtropical areas
Four species of malana parasite cause disease in humans (Plasmodium falciparum, P vivax, P malaria, and P ovale) However, P falciparum and P vivax species are accountable for nearly 95% of malana cases, and P falciparum causes most problems as a result of its prevalence, virulence and drug resistance, and nearly all deaths are attnbuted to this single parasite species.
Life cycle of malana parasite has vanous stages, and each stage has different degree of susceptibility to available antimalanal agents. The currently available antimalanal agents are conveniently divided into following two categones i e blood-schizontocidal antimalanal agents, which exert their biological activity against the erythrocytic asexual (blood) stages of the malana parasite, and tissue-schizontocidal antimalanal agents, which exert their antimalanal action on the asexual exoerythrocytic (tissue) stages of the human malana parasite All of the available antimalanal drugs are losing their power to treat infection and have become inadequate for the treatment of malana infection P. falciparum has developed resistance against majonty of blood-schizontocides such as chloroquine and mefloquine On the other hand, available tissue-schizontocide such as pnmaquine is relatively ineffective against the blood schizonts. Additionally, the toxicity of pnmaquine requires it to be given in divided doses over 14 days to achieve radical curative effects in humans These problems could be alleviated by the development of compounds, which, while retaining the tissue-schizontocidal activity of 8-aminoquinolines, have increased blood-schizontocidal activity comparable to that of chloroquine and mefloquine This would enable single drug treatment for suppression as well as radical cure of the malana infection. The logical lead compound for this research is pnmaquine, pnmanly because of its weak to moderate biological effects against all of the stages of malana parasite. This observation is further supported by the facts that pnmaquine is found to have antimalanal activity against chloroquine and mefloquine resistant P. falciparum strains.
Despite research efforts of more than 60 years malaria is still one of the major killer of the world Majority of people suffenng from malaria belong to poorer section of society/countries, and are unable to afford expensive treatment One of the factors for the development of resistance to the majority of drugs is believed to be the poor patient compliance Therefore, elimination of expensive multi-drug therapies, with single drug will help in reducing the cost of treatment. This reduction in the cost would lead to more patient compliance This would give better results in the prevention, spread and treatment of malaria.
Most of the available antimalanal drugs are incapable and ineffective for the treatment of malarial infection Development of resistance by P falciparum has been documented against majonty of blood-schizontocides. Furthermore, available tissue-schizontocides are highly toxic for human use as causal prophylactics and gametocytocides
Pnmaquine, N8-(4-amino-l-methylbutyl)-6-methoxy-8-quinolinamine, is highly effective tissue-schizontocidal agent, and has direct and fast gametocytocidal action on all species of malanal parasite. The drug also has blood-schizontocidal activity but only at dangerously toxic doses for human use. Its high toxicity profile [methemoglobinemia and hemolysis particularly in individuals who are genetically deficient of glucose-6-phosphate dehydrogenase (G-6PD)] has largely deterred clinician from its safer use Recent reports suggested that 5-alkoxy pnmaquine denvatives have shown high blood-schizontocidal activity compared to pnmaquine (Chen, E. H., Tanabe, K., Saggiomo, A J and Nodiff, E. A J Med. Chem. 30, p 1193, 1987). Furthermore, 4-ethyl pnmaquine denvative has been found to have less toxicity when compared to pamaquine or its 4-methyl counterpart (Carroll, F I., Berrang, B., Linn, C. P and Twine, C. E. J. Med. Chem. 22, p 694, 1979)
The requisite N8-(4-amino-l-methylbutyl)-4-ethyl-6-methoxy-5-alkoxy-8-
quinolinamines denvatives (1, R2= H) were synthesized from appropnate 5-alkoxy-4-ethyl-8-amino-6-methoxyquinoline denvatives in two steps following the procedures reported earlier (Jain, R , Jain, S., Gupta, R. C , Anand, N, Dutta, G P and Pun, S K. Ind J Chem. 33B, p 251, 1994) The scheme is represented as herein below
(Scheme Removed)
Scheme-1 l) 1-chloro-3-pentanone, o-H3PO4, As2O5, 80 °C, 3 h, ll) raney-nickel (T1), EtOH, H2 40 psi, 45 min, lll) 2-(4-bromopentyl)-1,3-isoindolmedione, Et3N, 120 °C, 21 h, iv) hydrazine hydrate, EtOH, reflux, 6 h
Pamaquine is known to have very poor pharmacokinetic properties. Furthermore, the drug has a short half-life (4-6 hrs), low therapeutic index and high toxicity, which are the limiting factors in its use as a long acting drug. The duration of action of a drug is dependent on the rate at which it is absorbed, metabolized and excreted. The persistence of a drug in the body can be prolonged by delaying its degradation and excretion or by reducing its rate of absorption. These factors can be modified by prodrug approach, which involves appropriate chemical modification of the drug. Therefore, we have decided to synthesize a variety of amino acid denvatives of primaquine and recently emerged potential antimalarial agents as their prodrugs. The prodrugs were synthesized, which would possibly possess better therapeutic index and longer half-life compared to parent drugs
Synthesis of Compounds 3-(3',6'-Dioxo-2',4'-dimethyl-cyclohexa-i',4'-diene)-3,3-dimethylpropionic acid (4) (Amsberry, K. L and Borchardt, R T. J Org Chem. 55, p 5867, 1990) or 3-(2'-acetoxy-4',6'-dimethylphenyl)-3,3-dimethylpropionic acid (5) (Amsberry, K L., Gerstenberger, A. E. and Borchardt, R T. Pharm Res 8, p 255, 1991) has been reported in these prior arts
(Formula Removed)
It is well known that malaria parasites live in the hepatic cells as hypnozoites, become active periodically and thus their maximum population is found in the liver at the time of their activation Hence anti-relapse drugs in large concentrations are required in the liver to achieve radical cure of the disease Furthermore, it has been also found that the enzymes esterases and reductases are present in the liver at maximum levels. Therefore, it is ideal to synthesize drugs together with a earner molecule, which can carry the drug molecule to the site of action and be activated by esterases or reductases present in vivo.
In the light of the above discussion, the present invention describes a unique denvatization of amines, which imparts ester qualities (e.g. lability) to amide prodrugs to form pro-prodrugs. A pro-prodrug, by definition, is a derivative, which must undergo two independent reactions in order to regenerate the parent drug In the case of pro-prodrugs, the intermediate prodrug is a chemically reactive species, which rapidly undergoes chemical conversion to the parent drug under physiological conditions. However, this reactive prodrug is generated only after an enzymatic reaction on the chemically stable pro-prodrug. The biologically available esterases or reductases convert the pro-prodrug anchors chosen for this specific study into prodrug and then on chemical modification prodrug converts to the parent drug. The concept of hooking the pro-prodrug anchors represented by formula 4 and 5 mentioned above to the alkoxy substituted 8-aminoquinolines (I, R.2= H). In the presence of 1,3-dicyclohexylcarbodnmide and catalytic amount of 4-(dimethylamino)pyndine in an organic solvent at room temperature to obtain the pro-prodrug derivatives (1, R2= 2 or 3) in quantitative yield, which were optionally converted to their pharmaceutically acceptable salts.
OBJECTS OF THE INVENTION
The main object of the present invention is to provide analogues of compound having general formula (I) and its pharmaceutically acceptable salts for an improved means for chemotherapy of malaria.
Another object of the present invention is to provide an efficient synthetic route for the preparation of analogues of compound having formula (I)
Yet, another object of the present invention is to provide compound of formula (I) having a unique blend of broad-spectrum activity against the blood as well as tissue stages of the human malaria parasites.
Another object of the invention is to provide compounds having better antimalarial activity than the available antimalarial drug in the market.
Still another object of the present invention is to provide antimalarial agents to suppress as well as radical cure of the malaria infection with single drug therapy
Still yet another object of the present invention is to provide an easy and economical process for the preparation of compounds of general formula (I) to be used in the improved treatment of malaria
Another object of the present invention is to provide a broad range of activity against blood and tissue stages of the effected individuals.
Another object of the present invention is to provide compounds having antimalarial activity against drug resistant strains of malaria parasite
One more objedt of the invention is to provide a pharmaceutical composition comprising 4-ethyl-5-alkoxy-pnmaquine or its denvatives for treating malaria
SUMMARY OF THE INVENTION
Accordingly, the present invention provides biologically active denvatives of 4-ethyI-5-alkoxy-primaquine represented by the formula (I) and its process for the preparation to offer an improved means for the chemotherapy of malaria.
DETAIL DESCRIPTION OF THE INVENTION
In accordance to the objectives, the present invention provides compounds of 4-ethyl-5-alkoxypnmaquine denvatives represented by Formula (I) and its pharmaceutically acceptable salts having broad-spectrum anti-malarial activity
OR C2H5

(Formula Removed)
wherein R1 represents straight-chain alkyl groups containing 1 to 10 carbon atoms, R2 represents hydrogen or all (R)- and (S)-enantiomers of proteiogenic amino acids or L-unnatural amino acids or pro-prodrug anchors of the formula 2 and 3.
In an embodiment, the present invention provides the preferred compounds 4-ethyl-5-alkoxy-pnmaquine derivatives of general formula (I) are:
(Formula Removed)
In yet another embodiment, compounds of general formula (1) possess curative and suppressive activity against infection caused by parasites Plasmodium berghei, P.lasmodium yoelli nigeriensis and Plasmodium falciparum.
In yet another embodiment, compounds of general formula (1) are active in vivo and in vitro systems.
In another embodiment, compounds of general formula (1) are more effective in vitro susceptibility of an isolate of P.falciparum than the available drug chloroquine phosphate.
In yet another embodiment, compounds of general formula (1) wherein the pharmaceutically acceptable salts are selected from a group consisting of hydrochloride, sulphonate, citrate, maleate or camphor sulphonate salts.
In yet another embodiment, compounds of general formula (1) have in vitro IC50 value in the range of 10 ng/ml to 180 ng/ml.
In still another embodiment, compounds of general formula (1), provides single drug treatment for suppression as well as radical cure for all species of human malaria infection
In still another embodiment, compounds of general formula (1) have a unique blend of broad-spectrum activities against the blood as well as tissue stages of the human malana parasites.
In still yet another embodiment, compounds of general formula (1), wherein effective curative dosage is in the range of 5 mg/kg to 100 mg/kg for four days and followed up to sixty days
In still another embodiment, compounds of general formula (1), wherein suppressive dosage is in the range of 5-mg/kg to 100 mg/kg for four days and followed up to sixty days
In still yet another embodiment, a process for the preparation of compounds of formula (1), the said process composing steps of-
a) treating compound of formula (I-a) with suitable N-protected amino acid or propionic acid derivative of formula (4 or 5) in an organic solvent in presence of a condensing
agent, optionally an organic base at a temperature range of 0°C to room temperature for a period of 2 hrs to 12 hrs
b) brining the temperature of the reaction mixture of step (a) to room temperature, if required filtering to obtain a clear filtrate,
c) concentrating the clear filtrate of step(b) to obtain a residue
d) adding ethyl acetete to the residue of step (c), cooling to a temperature in the range of in 5 - 10°C, separating precipitated solid from the cooled solution to obtain a clear solution,
e) washing the clear solution of step(d) with saturated bicarbonate solution, followed by water, drying over anhydrous sodium sulphate, filtering and evaporating to afford a residue,
f) purifying the residue of step (e) over silica gel column using chloroform /methanol mixture as an eluant to yield the required product of formula (I) wherein R2 is defined above, and
g) optionally converting compound of step (f) to its pharmaceutically acceptable salts
(Scheme Removed)
Scheme-1. l) Z/Boc-AA-OH, DCC, DCM, 0 °C, Pd/C, H2, rt or 6N HCI, reflux, n) 3-(3',6'-Dioxo-2,,4,-dimethyl-cyclohexa-1',4'-diene)-3,3-dimethylpropionic acid (4) or 3-(2'-acetoxy-4',6'-dimethylphenyl)-3,3-dimethyl-propionic acid (5), DCC, DMAP, DCM, rt
In yet another embodiment, the organic solvent in step (a) is selected from a group consisting of carbon tetrachlonde, dichloromethane, chloroform, toluene or mixtures thereof
In still yet another embodiment, the amino acid used in step (a) is selected from a group consisting of R or S enantiomers of proteiogenic amino acids.
Another embodiment of the present invention provides a process, the protected amino acid in step (a) is selected from denvatives of N-tert-butoxycarbonyl and N-carbobenzyloxy denvatives of R or S enantiomers of proteiogenic amino acids or L-unnatural amino acids.
In yet another embodiment, the propionic acid derivative used in step (a) is selected from a group consisting of 3-(3',6'-dioxo-2',4'-dimethyl-cyclohexa-l,4'-diene)-3,3-dimethylprop-ionic acid or 3-(2'-acetoxy-4',6'-dimethylphenyl)-3,3-dimethylpropionic acid
Still yet another embodiment, in step (a) the condensing agent used is selected from a group consisting of 1,3-dicyclohexylcarbodnmide (DCC)
In still yet another embodiment, in step (a) the organic base used is selected from pyridine, piperidine, N-methyl pipendine or 4-(dimethyIamino) pyridine.
In still yet another embodiment, in step (a) the protected amino acid used is N-tert-butoxycarbonyl and N-carbobenzyloxy derivative of the amino acid.
In still yet another embodiment, in step (g), the deprotection of rerr-butoxycarbonyl group is performed by treating with methanohc hydrochlonc acid for 10-12 h and deprotection in the case of N-carboenzyloxy group with 10% Pd-C in the presence of H2 for 2 to 12 h.
Yet in another embodiment, in step (h) the acid used is selected from a group consisting of hydrochlonc acid, sulphomc acid, maleic acid, succinic acid, fumanc acid, or camphor sulphomc acid
In still another embodiment, a method of treating an ailment caused by malaria parasite in a subject, the said method compnsing administering a phrmaceutically effective dosage of 4-ethyl-5-alkoxy-pirmaquine denvatives or a combination thereof.
In yet another embodiment, a method wherein 4-ethyl-5-alkoxy-primaquine denvatives used singly or in combination with pharmaceutically acceptabl carners.
In yet another embodiment, a method wherein the 4-ethyl-5-alkoxy pnmaquine denvatives may be administered systemically or orally.
In ye't another embodimet, a method leads to the treatment of the pathological conditions of vanous stages caused by malanal parasites.
In an embodiment, the subject is selected from mammals.
In yet another embodiment the 4-ethyl-5-alkoxy pnmaquine denvatives are administered to the subject in combination with a pharmaceutically acceptable additive, carrier, diluent, solvent, filter, lubncant, excipient, binder or stabilizer
In an embodiment the 4-ethyl-5-alkoxy-pnmaquine denvatives represented by formula 1 described in the present invention offer a broad range of activity against blood and tissue stages of the infected individuals
The compounds (1a, R2= H) on reaction with Z- or Boc-protected amino acids in the presence of dicyclohexylcarbodrimide (DCC) in anhydrous dichloromethane afforded the protected amino acid derivatives in excellent yield. Removal of protective group from the latter compounds either by catalytic hydrogenation in the presence of 10% Pd-C or acid hydrolysis with 6N HC1 at reflux for 2 hours as in the case of Boc-group provided the N'-[4-(4-ethyl-6-methoxy-5-alkoxy-8-quinolylamino)pentyl]-2-amino-2-substituted acetamide derivatives (1, R2= various (R)- and (S)-amino acids) in quantitative yield.
Examples
The present invention is illustrated with the following examples, which should not be construed to limit the scope of the invention:
General Method for the synthesis of 4-ethyl-5-alkoxy-6-methoxy-8-nitroquinoline Method 1:
A homogeneous mixture of 3-alkoxy-4-methoxy-6-nitroanihne (Drake, N. L., Hams, H. C, Jaeger, C B. J. Am. Chem. Soc. 70, p 168, 1948; Jain, R., Jain, S , Gupta, R. C, Anand, N., Dutta, G. P. and Pun, S. K. Ind. J. Chem. 33B, p 251, 1994) (0.037 mol), l-chloro-3-pentanone (0.020 mol) and o-phosphonc acid (85%, 15 ml) was placed in a three necked flask fitted with a thermometer and a dropping funnel. The reaction mixture was heated at 80 °C (internal) with mechanical stirnng for 10 nun. An additional quantity of l-chloro-3-pentanone (0 020 mol) was added and stirnng continued for another 10 min at 80 °C Evolution of some hydrogen chlonde gas was observed. Arsenic (V) oxide (0 029 mol) was then added at once to the reaction mixture and stirnng was continued for 2.5 hr at 80 °C The dark colored mixture was cooled, diluted with water (100 mL) and filtered. The filtrate was basified with 25% NH4OH solution, extracted with dichloromethane (3 x 100 mL), washed with bnne (2 x 20 mL) and water (2 x 10 mL), and dned over sodium sulfate. The solvent was removed in vacuo to afford brown crude product. The latter was punfied by flash column chromatography on silica gel (230-400 mesh) using ethyl acetate/hexane (20 80) as eluant to afford 4-ethyl-5-alkoxy-6-methoxy-8-nitroquinoline (20-30%) as low melting orange solid. Method 2:
A stirred mixture of 4-ethyl-5-hydroxy-6-methoxy-8-nitroquinoIine (Carroll, F. I, Berrang, B. and Linn, C. P. J. Med. Chem. 28, p 1564, 1985) (0.01 mol), n-alkyl bromide (0.02 mol), triethylamine (0.003 mol), and hexamethylphosphonc tnamide (2 mL) was heated at 140-
min After 1 5 hr, additional amount of propylene oxide (1 mL) was added The reaction mixture was heated for another 1 hour at the same temperature and then cooled to room temperature, diluted with acetone (100 mL), and filtered The dark filtrate was concentrated and the residue was dissolved in ether The ethereal solution was extracted with dilute NaOH, washed with water, dried (K2CO3), and treated with charcoal. Removal of solvent left crude product, which was purified by flash column chromatography on silica gel (230-400 mesh) using ethyl acetate/hexane (20:80) as solvent to give 75-80% of 4-ethyl-alkoxy-6-methoxy-8-nitroquinoline as low melting solid.
Example 1 4-Ethyl-6-methoxy-5-propoxy-8-nitroquinoline
Yield: 69%; mp 43-44 °C, IR (KBr). 1529 and 1337 cm-1 (N02); 1H NMR (CDCl3) δ 8.76 (d, 1H, 2-Ar-H, J= 4.3 Hz), 7.84 (s, 1H, 7-Ar-H), 7.27 (d, 1H, 3-Ar-H, J= 4.3 Hz), 4 14 (t, 2H, OCH2, J= 6.8 Hz), 4.02 (s, 3H, OCH3), 3.32 (m, 2H, CH2), 1.90 (m, 2H, CH2), 1 33 (t, 3H, CH3, J= 7.4 Hz), 1 06 (t, 3H, CH3, J= 7.4 Hz); 13C NMR (CDCl3) 5 150 6, 150.4, 147 9, 147.0, 144.7, 136.7, 123.9, 123.2, 112.4, 75.9, 57.2, 30.0, 23.3, 15 4, 10.5; HRMS (ESI): m/z 291 (M+l)
Example 2 5-Butoxy-4-ethyl-6-methoxy-8-nitroquinoline
Yield: 68%, mp 51-52 °C; IR (KBr): 1528 and 1338 cm-1 (NO2), 1H NMR (CDC13) 5 8.76 (d, 1H, 2-Ar-H, J= 4.3 Hz), 7.84 (s, 1H, 7-Ar-H), 7.27 (d, 1H, 3-Ar-H, J= 4 3 Hz), 4.14 (t, 2H, OCH2, J= 6.8 Hz), 4.02 (s, 3H, OCH3), 3.32 (m, 2H, CH2), 1.90 (m, 2H, CH2), 1 50 (m, 2H, CH2), 1 30 (t, 3H, CH3, J= 7 4 Hz), 1.00 (t, 3H, CH3, J= 7.4 Hz); l3C NMR (CDCl3). 5 150 5, 150.1, 148 0, 147 2, 144 5, 136 6, 123.5, 123.0, 112.1, 75.7, 57 2, 30 1, 28 4, 23.2, 15 3, 10 4, HRMS (ESI)- m/z 305 (M+l). Example 3
4-Ethyl-6-methoxy-5-pentoxy-8-nitroquinoline
Yield: 80%; mp 47-48 °C, IR (KBr). 1530 and 1350 cm-1 (N02); 1H NMR (CDCl3)- 5 8 75 (d, 1H, 2-Ar-H, J= 4.4 Hz), 7.84 (s, 1H, 7-Ar-H), 7.26 (d, 1H, 3-Ar-H, J= 4.4 Hz), 4.14 (t, 2H, OCH2, J= 6.8 Hz), 4.02 (s, 3H, OCH3), 3.30 (m, 2H, CH2), 1.89 (m, 2H, CH2), 1.46 (m, 4H, 2 x CH2), 1.33(t, 3H, CH3, J= 7.3 Hz), 0.96 (t, 3H, CH3, J= 7.0 Hz); l3C NMR (CDCl3):
5 150.5, 150 4, 147 9, 146 9, 144 6, 136.6, 123 8, 123 1, 112 2, 74 4, 57 1, 29 6, 28 9, 28 4, 22 5, 15 4, 14 0; HRMS (ESI) m/z 319 (M+l).
Example 4 4-Ethyl-5-hexoxy-6-methoxy-8-nitroquinoIine
Yield 75%, mp 46-47 °C; IR (KBr) 1530 and 1350 cm-1 (NO2), 1H NMR (CDCl3) δ 8 62 (d, 1H, 2-Ar-H, J= 4.4 Hz), 7.74 (s, 1H, 7-Ar-H), 7 14 (d, 1H, 3-Ar-H, J= 4 4 Hz), 4 04 (t, 2H, OCH2, J= 6.8 Hz), 3.92 (s, 3H, OCH3), 3 2 (m, 2H, CH2), 1 77 (m, 2H, CH2), 1 41 (m, 2H, CH2), 1.25 (m, 4H, 2 x CH2), 1 19 (t, 3H, CH3, J= 7 4 Hz), 0 82 (t, 3H, CH3, J= 6.8 Hz), t3C NMR (CDCl3): δ 150 6, 147 9, 147 0, 144.7, 136.7, 123 9, 123.2, 112 3, 110.7, 74.5, 57 2, 31 7, 29 7, 29 0, 25.6, 22 7, 15.4, 14 1; MS (EI), m/z 332 (M+)
Example 5 4-Ethyl-5-heptoxy-6-methoxy-8-nitroquinoline
Yield: 63%; mp 41-42 °C;' IR (KBr): 1531 and 1340 cm-1 (NO2); 1H NMR (CDCl3): δ 8.75 (d, 1H, 2-Ar-H, J= 4.4 Hz), 7 84 (s, 1H, 7-Ar-H), 7.26 (d, 1H, 3-Ar-H, J= 4 4 Hz), 4 14 (t, 2H, OCH2, J= 6.8 Hz), 4.02 (s, 3H, OCH3), 3 3 (m, 2H, CH2), 1 89 (m, 2H, CH2), 1 46 (m, 8H, 4 x CH2), 1 33 (t, 3H, CH3, J= 7.3 Hz), 0 91 (t, 3H, CH3, J= 7.0 Hz); 13C NMR (CDC13): 6 150.6, 150.5, 147 7, 146 6, 144.8, 136 4, 123.9, 123 2, 112.0, 74 3, 57 0, 31.7, 29 6, 29.6, 29.2, 25 8, 22 5, 15 4, 14.1, HRMS (ESI): m/z 347 (M+l) Example 6
4-Ethyl-6-methoxy-5-octoxy-8-nitroquinoline
Yield- 32%; mp 40-41 °C; IR (KBr): 1532 and 1340 cm-1 (NO2); 1H NMR (CDCl3): δ 8 75 (d, 1H, 2-Ar-H, J= 4 2 Hz), 7 84 (s, 1H, 7-Ar-H), 7.26 (d, 1H, 3-Ar-H, J= 4 2 Hz), 4 16 (t, 2H, OCH2, J= 6.7 Hz), 4.02 (s, 3H, OCH3), 3.32 (m, 2H, CH2), 1 88 (m, 2H, CH2), 1.60-1 35 (m, 10H, 5 x CH2), 1.33 (t, 3H, CH3, J= 7.3 Hz), 0.91 (t, 3H, CH3, J= 7.0 Hz); l3C NMR (CDCl3): δ 150.4, 150 3, 147 8, 146.9, 144.6, 136 6, 123.8, 123 1, 112.3, 74.5, 57 1, 31 8, 30 0, 29.4, 29.3, 29 0, 25.9, 22.7, 15.3, 14.0; HRMS (ESI), m/z 361(M+1)
General method for the synthesis of 4-ethyl-5-alkoxy-6-methoxy-8-quinolinamine
A solution of 4-ethyl-5-alkoxy-6-methoxy-8-nitroquinohne (6.6 mmol) in ethyl alcohol (20 ml) was hydrogenated over raney nickel (T1 grade) for 45 min at 45 psi in a parr
hydrogenator Catalyst was removed by filtration, and solvent was removed in vacuo to
afford 4-ethyl-5-alkoxy-6-methoxy-8-quinolinarmne as brown oil
Example 7
4-Ethyl-6-methoxy-5-propoxy-8-quinolinamine
Yield: 94%, brown oil; IR (KBr)- 3427 and 762 cm-1 (NH2), 1H NMR (CDCl3) δ 8.46 (d,
1H, 2-Ar-H, J= 4 2 Hz), 7 14 (d, 1H, 3-Ar-H, J= 4 2 Hz), 6 75 (s, 1H, 7-Ar-H), 4 58 (bs, 2H,
NH2), 3 92 (s, 3H, OCH3), 3.87 (t, 2H, OCH2, J= 6 9 Hz), 3.27 (m, 2H, CH2), 1.87 (m, 2H,
CH2), 131 (t, 3H, CH3, J= 7 3 Hz), 1.05 (t, 3H, CH3, J= 7 0 Hz); ,3C NMR (CDC13)- 5
150 4, 149 8, 145.2, 141 0, 134 5, 134 4, 123 5, 122 3, 99.9, 75 8, 56 6, 28 6, 23 2, 14 2,
8.6, HRMS (APCI): m/z 261 (M+l)
Example 8
5-Butoxy-4-ethyl-6-methoxy-8-quinolinamine
Yield: 72%, brown oil, IR (KBr): 3434 cm-1 (NH2); 1H NMR (CDCl3): δ 8 48 (d, 1H, 2-Ar-
H, J= 4.2 Hz), 7.13 (d, 1H, 3-Ar-H, J= 4.2 Hz), 6.76 (s, 1H, 7-Ar-H), 4.58 (bs, 2H, NH2),
3 94 (s, 3H, OCH3), 3.87 (t, 2H, OCH2, J= 6.9 Hz), 3.25 (m, 2H, CH2), 1.81 (m, 4H, 2 x
CH2), 1 31 (t, 3H, CH3, J= 7 4 Hz), 0.95 (t, 3H, CH3, J= 7.1 Hz); 13C NMR (CDCl3): δ
149 5, 145.0, 141.3, 139 1, 134 2, 122.1, 122.1, 98.7, 97.2, 74.1, 56.5, 31 8, 30.1, 28 6, 15.4,
14.2; HRMS (APCI): m/z 275 (M+l).
Example 9
4-Ethyl-6-methoxy-5-pentoxy-8-quinoIinamine
Yield: 92%; brown oil; IR (KBr): 3349 and 760 cm-1 (NH2); 1H NMR (CDCl3) δ 8 47 (d,
1H, 2-Ar-H, J= 4 2 Hz), 7.13 (d, 1H, 3-Ar-H, J= 4 2 Hz), 6 76 (s, 1H, 7-Ar-H), 4 57 (bs, 2H,
NH2), 3.93 (s, 3H, OCH3), 3 88 (t, 2H, OCH2, J= 6.9 Hz), 3.26 (m, 2H, CH2), 1.84 (m, 2H,
CH2), 1 44 (m, 4H, 2 x CH2), 1 33 (t, 3H, CH3, J= 7.4 Hz), 0.95 (t, 3H, CH3, J= 7 I Hz), l3C
NMR (CDC13)- 5 149 9, 145.3, 1416, 139 5, 134 2, 122.1, 122 0, 98 8, 97 1, 74 4, 56.3,
31 9, 28 7, 25 7, 22.5, 15 4, 14 0; HRMS (APCI): m/z 289 (M+l)
Example 10
4-EthyI-5-hexoxy-6-methoxy-8-quinolinamine
Yield, 95%, brown oil; IR (KBr) 3381 and 758 cm-1 (NH2), 1H NMR (CDC13)- δ 8 47 (d,
1H, 2-Ar-H, J= 4 2 Hz), 7 13 (d, 1H, 3-Ar-H, J= 4 2 Hz), 6 76 (s, 1H, 7-Ar-H), 4.57 (bs, 2H,
NH2), 3.93 (s, 3H, OCH3), 3.87 (t, 2H, OCH2, J= 6.9 Hz), 3.25 (m, 2H, CH2), 1.81 (m, 4H,
2 x CH2), 1.44 (m, 4H, 2 x CH2), 1.31 (t, 3H, CH3, J= 7.4 Hz), 0.95 (t, 3H, CH3, J= 7.1 Hz);
I3C NMR (CDCl3). 5 149.6, 145.1, 141 5, 139 0, 134 0, 122 3, 122 0, 98 9, 97 0, 74 2, 56 5.
318,30 0,28 6,25 7,22 7,15 5, 14 1, MS (EI), m/z 302 (M+)
Example 11
4-Ethyl-5-heptoxy-6-methoxy-8-quinoIinamine
Yield 98%; brown oil, IR (KBr)- 3381 and 758 cm-1 (NH2); 1H NMR (CDCl3): δ 8 45 (d,
1H, 2-Ar-H, J= 4 2 Hz), 7 13 (d, 1H, 3-Ar-H, J= 4 2 Hz), 6.76 (s, 1H, 7-Ar-H), 4 57 (bs, 2H,
NH2), 3.93 (s, 3H, OCH3), 3.87 (t, 2H, OCH2, J= 6.9 Hz), 3 25 (m, 2H, CH2), 1 81 (m, 4H,
2 x CH2), 1.44 (m, 6H, 3 x CH2), 1.31 (t, 3H, CH3, J= 7.4 Hz), 0.92 (t, 3H, CH3, J= 7.1 Hz);
13C NMR (CDC13)- 5 150 6, 149 6, 145 1, 141.5, 134.1, 122.6, 122.3, 98.9, 74 2, 56 5, 31 8,
30 0, 29 7, 29 2, 28.6, 26 0, 22.7, 15.5, 14 1; HRMS (APCI): m/z 317 (M+l)
Example 12
4-Ethyl-6-methoxy-5-octoxy-8-quinolinamine
Yield: 98%; brown oil; IR (KBr): 3363 and 722 cm-1 (NH2); 1H NMR (CDC13). 5 8.45 (d,
1H, 2-Ar-H, J= 4.2 Hz), 7.13 (d, 1H, 3-Ar-H, J= 4.2 Hz), 6.76 (s, 1H, 7-Ar-H), 4.57 (bs, 2H,
NH2), 3.93 (s, 3H, OCH3), 3 87 (t, 2H, OCH2, J= 6.9 Hz), 3.25 (m, 2H, CH2), 1 81 (m, 4H,
2 x CH2), 1 44 (m, 8H, 4 x CH2), 1.24 (t, 3H, CH3, J= 7.4 Hz), 0.90 (t, 3H, CH3, J= 7.1 Hz),
13C NMR (CDCl3): 8 150.8, 149.9, 145.3, 141.6, 134.2, 122.8, 122.1, 98.8, 74 0, 56 4, 31.8,
30 1, 29 6, 29.1, 28.6, 26.2, 24 2, 22.9, 15 6, 14.0; HRMS (APCI). m/z 331 (M+l).
General method for the synthesis of 2-[4-(4-ethyl-5-alkoxy-6-methoxy-8-quinolylamino)pentyI]-l,3-isoindolinedione
A mixture of 4-ethyl-5-alkoxy-6-methoxy-8-quinolinamine (6 mmol), 2-(4-bromopentyl)-1,3-isoindolinedione (6 mmol) and tnethylamine (6 mmol) was heated at 120 °C with stirring for 3 h. An additional quantity of 2-(4-bromopentyl)-l,3-isoindolinedione (6 mmol) and tnethylamine (6 mmol) was added and stirring was continued with heating for 4 hr. A third equivalent of 2-(4-bromopentyl)-l,3-isoindolinedione (6 mmol) and of tnethylamine (6 mmol) was added and the reaction mixture was heated at 120 °C for 16 h The dark brown reaction mixture was then diluted with ethyl acetate (100 mL) and filtered. The filtrate was basified with 2N NaOH solution and extracted with ethyl acetate (3 x 50 mL) The extract was washed with water, dned over sodium sulfate and concentrated to yield dark residue, which was flash chromatographed over silica gel column (230-400 mesh) using ethyl acetate/hexane (1585) as eluant to provide 2-[4-(4-ethyI-5-alkoxy-6-methoxy-8-quinolylamino)pentyl]-1,3-isoindolinediones as yellow oil.
Example 13 2-[4-(4-Ethyl-6-methoxy-5-propoxy-8-quinolylamino)pentyl]-l,3-isoindolinedione
Yield- 79%, yellow oil; IR (KBr)- 3378 cm-1 (NH2), 1712 (C=O), 1H NMR (CDCl3)- δ 8 38 (d, 1H, 2-Ar-H, J= 4 4 Hz), 7 82 (m, 2H, Ar-H), 7.71 (m, 2H, Ar-H), 7 10 (d, 1H, 3-Ar-H, J= 4 4 Hz), 6 44 (s, 1H, 7-Ar-H), 6 07 (bs, 1H, NH), 3 96 (s, 3H, OCH3), 3 87 (t, 2H, OCH2, J= 6 9 Hz), 3 75-3 66 (m, 3H, N-CH, and N-CH2), 3 25 (m, 2H, CH2), 1 90-1 67 (m, 6H, 3 x CH2), 1 3 (m, 6H, 2 x CH3), 1 04 (t, 3H, CH3, J= 7 9 Hz), l3C NMR (CDCl3): δ 168.5, 1511, 149 4, 145 1, 144 4, 142.0, 133 9, 132.3, 123 7, 123.2, 122 5, 98 9 94 3, 70 3, 56 8, 48 0, 37 8, 34 0, 28.6, 24 7, 23.3, 20 7, 15 5, 10 6; HRMS (APCI). m/z 476 (M+l). Example 14
2-[4-(5-Butoxy-4-ethyI-6-methoxy-8-quinoIylamino)pentyl]-l,3-isoindolinedione Yield. 77%, yellow oil, IR (KBr): 3414 cm-1 (NH2), 1722 (C=O), 1H NMR (CDCl3): δ 8 38 (d, 1H, 2-Ar-H, J= 4.4 Hz), 7.82 (m, 2H, Ar-H), 7.71 (m, 2H, Ar-H), 7 10 (d, 1H, 3-Ar-H, J= 4.4 Hz), 6.44 (s, 1H, 7-Ar-H), 6 07 (bs, 1H, NH), 3.96 (s, 3H, OCH3), 3 87 (t, 2H, OCH2, J= 6.9 Hz), 3.67-3.75 (m, 3H, N-CH, and N-CH2), 3 24 (m, 2H, CH2), 1.85-1 41 (m, 8H, 4 x CH2), 1.3 (m, 6H, 2 x CH3), 0.95 (t, 3H, CH3, J= 7.9 Hz); 13C NMR (CDCl3) δ 168.4, 151.1, 149.5, 145.2, 144.3, 142.0, 133.8, 132.5, 123 7, 123.1, 122.6, 98.9, 94.4, 74.3, 56.9, 48 1, 38 0, 34 2, 30 1, 28 4, 28 3, 22.7, 20.8, 15.6, 14.1, HRMS (APCI) m/z 490 (M+l) Example 15
2-[4-(4-Ethyl-6-methoxy-5-pentoxy-8-quinolylamino)pentyl]-l,3-isoindolinedione Yield: 67%, yellow oil; IR (KBr): 3379 cm-1 (NH2), 1712 (C=O); 1H NMR (CDCl3): δ 8.39 (d, 1H, 2-Ar-H, J= 4.4 Hz), 7 82 (m, 2H, Ar-H), 7 71 (m, 2H, Ar-H), 7 10 (d, 1H, 3-Ar-H, J= 4.4 Hz), 6 44 (s, 1H, 7-Ar-H), 6.07 (bs, 1H, NH), 3 96 (s, 3H, OCH3), 3 87 (t, 2H, OCH2, J= 6 9 Hz), 3 75-3 67 (m, 3H, N-CH, and N-CH2), 3.24 (m, 2H, CH2), 1 85-1 41 (m, 10H, 5 x CH2), 1 3 (m, 6H, 2 x CH3), 0 95 (t, 3H, CH3, J= 7 9 Hz); 13C NMR (CDC13) 5 168 5, 151 2, 149 5, 145 1, 144 4, 142.0, 133.9, 132 3, 123.7, 123 2, 122 5, 98 9 94 3, 74 3, 56 8, 48 0, 38.0, 34 1, 30 1, 28 7, 28.3, 25.5, 22.7, 20 8, 15 6, 14 1, HRMS (APCI) m/z 504 (M+l). Example 16 2-[4-(4-Ethyl-5-hexoxy-6-methoxy-8-quinolyIamino)pentyl]-1,3-isoindolinedione
Yield 81%, yellow oil, IR (KBr) 3382 cm-1 (NH2), 1710 (C=O), 1H NMR (CDCl3): δ 8 38 (d, 1H, 2-Ar-H, J= 4 4 Hz), 7 83 (m, 2H, Ar-H), 7 7 (m, 2H, Ar-H), 7 11 (d. 1H, 3-Ar-H, J= 4 4 Hz), 6.44 (s, 1H, 7-Ar-H), 6 07 (bs, 1H, NH), 3 96 (s, 3H, OCH3), 3 87 (t, 2H, OCH2, J= 6 9 Hz), 3 67-3 75 (m, 3H, N-CH, and N-CH2), 3 24 (m, 2H, CH2), 1 85-1 41 (m, 12H, 6 x CH2), 1 3 (m, 6H, 2 x CH3), 0 94 (t, 3H, CH3, J= 7.9 Hz); l3C NMR (CDCl3): δ 168 5, 151 1, 149.5, 144.3, 142.1,133 9, 132.3, 132.1, 123 7, 123.2, 122 4, 112 0,94 3,77.5,77 3, 77 1, 76 6, 74 3, 56 8, 48 0, 38 0, 34.1, 31 8, 30.0, 28 6, 25 8, 22.7, 20 7, 15 5, 14.0, MS (EI) m/z517(M+). Example 17
2-[4-(4-Ethyl-5-heptoxy-6-methoxy-8-quinoIylamino)pentyl]-l,3-isoindolinedione Yield: 78%; yellow oil; IR (KBr). 3365 cm-1 (NH2), 1710 (C=O); lH NMR (CDC13). 5 8 39 (d, 1H, 2-Ar-H, J= 4.4 Hz), 7.82 (m, 2H, Ar-H), 7 71 (m, 2H, Ar-H), 7 10 (d, 1H, 3-Ar-H, J= 4.4 Hz), 6 44 (s, 1H, 7-Ar-H), 6 07 (bs, 1H, NH), 3.96 (s, 3H, OCH3), 3 87 (t, 2H, OCH2, J= 6.9 Hz), 3 75-3.67 (m, 3H, N-CH, andN-CH2), 3 25 (m, 2H, CH2), 1.89-1 61 (m, 14H, 7 x CH2), 1.30 (m, 6H 2 × CH3), 1 04 (t, 3H, CH3, J= 7 9 Hz); 13C NMR (CDC13). 5 168 6, 151.1, 149 6, 145 2, 144 4, 142.1, 133.9, 132.2, 123 5, 123.1, 122.7, 98.8, 94 2, 74.2, 56.6, 48 1, 38.2, 34.1, 33.5, 31.7, 30.1, 28.9, 28.5, 25.5, 22.9, 20 1, 15 6, 14 1; HRMS (APCI)-m/z 532 (M+l). Example 18
2-[4-(4-EthyI-6-methoxy-5-octoxy-8-quinolylamino)pentyl]-13-isoindolinedione Yield: 75%; yellow oil; IR (KBr)- 3407 cm-1 (NH2), 1713 (C=O); 1H NMR (CDC13). 5 8.39 (d, 1H, 2-Ar-H, J= 4 4 Hz), 7.82 (m, 2H, Ar-H), 7 71 (m, 2H, Ar-H), 7.10 (d, 1H, 3-Ar-H, J= 4.4 Hz), 6.44 (s, 1H, 7-Ar-H), 6.07 (bs, 1H, NH), 3.96 (s, 3H, OCH3), 3 87 (t, 2H, OCH2, J= 6 9 Hz), 3.75-3 67 (m, 3H, N-CH, and N-CH2), 3.25 (m, 2H, CH2), 1.89-1 61 (m, 16H, 8 x CH2), 1 30 (m, 6H, 2 x CH3), 1 04 (t, 3H, CH3, J= 7.9 Hz); 13C NMR (CDCl3): δ 168 5, 1511, 149 2, 145 0, 144 4, 142 2, 133 9, 132.1, 123 6, 123 1, 122 3, 98.9, 94 1, 74 3, 56 8, 48 1, 38 5, 34 1, 33 3, 31.4, 30 1, 28.7, 28.3, 25 5, 22.7, 21 9, 20 8, 15 7, 14 2, HRMS (APCI)-m/z 546 (M+l).
General method for the synthesis of N8- (4-amino-l-methylbutyl)-5-alkoxy-4-ethyl-6-methoxy-8-quinolinamines
To a solution of 2-[4-(5-alkoxy-4-ethyl-6-methoxy-8-qumolylamino)pentyl]-l,3-lsoindolinedione (4 mmol) in 95% ethanol (20 mL), was added hydrazine hydrate (100
mmol) and the reaction mixture was stirred with refluxing for 6 h Solvent was removed under reduced pressure and the residue was diluted with water (20 mL) The reaction mixture was basified with 8N NaOH solution, extracted with chloroform (3 x 20 mL), washed with water, dried over sodium sulfate and concentrated under reduced pressure to yield N8-(4-amino-l-methylbutyl)-5-alkoxy-4-ethyl-6-methoxy-8-quinolinamine as oil, which on treatment with ethereal hydrochloric acid provided N3-(4-amino-l-methylbutyl)-5-alkoxy-4-ethyl-6-methoxy-8-quinolinamine salts. Example 19
N8-(4-Amino-l-methylbutyl)-4-ethyl-6-methoxy-5-propoxy-8-quinolinamine Yield. 96%; mp (salt): 107-112 °C (dec); IR (KBr): 3425 and 759 cm-1 (amine), 1H NMR (free base, CDC13)- 5 8.38 (d, 1H, 2-Ar-H, J= 4.3 Hz), 7.11 (d, 1H, 3-Ar-H, J= 4 3 Hz), 6.44 (s, 1H, 7-Ar-H), 6.11 (bs, 1H, NH), 3.96 (s, 3H, OCH3), 3.87 (t, 2H, OCH2, J= 6 9 Hz), 3 64 (s, 1H, N-CH), 3 25 (m, 4H, 2 x CH2), 1.99-1.62 (m, 8H, 3 x CH2 and NH2), 1 32 (m, 6H, 2 x CH3), 1.05 (t, 3H, CH3, J= 7.9 Hz); 13C NMR (free base, CDC13): 5 167 1, 151 2, 149 5, 144.4, 142.2, 134.1, 123.7, 122.4, 94 3, 75.8, 56.9, 51 5, 48.2, 34.9, 28.6, 27 7, 23.3, 20.7, 15 5, 10.6; HRMS (APCI): m/z 346 (M+l). Example 20
N8-(4-Ainino-l-methylbutyl)-5-butoxy-4-ethyl-6-methoxy-8-quinolinamine Yield: 84%; mp (salt)- 106-113 °C (dec); IR (KBr)- 3410 and 764 cm-1 (amine); 1H NMR (free base, CDC13): 8 8.39 (d, 1H, 2-Ar-H, J= 4 3 Hz), 7.11 (d, 1H, 3-Ar-H, J= 4 3 Hz), 6 44 (s, 1H, 7-Ar-H), 6 11 (bs, 1H, NH), 3.97 (s, 3H, OCH3), 3 89 (t, 2H, OCH2, J= 6 9 Hz), 3 64 (s, 1H, N-CH), 3.25 (m, 2H, CH2), 2.75 (t, 2H, N-CH2, J= 6.9 Hz), 1.92-1.50 (m, 10H, 4 x CH2 and NH2), 1.37 (m, 6H, 2 x CH3), 1.00 (t, 3H, CH3, J= 7.9 Hz); 13C NMR (free base, CDC13) 5 167 0, 151.1, 149.4, 144.4, 142.0, 134 2, 123 5, 122.0, 94 1, 75 9, 56.7, 515, 48 0, 34 9, 28.1, 27.5, 23 3, 20 5, 15 5, 14 1, 10 5; HRMS (APCI): m/z 360 (M+l) Example 21
N8-(4-Amino-l-methylbutyl)-4-ethyI-6-methoxy-5-pentoxy-8-quinoIinamine Yield: 96%; mp (salt): 86-89 °C (dec); IR (KBr). 3408 and 764 cm-1 (amine), 1H NMR (free base, CDC13). 5 8.39 (d, 1H, 2-Ar-H, J= 4.3 Hz), 7.11 (d, 1H, 3-Ar-H, J= 4 3 Hz), 6 44 (s, 1H, 7-Ar-H), 6.10 (bs, 1H, NH), 3 96 (s, 3H, OCH3), 3.90 (t, 2H, OCH2, J= 6.9 Hz), 3 64 (s, 1H, N-CH), 3.25 (m, 2H, CH2), 2.75 (t, 2H, N-CH2, J= 6.9 Hz), 1.86-1.39 (m, 12H, 5 x CH2 and NH2), 1.30 (m, 6H, 2 x CH3), 0.95 (t, 3H, CH3, J= 7.9 Hz); l3C NMR (free base.
CDC13) 5 1511, 149 5, 144 3, 142.1, 134 0, 132 2, 123.7, 122 3, 93 9, 74 2, 56 8, 48 2. 42.2, 34 2, 30 2, 29.7, 28 6, 28 2, 22.6, 20.7, 15.5, 14 0; HRMS (APCI)- m/z 374 (M+l) Example 22
N8-(4-Amino-l-methyIbutyl)-4-ethyl-5-hexoxy-6-methoxy-8-quinolinamine Yield 94%, mp (salt) 76-79 °C (dec), IR (KBr) 3388 and 759 cm-1 (amine), 1H NMR (free base, CDC13): 5 8.40 (d, 1H, 2-Ar-H, J= 4.3 Hz), 7.12 (d, 1H, 3-Ar-H, J= 4 3 Hz), 6.44 (s, 1H, 7-Ar-H), 6 07 (bs, 1H, NH), 3.96 (s, 3H, OCH3), 3 90 (t, 2H, OCH2, J= 6 9 Hz), 3 85 (s, 1H, N-CH), 3 28 (m, 2H, CH), 2.76 (t, 2H, N-CH2, J= 5.8 Hz), 1 85-1 41 (m, 14H, 6 x CH2 and NH2), 1.35 (m, 6H, 2 x CH3), 0 94 (t, 3H, CH3, J= 7 95 Hz); 13C NMR (free base, CDC13) 5 167 8, 151.1, 149 6, 144.4, 142.0, 132 5, 130.9, 128.8, 123 7, 122 5, 94 4, 74 2, 68 2, 56.8, 48.2, 38 7, 31 8, 30.4, 28 9, 25 8, 22.9, 20.6, 15 5, 14 1, 10 9, HRMS (APCI)-m/z 388 (M+l). Example 23
/V8-(4-Amino-l-methylbutyl)-4-ethyl-5-heptoxy-6-methoxy-8-quinolinamine Yield: 99%; mp (salt): 74-78 °C (dec); IR (KBr). 3411 and 734 cm-1 (amine); [H NMR (free base, CDC13): 5 8.39 (d, 1H, 2-Ar-H, J= 4 3 Hz), 7 11 (d, 1H, 3-Ar-H, J= 4 3 Hz), 6.44 (s, 1H, 7-Ar-H), 6.10 (bs, 1H, NH), 3.97 (s, 3H, OCH3), 3 85 (t, 2H, OCH2, J= 6 9 Hz), 3 64 (s, 1H, N-CH), 3 23 (m, 2H, CH2), 2.74 (t, 2H, N-CH2, J= 6.9 Hz), 1.94-1.62 (m, 16H, 7 x CH2 and NH2), 1 30 (m, 6H, 2 x CH3), 1.05 (t, 3H, CH3, J= 7.9 Hz); l3C NMR (free base, CDC13): 5 151.0, 149.4, 144.3, 142.5, 134.2, 132.0, 123.4, 122.1, 94 2, 74 2, 56.5, 48 2, 42 1, 34.2, 31 9, 30.1, 30.9, 29.2, 28.6, 26.1, 22.7, 20.5, 15.5, 14.2; HRMS (APCI)- m/z 402 (M+l) Example 24
N8-(4-A mino-l-methylbutyl)-4-ethyI-6-methoxy-5-octoxy-8-quinolinamine Yield: 84%; mp (salt): 70-72 °C (dec); IR (KBr). 3434 and 734 cm-1 (amine), 1H NMR (free base, CDC13): 5 8 36 (d, 1H, 2-Ar-H, J= 4.3 Hz), 7.10 (d, 1H, 3-Ar-H, J= 4 3 Hz), 6 43 (s, 1H, 7-Ar-H), 6 11 (bs, 1H, NH), 3 95 (s, 3H, OCH3), 3 87 (t, 2H, OCH2, J= 6 9 Hz), 3 61 (s, 1H, N-CH), 3.24 (m, 2H, CH2), 2.80 (t, 2H, N-CH2, J= 6 9 Hz), 1 89-1 41 (m, 18H, 8 x CH2 and NH2), 1.29 (m, 6H, 2 x CH3), 0 89 (t, 3H, CH3, J= 7 9 Hz); l3C NMR (free base, CDC13) 5 151.1, 149.7, 144.4, 141.8, 134.1, 132.5, 123.7, 122.5, 94 7, 74 3, 56.9, 50 7, 48 0, 40.2, 33.9, 31.9, 30.0, 29.3, 28.6, 26 1, 23.4, 22.7, 20.6, 15.5, 14.1, HRMS (APCI)-m/z 416 (M+l).
General method for the synthesis of N1-[4-(S-alkoxy-4-ethyl-6-methoxy-8-quinolylamino/6-methoxy-8-quinolylamino)pentyl]-(25)-2-(aminobenzylformate/ tert-butyloxyformamido)-2-alkylalkanamides
To an ice cooled stirred solution of N8-(4-amino-l-methylbutyl)-5-alkoxy-4-ethyl-6-methoxy-8-quinolinamine or N8-(4-amino-l-methylbutyl)-6-methoxy-8-quinolin-amine (1 mmol) and suitably N-protected amino acid (1 1 mmol) in dichloromethane (15 mL), 1,3-dicyclohexylcarbodnmide (1 1 mmol) was added. Reaction mixture was allowed to attain room temperature and stirring was continued for another 4 h. The reaction mixture was kept in refrigerator overnight and the separated 1,3-dicyclohexylurea (DCU) filtered, and filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue and the additional quantity of separated DCU was again removed by filtration The filtrate was washed with saturated sodium bicarbonate solution (3 x 10 mL) followed by water (2 x 10 mL), and dried over Na2SO4. The solvent was removed in vacuo to afford the crude product, which was purified by flash column chromatography on silica gel (230-00 mesh) using 2% methanol in chloroform to afford the product. Example 25
N1-[4-(4-Ethyl-6-methoxy-5-propoxy-8-quinolylamino)pentyl]-(2S)-2-aminoben-zylformate propanamide
Yield: 58%, oil; IR (KBr): 3433 cm-1 (NH), 1742 (ester), 1643 (amide carbonyl); 1H NMR (CDCl3): δ 8 41 (d, 1H, 2-Ar-H, J= 4.3 Hz), 7.31 (m, 5H, Ar-H), 7.13 (d, 1H, 3-Ar-H, J= 4 3 Hz), 6 44 (s, 1H, 7-Ar-H), 6.36 (bs, 1H, NH), 5 41 (bs, 1H, NH), 5 06 (m, 2H, OCH2Ph), 4.17 (m, 1H, CH), 3 96 (s, 3H, OCH3), 3 90 (t, 2H, OCH2, J= 6.9 Hz), 3.72 (m, 1H, N-CH), 3.26 (m, 5H, 2 x CH2, NH), 2.76 (t, 2H, N-CH2, J= 5.8 Hz), 1.90-1.62 (m, 4H, 2 x CH2), 1.38 (m, 9H, 3 x CH3), 1.01 (t, 3H, CH3, J= 7 9 Hz); 13C NMR (CDCl3): δ 172.4, 156 4, 151.1", 150.0, 144 5, 142.0, 136 3, 132 6, 128.4, 124.1, 122.7, 94 8, 74 5, 67 1, 57.4, 50 9, 48.0, 39.8, 34 1, 30 4, 28 9, 26 4, 22.7, 18.9, 15 5; MS (EI) m/z 550 (M+) Example 26
A1-[4-(5-Butoxy-4-ethyl-6-methoxy-8-quinolylamino)pentyl]-(2S)-2-aminobenzyl-formate propanamide
Yield: 86%, oil; IR (KBr): 3434 cm-1 (NH), 1747 (ester), 1642 (amide carbonyl), 1H NMR (CDCl3): δ 8.40 (d, 1H, 2-Ar-H, J= 4.3 Hz), 7.31 (m, 5H, Ar-H), 7.13 (d, 1H, 3-Ar-H, J= 4.3 Hz), 6 44 (s, 1H, 7-Ar-H), 6.37 (bs, 1H, NH), 5.41 (bs, 1H, NH), 5.06 (m, 2H, OCH2Ph), 4.17 (m, 1H, CH), 3.96 (s, 3H, OCH3), 3.90 (t, 2H, OCH2, J= 6.9 Hz), 3.72 (m,
1H, N-CH), 3 26 (m, 5H, 2 x CH2, NH), 2 76 (t, 2H, N-CH2, J= 5 8 Hz), 1 88-1 65 (m, 6H,
3 x CH2), 1 35 (m, 9H, 3 x CH3), 0 94 (t, 3H, CH3, J= 7.9 Hz), 13C NMR (CDCl3): δ 172 5,
156 2, 151.3, 150 1, 144 4, 142 0, 136 6, 132 2, 128 3, 124 1, 122 9,94 8,74 6,67 2. 57 2,
50 7, 48 3, 39 5, 34 2, 30 1, 28.9, 26 2, 22 7, 21 1, 18 8, 15 7, MS (EI) m/z 564 (M+)
Example 27
N1-[4-(4-Ethyl-6-methoxy-5-pentoxy-8-quinoIylamino)pentyl]-(2S)-2-aminoben-zylformate propanamide
Yield- 83%, oil, IR (KBr): 3412 cm-1 (NH), 1743 (ester), 1642 (amide carbonyl), !H NMR (CDCl3) δ 8 40 (d, 1H, 2-Ar-H, J= 4.3 Hz), 7 31 (m, 5H, Ar-H), 7.13 (d, 1H, 3-Ar-H, J=
4 3 Hz), 6.44 (s, 1H, 7-Ar-H), 6 37 (bs, 1H, NH), 5 41 (bs, 1H, NH), 5 06 (m, 2H,
OCH2Ph), 4 17 (m, 1H, CH), 3 96 (s, 3H, OCH3), 3 90 (t, 2H, OCH2, J= 6.9 Hz), 3 72 (m,
1H, N-CH), 3 26 (m, 5H, 2 x CH2, NH), 2.76 (t, 2H, N-CH2, J= 5.8 Hz), 1 85-1 48 (m, 8H,
4 x CH2), 1.35 (m, 9H, 3 x CH3), 0.94 (t, 3H, CH3, J= 7 9 Hz); 13C NMR (CDC13)- 5 172.5,
156 3, 151.4, 150.0, 144 6, 142 1, 136.4, 132.6, 128 5, 124 0, 122.8, 94.8, 74 5, 67.3, 57.2,
50 9, 48 3, 39.8, 34 3, 30.0, 28.9, 26 5, 22.9, 21 0, 18 9, 15.8, 14.4, MS (EI): m/z 578 (M+).
Example 28
N1-[4-(4-Ethyl-5-hexoxy-6-methoxy-8-quinolylamino)pentyl]-(2S)-2-aminoben-zylformatepropanamide
Yield: 58%, oil; IR (KBr): 3410 cm-1 (NH), 1741 (ester), 1671 (amide carbonyl), 1H NMR (CDCl3): δ 8.40 (d, 1H, 2-Ar-H, J= 4 3 Hz), 7 32 (m, 5H, Ar-H), 7.12 (d, 1H, 3-Ar-H, J= 4 3 Hz), 6 44 (s, 1H, 7-Ar-H), 6 37 (bs, 1H, NH), 5.41 (bs, 1H, NH), 5.06 (m, 2H, OCH2Ph), 4.17 (m, 1H, CH), 3 96 (s, 3H, OCH3), 3.90 (t, 2H, OCH2, J= 6.9 Hz), 3 72 (m, 1H, N-CH), 3.26 (m, 5H, 2 x CH2, NH), 2.76 (t, 2H, N-CH2, J= 5 8 Hz), 1.85-1 48 (m, 10H, 5 x CH2), 1.35 (m, 9H, 3 x CH3), 0.94 (t, 3H, CH3, J= 7 9 Hz); 13C NMR (CDCl3): δ 172 9, 156 2, 151 0, 150 1, 144.6, 142.3, 136.1, 132.5, 128.4, 124.1, 122.7, 94 5, 74.5, 67 1, 57 3, 50 6, 48.0, 39 8, 34.1, 30 0, 28.8, 28.5, 26.4, 22.8, 21.1, 18.9, 15.7, 14 4; HRMS (APCI). m/z 593 (M+l). Example 29
N1-[4-(4-EthyI-5-heptoxy-6-methoxy-8-quinolylamino)pentyl]-(25)-2-aminobenz-ylformatepropanamide
Yield: 80%; oil; IR (KBr): 3412 cm-1 (NH), 1743 (ester), 1642 (amide carbonyl), 1H NMR (CDCl3): δ 8.40 (d, 1H,1 2-Ar-H, J= 4.3 Hz), 7.32 (m, 5H, Ar-H), 7.13 (d, 1H, 3-Ar-H, J= 4.3 Hz), 6.44 (s, 1H, 7-Ar-H), 6.25 (bs, 1H, NH), 6.05 (bs, 1H, NH), 5.38 (bs, 1H, NH),
5 08 (m, 2H, OCH2Ph), 4 18 (m, 1H, CH), 3.96 (s, 3H, OCH3), 3 85 (t, 2H, OCH2) J= 6 9
Hz), 3 70 (m, 1H, N-CH), 3.23 (m, 5H, 2 x CH2, NH), 2 76 (t, 2H, N-CH2, J= 5 8 Hz),
1 94-1 67 (m, 6H, 3 x CH2), 1 47-1 32 (m, 6H, 3 x CH2), 1 30 (m, 9H, 3 x CH3), 0 90 (t, 3H,
CH3, J= 7.9 Hz); l3C NMR (CDCl3): δ 172.5, 155 9, 151 1, 149 7, 144 4, 1419, 136 2 ,
130 5, 128 5, 123 7, 122 5, 94 5, 74 3, 67 0, 56 9, 50 6, 48 0, 39 5, 33 9, 31 9, 30 0, 29 7,
29 2, 26.1, 24 9, 22.7, 20.7, 18 6, 15 5, 14 1, MS (EI), m/z 606 (M+)
Example 30
N1-[4-(4-Ethyl-6-methoxy-5-octoxy-8-quinoIyIamino)pentyl]-(25)-2-aminobenzyl-
formatepropanamide
Yield: 67%; oil; IR (KBr): 3410 cm-1 (NH), 1745 (ester), 1640 (amide carbonyl); lH NMR
(CDCl3): δ 8.40 (d, 1H, 2-Ar-H, J= 4.3 Hz), 7.32 (m, 5H, Ar-H, J= 2.8 Hz), 7.14 (d, 1H, 3-
Ar-H, J= 4.3 Hz), 6.45 (s, 1H, 7-Ar-H), 6.23 (bs, 1H, NH), 6.05 (bs, 1H, NH), 5 38 (bs, 1H,
NH), 5 06 (m, 2H, OCH2Ph), 4 16 (m, 1H, CH), 3.96 (s, 3H, OCH3), 3 87 (t, 2H, OCH2, J=
6 9 Hz), 3.62 (m, 1H, N-CH), 3.23 (m, 4H, 2 x CH2), 2.76 (t, 2H, N-CH2, J= 5 8 Hz), 1.87
1.94-1.67 (m, 6H, 3 x CH2), 1.47-1.32 (m, 6H, 3 x CH2), 1 30 (m, 9H, 3 x CH3), 0.90 (t, 3H,
CH3, J= 7.9 Hz); 13C NMR (CDCl3): δ 172.6, 156.2, 151.7, 149.7, 143 8, 141 8, 136.5 ,
132 7, 128.5, 124.2, 122.6, 95 3, 74.6, 67.3, 57 1, 50 9, 48.5, 39 7, 34 2, 32.2, 30 3, 29 8,
29 6, 29.1, 26.4, 23 0, 20 9, 19 0, 15 8, 14 4; MS (EI): m/z 620 (NT).
Example 31
N1-[4-(4-Ethyl-6-methoxy-5-propoxy-8-quinolylamino)pentyI]-(2S)-2,6-dibenzyl-
oxyformamidohexanamide
Yield: 72%; oil; IR (KBr): 3409 cm'1 (NH), 1721 (ester), 1681 (amide carbonyl), lH NMR
(CDCl3): δ 8.40 (d, 1H, 2-Ar-H, J= 4.3 Hz), 7.30 (m, 10H, Ar-H), 7.12 (d, 1H, 3-Ar-H, J=
4 3 Hz), 6.45 (s, 1H, 7-Ar-H), 6.35 (bs, 1H, NH), 5.6 (bs, 1H, NH), 5 07 (s, 4H, 2 x
OCH2Ph), 4 90 (bs, 1H, NH), 4 13 (m, 3H, 2 x CH, NH), 3.96 (s, 3H, OCH3), 3 86 (t, 2H,
OCH2, J= 6 9 Hz), 3.61 (s, 1H, N-CH), 3 26 (m, 6H, 3 x CH2), 1.89-1 47 (m, 12H, 6 x
CH2), 1.26 (m, 6H, 2 x CH3), 1 05 (t, 3H, CH3, J= 7.9 Hz), ,3C NMR (CDC13) 5 175 8,
171 8, 156 4, 151 1, 149 7, 144 5, 141 9, 136.6, 134 1, 128 5, 123 8, 122.5, 94 6, 75 8, 67 1,
57 0, 54 9, 40 2, 39.5, 34 1, 31 9, 29 4, 28.6, 25 6, 24 9, 23 3, 22 4, 20.8, 15 5, 10 6, HRMS
(APCI)- m/z742(M+l).
Example 32
N -[4-(5-Butoxy-4-ethyl-6-methoxy-8-quinolylamino)pentyl]-(25)-2,6-dibenzyl-
oxyformamidohexanamide
Yield 89%, oil, IR (KBr). 3415 cm'1 (NH), 1722 (ester), 1680 (amide carbonyl); 1H NMR (CDC13)- 5 8.38 (d, 1H, 2-Ar-H, J= 4.3 Hz), 7 30 (m, 10H, Ar-H), 7.11 (d, 1H, 3-Ar-H, J= 4 3 Hz), 6 44 (s, 1H, 7-Ar-H), 6.36 (bs, 1H, NH), 6 05 (bs, 1H, NH), 5 6 (bs, 1H, NH), 5 06 (s, 4H, 2 x OCH2Ph), 4 96'(bs, 1H, NH), 4 13 (m, 1H, CH), 3.96 (s, 3H, OCH3), 3 88 (t, 2H, OCH2, J= 6 9 Hz), 3 62 (s, 1H, N-CH), 3 27-3 13 (m, 6H, 3 x CH2), 1 86-1 45 (m, 14H, 7 x CH2), 1 28 (m, 6H, 2 x CH3), 0 88 (t, 3H, CH3, J= 7 9 Hz), 13C NMR (CDC13) 8 171 9, 156 5, 1510, 149 2, 144 0, 142.1, 136.9, 136.0, 133.2, 132 1, 128 2, 123 5, 122.0, 94.7, 73 9, 67 1, 66.8, 56.1, 54 2, 47 5, 41 2, 40 1, 34.5, 32 1, 29 2, 28 7, 25.6, 22 3, 21.1, 20 7, 19 3, 15.5, 14.2; HRMS (APCI): m/z 756 (M+l) Example 33
N1-[4-(4-Ethyl-6-methoxy-5-pentoxy-8-quinolylamino)pentyl]-(2S)-2,6-dibenzyl-oxyformamidohexanamide
Yield: 99%; oil, IR (KBr). 3387 cm'1 (NH), 1722 (ester), 1686 (amide carbonyl); 1H NMR (CDC13) δ 8.38 (d, 1H, 2-Ar-H, J= 4.3 Hz), 7.30 (m, 10H, Ar-H), 7 10 (d, 1H, 3-Ar-H, J= 4.3 Hz), 6.44 (s, 1H, 7-Ar-H), 6.35 (bs, 1H, NH), 5.61 (bs, 1H, NH), 5.06 (s, 4H, 2 x OCH2Ph), 4.95 (bs, 2H, 2 x NH), 4.14 (m, 1H, CH), 3.95 (s, 3H, OCH3), 3.87 (t, 2H, OCH2, J= 6.9 Hz), 3.63 (s, 1H, N-CH), 3.27-3.13 (m, 6H, 3 x CH2), 1.85-1.43 (m, 16H, 8 x CH2), 1.28 (m, 6H, 2 x CH3), 0.94 (t, 3H, CH3, J= 7.9 Hz); 13C NMR (CDC13)- 8 171.7, 156.7, 156.3, 151 1, 149.6, 144.4, 1419, 136.6, 136 1, 134.0, 132.4, 128 1, 123.7, 122.5, 94.5,
74.2, 67 0, 66.6, 56.9, 54 9, 47.9, 40 2, 39 5, 34 1, 31.9, 29 7, 29 4, 28.6, 28 2, 26.2, 24.9,
22 6, 20 7, 15.5, 14.1, HRMS (APCI): m/z 770 (M+l).
Example 34
N1-[4-(4-Ethyl-5-hexoxy-6-methoxy-8-quinoIylamino)pentyI]-(25)-2,6-dibenzyI-oxyformamidohexanamide
Yield: 65%; oil; IR (KBr)- 3420 cm'1 (NH), 1721 (ester), 1681 (amide carbonyl); !H NMR (CDC13). δ 8.40 (d, 1H, 2-Ar-H, J= 4 3 Hz), 7 30 (m, 10H, Ar-H), 7 12 (d, 1H, 3-Ar-H, J= 4 3 Hz), 6.44 (s, 1H, 7-Ar-H), 6 35 (bs, 1H, NH), 6.17 (bs, 1H, NH), 5.6 (bs, 1H, NH), 5 06 (s, 5H, 2 x OCH2Ph, NH), 4.17 (m, 1H, CH), 3.96 (s, 3H, OCH3), 3.90 (t, 2H, OCH2, J= 6 9 Hz), 3.62 (s, 1H, N-CH), 3 25 (m, 6H, 3 x CH2), 1 81-1 45 (m, 18H, 9 x CH2), 1 32 (m, 6H, 2 x CH3), 0 99 (t, 3H, CH3, J= 7.9 Hz); 13C NMR (CDC13): 6 171.2, 156 5, 156.4, 151 6, 150 1, 144.9, 141.2, 136.1, 134.3, 133.4, 132.0, 128.5, 128.1, 123.4, 122.1, 94.7, 73.9, 67 2,
66.3, 56.0, 54.8, 47.7, 40.5, 37.3, 34.1, 32.1, 29.1, 28.7, 25.6, 22.3, 21.1, 20.5, 19.3, 15.2,
14.2, 14.0; HRMS (APCI): m/z 785 (M+l).
Example 35
/V1-[4-(4-Ethyl-5-heptoxy-6-methoxy-8-quinolyIamino)pentyl]-(25)-2,6-dibenzyl-
oxyformamidohexanamide
Yield, 81%, oil, IR (KBr)- 3383 cm'1 (NH), 1720 (ester), 1643 (amide carbonyl), 1H NMR (CDCl3): δ 8 38 (d, 1H, 2-Ar-H, J= 4.3 Hz), 7 30 (m, 10H, Ar-H), 7 11 (d, 1H, 3-Ar-H, J= 4 3 Hz), 6.44 (bs, 2H, 7-Ar-H, NH), 5.67 (bs, 1H, NH), 5 06 (m, 5H, 2 x OCH2Ph, NH), 4 45 (bs, 1H, NH), 4.10 (m, 1H, CH), 3.96 (s, 3H, OCH3), 3.84 (t, 2H, OCH2, J= 6.9 Hz),
3 61 (s, 1H, N-CH), 3.25-3 13 (m, 6H, 3 x CH2), 1.88-1.45 (m, 20H, 10 x CH2), 1 28 (m,
6H, 2 x CH3), 1.04 (t, 3H, CH3, J= 7 9 Hz); 13C NMR (CDC13). 5 171.8, 156.7, 151.1,
149 7, 144 3, 141.8, 136.1, 132.3, 128.1, 123.7, 122.5, 94.5, 75.8, 67 0, 66 6, 56 9, 54 9,
49 1, 47.9, 40 2, 39.5, 34 1, 33 8, 31 9, 29.7, 29 3, 26 1, 25 5, 24 9, 23 2, 22 3, 20.7, 15 5,
10.6, HRMS (APCI)- m/z 798 (M+l).
Example 36
N1-[4-(4-Ethyl-6-methoxy-5-octoxy-8-quinolylamino)pentyl]-(25)-2,6-dibenzyl-
oxyformamidohexanamide
Yield: 81%; oil; IR (KBr): 3384 cm-1 (NH), 1721 (ester), 1644 (amide carbonyl); LH NMR
(CDCl3): δ 8.38 (d, 1H, 2-Ar-H, J= 4.3 Hz), 7.30 (m, 10H, Ar-H), 7.11 (d, 1H, 3-Ar-H, J=
4 3 Hz), 6.44 (s, 1H, 7-Ar-H), 6.23 (bs, 1H, NH), 5.50 (bs, 1H, NH), 5.06 (s, 4H, 2 x
OCH2Ph), 4.86 (bs, 1H, NH), 4.05 (m, 1H, CH), 3.96 (s, 3H, OCH3), 3.87 (t, 2H, OCH2, J=
6 9 Hz), 3 62 (s, 1H, N-CH), 3 26-3 15 (m, 6H, 3 x CH2), 1.84-1.47 (m, 22H, 11 x CH2),
1.28 (m, 6H, 2 x CH3), 0.88 (t, 3H, CH3, J= 7 9 Hz); 13C NMR (CDCl3). 5 171.6, 156.7,
151.2, 149.7, 144.4, 141.9, 136.2, 132.3, 128.2, 123.7, 122.5, 94.6, 74.3, 67.1, 66.7, 56.9,
54 9, 49.2, 48.0, 40.2, 39.5, 34.1, 33 9, 31 9, 29.5, 29 3, 28 6, 26.2, 25 6, 24.9, 22 6, 22.3,
20 7, 15 5, 14.1; HRMS (APCI). m/z 812 (M+l)
Example 37
N1-[4-(4-Ethyl-6-methoxy-5-propoxy-8-quinolyIamino)pentyl]-(25)-2,5-dibenzyI-oxyformamidopentanamide
Yield 60%, oil; IR (KBr) 3321 cm-1 (NH), 1719 (ester), 1686 (amide carbonyl); 1H NMR (CDCl3)- δ 8.40 (d, 1H, 2-Ar-H, J= 4 3 Hz), 7.32 (m, 10H, Ar-H), 7 11 (d, 1H, 3-Ar-H, J= 4 3 Hz), 6 46 (bs, 2H, 7-Ar-H, NH), 5.55 (bs, 1H, NH), 5.07 (s, 4H, 2 x OCH2Ph), 4 26 (m, 4H, 2 x CH, 2 x NH), 3 97 (s, 3H, OCH3), 3.85 (t, 2H, OCH2, J= 6.9 Hz), 3 61 (s, 1H, N-CH), 3.26 (m, 6H, 3 x CH2), 1.95-1.38 (m, 10H, 5 x CH2), 1.26 (m, 6H, 2 x CH3), 1.05 (t, 3H, CH3, J= 7.9 Hz); 13C NMR (CDC13): δ 175.8, 171.8, 156.4, 151.1, 149.7, 144.5, 141.9,
136 6, 134 1, 128.5, 123 8, 122.5, 94 6, 75.8, 67 1, 57 0, 54 9, 40 2, 39 5, 34 1, 31 9, 29 4,
28 6, 25 6, 24 9, 22.4, 20 8, 15 5, 10 6, HRMS (APCI)- m/z 728 (M+l)
Example 38
N1-[4-(5-Butoxy-4-ethyl-6-methoxy-8-quinolylamino)pentyIl-(25)-2,5-dibenzyl-
oxyformamidopentanamide
Yield 75%, oil, IR (KBr)- 3302 cm-1 (NH), 1689 (ester), 1646 (amide carbonyl), 1H NMR
(CDCl3): δ 8 37 (d, 1H, 2-Ar-H, J= 4 3 Hz), 7 30 (m, 10H, Ar-H), 7 10 (d, 1H, 3-Ar-H, J=
4 3 Hz), 6 43 (bs, 2H, 7-Ar-H, NH), 5 53 (bs, 1H, NH), 5 07 (m, 6H, 2 x OCH2Ph, 2 x NH),
4 13 (m, 1H, CH), 3.95 (s, 3H, OCH3), 3.88 (t, 2H, OCH2, J= 6 9 Hz), 3 61 (s, 1H, N-CH),
3 23 (m, 6H, 3 x CH2), 1 89-1 47 (m, 12H, 6 x CH2), 1.26 (m, 6H, 2 x CH3), 0 99 (t, 3H,
CH3, J= 7 9 Hz), 13C NMR (CDCl3). 5 171.7, 156 7, 151.1, 149 6, 144 4, 1419, 136.6,
136 1, 134.0, 132.4, 128.2, 123 7, 122.5, 94 5, 73.9, 67.0, 66.6, 56 9, 54 9, 47 9, 41 2, 40 2,
34 1, 32.1, 29.4, 28.6, 25 6, 21.1, 20.7, 19 3, 15 5, 14.2; HRMS (APCI): m/z 742 (M+l).
Example 39
Nl-[4-(4-Ethyl-6-methoxy-5-pentoxy-8-quinolylamino)pentyl]-(2S)-2,5-dibenzyl-oxyformamidopentanamide
Yield: 70%; oil; IR (KBr)- 3299 cm'1 (NH), 1688 (ester), 1645 (amide carbonyl); lH NMR (CDCl3): δ 8.37 (d, 1H, 2-Ar-H, J= 4.3 Hz), 7.30 (m, 10H, Ar-H), 7.10 (d, 1H, 3-Ar-H, J=
4 3 Hz), 6.54 (bs, 1H, NH), 6.43 (s, 1H, 7-Ar-H), 5 59 (bs, 1H, NH), 5 05 (m, 5H, 2 x
OCH2Ph, NH), 4 25 (bs, 1H, NH), 4 10 (m, 1H, CH), 3.95 (s, 3H, OCH3), 3.87 (t, 2H,
OCH2, J= 6.9 Hz), 3.62 (s, 1H, N-CH), 3.27-3 14 (m, 6H, 3 x CH2), 2.0-1 47 (m, 14H, 7 x
CH2), 1 29 (m, 6H, 2 x CH3), 0.94 (t, 3H, CH3, J= 7 9 Hz); 13C NMR (CDC13)- 5 171.7,
157 0, 156.4, 151.2, 149.7, 144.4, 141.9, 136.5, 136.3, 132.5, 128.5, 128 0, 123.7, 122 5,
94 6, 74 2, 67 0, 66 6, 56.9, 53.7, 48.0, 39.5, 34 1, 30.4, 29.7, 28 6, 28 2, 26.2, 22 6, 20 7,
15 5, 14 1; HRMS (APCI): m/z 756 (M+l).
Example 40
N1-[4-(4-Ethyl-5-hexoxy-6-methoxy-8-quinolylamino)pentyl]-(25)-2,5-dibenzyl-oxyformamidopentanamide
Yield: 83%: oil; IR (KBr): 3420 cm-1 (NH), 1720 (ester), 1624 (amide carbonyl); 1H NMR (CDCl3) δ.8 37 (d, 1H, 2-Ar-H, J= 4 3 Hz), 7 30 (m, 10H, Ar-H), 7 10 (d, 1H, 3-Ar-H, J= 4 3 Hz), 6.51 (bs, 1H, NH), 6.44 (s, 1H, 7-Ar-H), 5.56 (bs, 1H, NH), 5 06 (s, 6H, 2 x OCH2Ph, 2 x NH), 4.13 (m, 1H, CH), 3.95 (s, 3H, OCH3), 3.87 (t, 2H, OCH2, J= 6.9 Hz), 3 61 (s, 1H, N-CH), 3.25 (m, 6H, 3 x CH2), 1.89-1.47 (m, 16H, 8 x CH2), 1.31 (m, 6H, 2 x
CH3), 0.86 (t, 3H, CH3, J= 7.9 Hz), 13C NMR (CDC13)- 5 171 8, 157.0, 156 3, 151 4, 150 8,
143 8, 141 4, 136 6, 136 3, 132 5, 128 5, 128.0, 123 9, 122 3, 95 0, 74 3, 66 9, 66 6, 60 4,
56 9, 53 7, 48.2, 39 5, 34 1, 32 8, 29 7, 26 1, 25 7, 24 9, 22 7, 20 6, 15 5, 14 1, HRMS
(APCI) m/z 770(M+l)
Example 41
N1-[4-(4-Ethyl-5-heptoxy-6-methoxy-8-quinolyIamino)pentyl]-(2S)-2,5-dibenzyl-
oxyformamidopentanamide
Yield: 67%, oil; IR (KBr): 3306 cm-1 (NH), 1690 (ester), 1646 (amide carbonyl), 1H NMR
(CDCl3): δ 8.37 (d, 1H, 2-Ar-H, J= 4 3 Hz), 7 30 (m, 10H, Ar-H), 7.10 (d, 1H, 3-Ar-H, J=
4 3 Hz), 6.63 (bs, 1H, NH), 6 43 (s, 1H, 7-Ar-H), 5.66 (bs, 1H, NH), 5 04 (m, 5H, 2 x
OCH2Ph, NH), 4.26 (m, 2H, CH, NH), 3.95 (s, 3H, OCH3), 3 84 (t, 2H, OCH2, J= 6 9 Hz),
3 61 (s, 1H, N-CH), 3.23 (m, 6H, 3 x CH2), 1.88-1.45 (m, 18H, 9 x CH2), 1 26 (m, 6H, 2 x
CH3), 1.04 (t, 3H, CH3, J= 7.9 Hz); 13C NMR (CDCl3): δ 171.7, 157.0, 156.3, 151 1, 149 6,
144 3, 141.9, 136.5, 133.9, 132.3, 128.5, 128.0, 123.8, 122.5, 94.5, 75.8, 66.9, 66.6, 56.9,
53 7, 49.1, 47.9, 39.7, 34.1, 30.3, 28.6, 26.1, 25.6, 24.9, 23.2, 20.6, 15 5, 10.6; HRMS
(APCI): m/z 784 (M+l).
Example 42
N1-[4-(4-Ethyl-6-methoxy-5-octoxy-8-quinolylamino)pentyI]-(2S)-2,5-dibenzyl-
oxyformamidopentanamide
Yield: 77%; oil; IR (KBr): 3306 cm-1 (NH), 1687 (ester), 1645 (amide carbonyl); !H NMR
(CDCl3): δ 8.38 (d, 1H, 2-Ar-H, J= 4.3 Hz), 7.30 (m, 10H, Ar-H), 7.11 (d, 1H, 3-Ar-H, J=
4 3 Hz), 6.48 (bs, 1H, NH), 6 43 (s, 1H, 7-Ar-H), 5 54 (bs, 1H, NH), 5 06 (s, 4H, 2 x
OCH2Ph), 4.99 (bs, 1H, NH), 4 25 (m, 2H, CH, NH), 3.95 (s, 3H, OCH3), 3 87 (t, 2H,
OCH2, J= 6.9 Hz), 3.61 (s, 1H, N-CH), 3.22 (m, 6H, 3 x CH2), 1 84-1.47 (m, 20H, 10 x
CH2), 1.30 (m, 6H, 2 x CH3), 0 89 (t, 3H, CH3, J= 7 9 Hz), 13C NMR (CDCl3): δ 171.6,
156 7, 151 2, 149 7, 144 4, 141.9, 136.2, 132.3, 128 2, 123.7, 122 5, 94 5, 74 3, 67 1, 66 7,
56.9, 54 9, 49 2, 48.0, 40.2, 39.5, 34.2, 33.9, 31 9, 29.5, 29.3, 28 5, 26 2, 25 7, 24 2, 22 6,
20 7, 15 5, 14.1, HRMS (APCI): m/z 798 (M+l).
Example 43
N -[4-(4-Ethyl-6-methoxy-5-propoxy-8-quinolylamino)pentyl]-(2S)-2-aminobenz-
ylformate-3-methylbutanamide
Yield: 69%; oil; IR (KBr): 3323 cm-1 (NH), 1713 (ester), 1687 (amide carbonyl); 1H NMR
(CDCl3): 8 8.44 (d, 1H, 2-Ar-H, J= 4.3 Hz), 7.31 (m, 5H, Ar-H), 7.17 (s, 1H, 3-Ar-H), 6.47
(m, 2H, 7-Ar-H, NH), 5.80 (bs, 2H, 2 x NH), 5 08 (s, 2H, OCH2Ph), 4 13 (m. 1H. CH), 3 97 (s, 3H, OCH3), 3 90 (t, 2H, OCH2, J= 6 9 Hz), 3 61 (m, 1H, N-CH), 3.40 (m, 4H, 2 x CH2), 1 90-1 67 (m, 6H, 3 x CH2), 1 33-1 20 (m, 4H, CH, CH3), 1 06 (t, 3H, CH3, J= 7 9 Hz), 0 91 (m, 6H, 2 x CH3); 13C NMR (CDCl3). 5 176.4, 171 7, 157 7, 156 6, 151 1, 144 5, 141 9, 136 3, 128 1, 123 8, 122 5, 94 8, 75 8, 67 0, 60.8, 57 0, 49 4, 39 5, 30 9, 28 7, 26 2. 25 6, 24 9, 23 3, 21.0, 19 3, 15 5, 10 6, HRMS (APCI). m/z 579 (M+l). Example 44
Nl-[4-(5-Butoxy-4-ethyI-6-methoxy-8-quinolylamino)pentyl]-(25)-2-aminobenzyl-formate-3-methylbutanamide
Yield: 91%; oil, IR (KBr): 3432 cm-1 (NH), 1722 (ester), 1607 (amide carbonyl), 1H NMR (CDCl3): δ 8.40 (d, 1H, 2-Ar-H, J= 4.3 Hz), 7.32 (m, 5H, Ar-H), 7 12 (d, 1H, 3-Ar-H, J= 4 3 Hz), 6.45 (s, 1H, 7-Ar-H), 6.15 (bs, 1H, NH), 5.47 (bs, 2H, 2 x NH), 5 08 (s, 2H, OCH2Ph), 4.27 (m, 1H, CH), 3.96 (s, 3H, OCH3), 3.89 (t, 2H, OCH2, J= 6 9 Hz), 3.62 (m, 1H, N-CH), 3.25 (m, 4H, 2 x CH2), 1.89-1.49 (m, 8H, 4 x CH2), 1.26 (m, 7H, CH, 2 x CH3), 0.99 (t, 3H, CH3, J= 7.9 Hz), 0.89 (m, 6H, 2 x CH3); 13C NMR (CDCl3) δ 171.4, 156 5, 151.2, 150 0, 144.4, 141.8, 139 3, 136 2, 133.9, 132.5, 128.2, 122.5, 94.7, 74 0, 67.0, 56 9, 48.1, 33.8, 33 2, 31.2, 29.7, 29 2, 28.6, 25 6, 24.9, 20.7, 19 3, 15 5, 14 0, HRMS (APCI)- m/z 593 (M+l) Example 45
N1-[4-(4-Ethyl-6-methoxy-5-pentoxy-8-quinolyIamino)pentyl]-(25)-2-aminobenz-ylformate-3-methylbutanamide
Yield: 89%, oil; IR (KBr): 3289 cm-1 (NH), 1689 (ester), 1646 (amide carbonyl); 1H NMR (CDCl3): δ 8.40 (d, 1H, 2-Ar-H, J= 4.3 Hz), 7.31 (m, 5H, Ar-H), 7 11 (d, 1H, 3-Ar-H, J= 4 3 Hz), 6.45 (s, 1H, 7-Ar-H), 6.14 (bs, 1H, NH), 5.44 (bs, 1H, NH), 5 08 (m, 3H, OCH2Ph, NH), 4.13 (m, 1H, CH), 3.96 (s, 3H, OCH3), 3.90 (t, 2H, OCH2, J= 6.9 Hz), 3 64 (m, 1H, N-CH), 3 26 (m, 4H, 2 x CH2), 1 85-1.44 (m, 10H, 5 x CH2), 1.28 (m, 7H, CH, 2 x CH3), 0 92 (m, 9H, 3 x CH3); ,3C NMR (CDCl3): δ 171.2, 156.4, 151.2, 149 7, 144 4, 141 8, 136 2, 134 1, 132.5, 128.5, 123 7, 122 5, 94.5, 74.2, 67.0, 60 7, 56.9, 49 2, 39 5, 34 1, 30 9, 29 7, 28 6, 28 2, 26 2, 24.9, 22 6, 20 7, 19 3, 17 8, 15 5, 14 1, HRMS (APCI). m/z 607 (M+L). Example 46
Al-[4-(4-Ethyl-5-hexoxy-6-methoxy-8-quinolylamino)pentyl]-(25)-2-aminobenz-ylformate-3-methyIbutanamide
Yield 69%, oil, IR (KBr) 3407 cm'1 (NH), 1720 (ester), 1665 (amide carbonyl), 1H NMR (CDC13)' 5 8 40 (d, 1H, 2-Ar-H, J= 4 3 Hz), 7 32 (m, 5H, Ar-H), 7 13 (d, 1H, 3-Ar-H, J= 4 3 Hz), 6 44 (s, IH 7-Ar-H), 6 06 (bs, 1H, NH), 5.38 (bs, 1H, NH), 5 08 (m, 2H, OCH2Ph), 4 26 (m, 2H, CH, NH), 3 96 (s, 3H, OCH3), 3 90 (t, 2H, OCH2, J= 6 9 Hz), 3 64 (m, 1H, N-CH), 3 25 (m, 4H, 2 x CH2), 1.85-1 48 (m, 12H, 6 x CH2), 1 32 (m, 7H, CH, 2 x CH3), 1 12 (t, 3H, CH3, J= 7 9 Hz), 0 91 (m, 6H, 2 x CH3), 13C NMR (CDCl3): δ 178 8. 172 0, 171 8, 157.7, 156 6, 154 0, 150 6, 147.7, 136 6, 128 5, 123 8, 122.9, 94 6, 74 3, 66 7, 60 4, 57 0, 49 5, 39.3, 33 7, 32 9, 31 4, 30 8, 29 1, 25 5, 24 8, 22 6, 21 0, 19 3, 17 8, 15 3, 14 1, HRMS (APCI)- m/z 621 (M+l) Example 47
N1-[4-(4-Ethyl-5-heptoxy-6-methoxy-8-quinolylamino)pentyI]-(25)-2-aminobenz-ylformate-3-methylbutanamide
Yield. 98%, oil; IR (KBr): 3427 cm-1 (NH), 1721 (ester), 1642 (amide carbonyl), 1H NMR (CDCl3): δ 8.40 (d, 1H, 2-Ar-H, J= 4.3 Hz), 7.32 (m, 5H, Ar-H), 7.12 (d, 1H, 3-Ar-H, J= 4 3 Hz), 6.44 (s, 1H, 7-Ar-H), 6.02 (bs, 1H, NH), 5.36 (bs, 1H, NH), 5 08 (m, 2H, OCH2Ph), 4 11 (m, 1H, CH), 3.96 (s, 3H, OCH3), 3.88 (t, 2H, OCH2, J= 6 9 Hz), 3 64 (m, 1H, N-CH), 3.23 (m, 5H, 2 x CH2) NH), 1.94-1.47 (m, 14H, 7 x CH2), 1.32-1 08 (m, 10H, CH, 3 x CH3), 0.90 (m, 6H, 2 x CH3); l3C NMR (CDC13): 8 171.1, 156 4, 151 1, 149.7, 144 4, 141.9, 136 2, 134.1, 132.4, 128.2, 123.7, 122.5, 94.5, 74.3, 67.0, 60.7, 56.9, 49.2, 48 0, 39.5, 34 2, 31.9, 30.0, 29 2, 28 6, 26.2, 24 9, 22.7, 20.7, 19.3, 17.8, 15 5, 14 1, HRMS (APCI)- m/z 635 (M+l). Example 48
N1-[4-(4-Ethyl-6-methoxy-5-octoxy-8-quinolylamino)pentyl]-(25)-2-aminobenzyI-formate-3-methylbutanamide
Yield: 87%, oil; IR (KBr): 3296 cm-1 (NH), 1727 (ester), 1685 (amide carbonyl); 1H NMR (CDC13)- 5 8 40 (d, 1H, 2-Ar-H, J= 4 3 Hz), 7.32 (m, 5H, Ar-H), 7.12 (d, 1H, 3-Ar-H, J= 4 3 Hz), 6 44 (s, 1H, 7-Ar-H), 6.04 (bs, 1H, NH), 5 38 (bs, 1H, NH), 5 09 (m, 2H, OCH2Ph), 4 15 (m, 1H, CH), 3 96 (s, 3H, OCH3), 3 87 (t, 2H, OCH2, J= 6 9 Hz), 3.64 (m, 1H. N-CH), 3 23 (m, 4H, 2 x CH2), 1 91-1.68 (m, 16H, 8 x CH2), 1.32 (m, 10H, CH, 3 x CH3), 0.90 (m, 6H, 2 x CH3); 13C NMR (CDCl3): δ 171.2, 157.1, 156.4, 151.2, 149 8, 144.4, 141.9, 134.0. 128.5, 123.8, 122.5, 94.7, 74.3, 67.1, 60.7, 56.9, 49.3, 48.1, 39.5, 33.9, 31.9, 30 0, 28.4, 26.3, 25.6, 24.9, 22.7, 20.8, 19.3, 17.8, 15.5, 14.1; HRMS (APCI): m/z 649 (M+l).
General method for the synthesis of N1-[4-(5-alkoxy-4-ethyl-6-methoxy-8-quino-Iylamino/6-methoxy-8-quinoIyIamino)pentyl]-(2S)-2-amino/diaminoalkanamides
To a mixture of N1-[4-(5-alkoxy-4-ethyl-6-methoxy-8-quinolylamino)pentyl]-(25)-2-aminobenzyIformate-2-alkylalkanamide/N1-[4-(6-methoxy-8-quinolylamino)pentyl]-(25)-2-aminobenzylformate-2-alkylalkanamides (0 5 mmol), glacial acetic acid (1 mL) and 10% Pd-C (0 lg) in methanol (20 mL) was bubbled hydrogen gas for 1 h The catalyst was filtered and filtrate was concentrated in vacuo to afford the product as oily syrup, which on treatment with a solution of ethereal HCl provided the corresponding hydrochloride salt derivatives.
Alternatively, in the cases involving the use of t-Boc protected amino acids, a solution of protected derivative (0.5 mmol) in methanolic hydrogen chlonde (20 mL) was stirred for overnight at room temperature The solvent was removed in vacuo to afford orange solid Recrystallized from methanol/diethyl ether.
Example 49
N1-[4-(4-Ethyl-6-methoxy-5-propoxy-8-quinolylamino)pentyl]-(25)-2-aminoprop-
anamide
Yield: 100%; mp (salt): 104-111 °C (dec); IR (KBr): 3434 cm-1 (NH2), 1665 (amide carbonyl); 1H NMR (free base, CDC13): 5 8.40 (d, 1H, 2-Ar-H, J= 4.2 Hz), 7 13 (d, 1H, 3-Ar-H, J= 4.2 Hz), 6.47 (s, 1H, 7-Ar-H), 4.42 (bs, 1H, NH), 4 22 (m, 1H, N-CH), 3.97 (s, 3H, OCH3), 3.88 (t, 2H, OCH2, J= 6.9 Hz), 3.63 (m, 1H, N-CH), 3.25 (m, 4H, 2 x CH2), 2 09 (s, 2H, NH2), 1 71-1 44 (m, 6H, 3 x CH2), 1.32 (m, 9H, 3 x CH3), 0 93 (t, 3H, CH3, J= 7 8 Hz); 13C NMR (free base, CDC13)- 5 176.1, 172 3, 152.2, 149 0, 144 5, 142 2, 134 2, 132 8, 123.1, 122.9, 120 0, 94 5, 74.8, 66 2, 57 1, 49 5, 39.0, 40 4, 32 4, 29 5, 28 2, 26.0, 15 6, 14 1, 11 5, MS (EI) m/z 416(M+). Example 50
N1 -[4-(5-Butoxy-4-ethyl-6-methoxy-8-quinoIylamino)pentyl]-(2S)-2-aminoprop-anamide
Yield: 100%; mp (salt)- 93-97 °C (dec); IR (KBr). 3427 cm-1 (NH2), 1642 (amide carbonyl); lH NMR (free base, CDC13): 5 8.39 (d, 1H, 2-Ar-H, J= 4 3 Hz), 7 11 (d, IH. 3-Ar-H, J= 4 3 Hz), 6 52 (s, 1H, 7-Ar-H), 4.51 (bs, 1H, NH), 4 18 (m, 1H, N-CH), 3 95 (s. 3H, OCH3), 3.88 (t, 2H, OCH2, J= 6 8 Hz), 3 60 (m, 1H, N-CH), 3 23 (m, 4H, 2 x CH2),
2 08 (s, 2H, NH2), I 86-1 48 (m, 8H, 4 x CH2), 1 29 (m, 9H, 3 x CH3), 0 98 (t, 3H, CH3, J=
7 6 Hz), 13C NMR (free base, CDC13). 5 175 2, 172 8, 151 6, 149 1, 144 7, 141 8, 134 0,
133 1, 123 6, 122 2, 120.1, 94 7, 74 1, 65.9, 57 8, 50 1, 39 4, 40 1, 32.1, 29 8, 28 2, 26 3,
212, 15.5,14 2,11.8, MS (El): m/z 430 (NT).
Example 51
N1-[4-(4-EthyI-6-methoxy-5-pentoxy-8-quinoIylamino)pentyl]-(25)-2-aminoprop-anamide
Yield: 98%, mp (salt): 82-86 °C (dec ); IR (KBr): 3412 cm-1 (NH2), 1664 (amide carbonyl); 1H NMR (free base, CDC13): 8 8 40 (d, 1H, 2-Ar-H, J= 4.2 Hz), 7.75 (bs, 1H, NH), 7 14 (d, 1H, 3-Ar-H, J= 4.2 Hz), 6.44 (s, 1H, 7-Ar-H), 4.10 (m, 1H, N-CH), 3.96 (s, 3H, OCH3), 3.87 (t, 2H, OCH2, J= 6.8 Hz), 3.63 (s, 1H, N-CH), 3.22 (m, 4H, 2 x CH2), 2.05 (s, 2H, NH2), 1.90-1.62 (m, 10H, 5 x CH2), 1.30 (m, 9H, 3 x CH3), 0.89 (t, 3H, CH3, J= 7.9 Hz), 13C NMR (free base, CDC13): 5 176.5, 173.0, 1519, 149.5, 145.1, 142 0, 134 4, 133 2, 124 2, 122.5, 119 9, 94.5, 74 3, 66.1, 57.0, 50.2, 39.6, 34 9, 32.0, 30 1, 28.5, 26 0, 24 4, 21 4, 15.8, 14 5, 11.0; MS (CI)- m/z 445 (M+l).
Example 52
N1-[4-(4-Ethyl-5-hexoxy-6-methoxy-8-quinoIyIamino)pentyl]-(2S)-2-aminoprop-
anamide
Yield. 96%, mp (salt) 77-79 °C (dec); IR (KBr). 3427 cm-1 (NH2), 1642 (amide carbonyl), lH NMR (free base, CDC13)- 5 8 40 (d, 1H, 2-Ar-H, J= 4 3 Hz), 7 76 (bs, 1H, NH), 7 12 (d, 1H, 3-Ar-H, J= 4.3 Hz), 6.45 (s, 1H, 7-Ar-H), 4.18 (m, 1H, N-CH), 3 96 (s, 3H, OCH3),
3 87 (t, 2H, OCH2, J= 6.91 Hz), 3.64 (s, 1H, N-CH), 3.22 (m, 4H, 2 x CH2), 2 07 (bs, 2H,
NH2), 1.95-1 67 (m, 12H, 6 x CH2), 1 29 (m, 9H, 3 x CH3), 0.87 (t, 3H, CH3, J= 7 9 Hz);
l3C NMR (free base, CDC13). 5 176.9, 173.4, 151.4, 150.1, 144.7, 142.1, 134 1, 132.6,
124.0, 122.8, 119.2, 94.8, 74.6, 66 1, 57.1, 50.3, 39.8, 34 4, 32.8, 30 3, 28.9, 26 4, 25.2,
21.4, 20 9, 15.8, 14.4, 11.7; HRMS (APCI): m/z 459 (M+l).
Example 53
Nl-[4-(4-Ethyl-5-heptoxy-6-methoxy-8-quinolylamino)pentyl]-(25)-2-aminoprop-anamide
Yield, 100%, mp (salt) 75-77 °C (dec), IR (KBr) 3438 cm-1 (NH2), 1663 (CONH), 1H NMR (free base, CDC13): 5 8.38 (d, 1H, 2-Ar-H, J= 4 2 Hz), 7 61 (bs, 1H, NH), 7 12 (d, 1H, 3-Ar-H, J= 4 2 Hz), 6 45 (s, 1H, 7-Ar-H), 4 18 (m, 1H, N-CH), 3 96 (s, 3H, OCH3), 3 90 (t, 2H, OCH2, J= 6 6 Hz), 3.63 (s, 1H, N-CH), 3 25 (m, 4H, 2 x CH2), 2 06 (s, 2H, NH2), 1.94-1 59 (m, 14H, 7 x CH2), 1.29 (m, 9H, 3 x CH3), 0.89 (t, 3H, CH3, J= 7 6 Hz), l3C NMR (free base, CDC13): 5 172.6, 158 2, 151.5, 150.2, 144.7, 142.2, 134 3, 132.8, 124 1, 122 9, 119 2, 95.0, 74 7, 57 3, 50 2, 48.5, 40.0, 34 1, 32 3, 30 4, 29 6, 26.4, 25 2, 21.6, 21 0, 19 3, 15 9, 14 5, MS (CI): m/z 473 (M+l) Example 54
N1-[4-(4-Ethyl-6-methoxy-5-octoxy-8-quinolylamino)pentyl]-(25)-2-aminoprop-anamide
Yield, 100%; mp (salt): 72-74 °C (dec); IR (KBr): 3360 cm-1 (NH2), 1641 (amide carbonyl); 1H NMR (free base, CDC13): 5 8.38 (d, 1H, 2-Ar-H, J= 4.3 Hz), 7.60 (bs, 1H, NH), 7 12 (d, 1H, 3-Ar-H, J= 4 3 Hz), 6.45 (s, 1H, 7-Ar-H), 3 96 (s, 3H, OCH3), 3 87 (t, 2H, OCH2, J= 6 9 Hz), 3.63 (s, 1H, N-CH), 3 23 (m, 4H, 2 x CH2), 2.07 (s, 2H, NH2), 1.95-1.37 (m, 16H, 8 x CH2), 1.29 (m, 9H, 3 x CH3), 0.89 (t, 3H, CH3, J= 6.7 Hz); 13C NMR (free base, CDC13): 5 173.4, 158.0, 151.4, 150 1, 144.7, 142.1, 134.1, 132.6, 124 0, 122 8, 119 2, 94.8, 74 6, 66.1, 57.1, 50.3, 48.4, 39.8, 34.4, 32.2, 30.3, 29.6, 26 4, 25.2, 23 0, 21 4, 20.9, 19 9, 15 8, 14.4; MS (CI): m/z 491 (M+l).
Example 55
N1-[4-(4-EthyI-6-methoxy-5-propoxy-8-quinolylamino)pentyI]-(25)-2,6-diamino-
hexanamide
Yield: 94%, mp (salt): 126-129 °C (dec); IR (KBr): 3425 cm-1 (NH2), 1667 (amide carbonyl), 1H NMR (free base, CDC13). 5 8 37 (d, 1H, 2-Ar-H, J= 4.3 Hz), 8.26 (bs, 1H, NH), 7 11 (d, 1H, 3-Ar-H, J= 4 3 Hz), 6.44 (s, 1H, 7-Ar-H), 3.95 (s, 3H, OCH3), 3.84 (t. 2H, OCH2, J= 6.7 Hz), 3 62 (s, 1H, N-CH), 3.39 (m, 2H, N-CH2), 3.23 (m, 6H, 3 x CH2), 2.91 (bs, 2H, NH2), 1.85-1.35 (m, 14H, 6 x CH2, NH2), 1.26 (d, 3H, CH3, J= 5.2 Hz), 1.18 (t, 3H, CH3, J= 6.2 Hz); 1.04 (t, 3H; CH3, J= 7.9 Hz); 13C NMR (free base, CDCl3): 5 170.4, 157.7,
151 2, 149 6, 144 5, 141 9, 134 0, 123 8, 122 4, 94 7, 75.8, 56 9, 53 0, 49 4, 48 1, 39 7, 33 7, 28 6, 25 6, 24 9, 22.2, 20 5, 15 5, 10 6, HRMS (ESI), m/z 474 (M+l) Example 56
N1-[4-(5-Butoxy-4-ethyl-6-methoxy-8-quinolylamino)pentyl]-(25)-2,6-diamino-hexanamide
Yield. 92%, mp (salt) 120-124 °C (dec); IR (KBr): 3332 cm'1 (NH2), 1665 (amide carbonyl); 1H NMR (free base, CDC13): 5 8.37 (d, 1H, 2-Ar-H, J= 4.2 Hz), 7 84 (bs, 1H, NH), 7 11 (d, 1H, 3-Ar-H, J= 4 2 Hz), 6 44 (s, 1H, 7-Ar-H), 3.95 (s, 3H, OCH3), 3 88 (t, 2H, OCH2, J= 5.8 Hz), 3 62 (s, 1H, N-CH), 3.23 (m, 4H, 2 x CH2), 2.91 (bs, 2H, NH2), 1-80-1 31 (m, 14H, 6 x CH2, NH2), 1.28 (m, 6H, 2 x CH3), 0.99 (t, 3H, CH3, J= 7 6 Hz), 13C NMR (free base, CDC13): 8 177.3, 170.2, 151 1, 149.7, 144.4, 141 9, 133.9, 132 3, 123 7, 122.2, 94 6, 74.0, 56.9, 53.1, 48.1, 39.8, 38.8, 34.3, 32.1, 28.6, 26.0, 21.4, 20 5, 19 3, 18 7, 15 5, 14.0; HRMS (APCI): m/z 488 (M+l). Example 57
N1-[4-(4-Ethyl-6-methoxy-5-pentoxy-8-quinolylamino)pentyl]-(25)-2,6-diamino-hexanamide
Yield: 99%; mp (salt): 118-121 °C (dec); IR (KBr): 3358 cm-1 (NH2), 1651 (amide carbonyl); 1H NMR (free base, CDCl3): 5 8.36 (d, 1H, 2-Ar-H, J= 3 6 Hz), 8 2 (bs, 1H, NH), 7.10 (d, 1H, 3-Ar-H, J= 3 6 Hz), 6 44 (s, 1H, 7-Ar-H), 3.95 (s, 3H, OCH3), 3.87 (t, 2H, OCH2, J= 6.6 Hz), 3.62 (s„ 1H, N-CH), 3.47 (bs, 2H, NH2), 3.24 (m, 4H, 2 x CH2), 2 92 (m, 2H, N-CH2), 1 82-1 43 (m, I8H, 8 x CH2, NH2), 1.26 (m, 6H, 2 x CH3), 0 94 (t, 3H, CH3, J= 6 4 Hz); 13C NMR (free base, CDCl3): 5 177.1, 170.2, 150.9, 149.5, 144.3, 141 8, 133.7, 123 5, 122.2, 94.4, 74.0, 57.0, 53.0, 47.8, 39 6, 38.7, 34.2, 33 5, 31.1, 29.6, 28 1, 25.5, 24 8, 22.7, 21 7, 21.2, 20.4, 15.4, 14.0; HRMS (APCI): m/z 502 (M+l).
Example 58
i
Nl-[4-(4-Ethyl-5-hexoxy-6-methoxy-8-quinolyIamino)pentyI]-(2S)-2,6-diamino-hexanamide
Yield: 90%; mp (salt): 114-116 °C (dec); IR (KBr)- 3357 cm-1 (NH2), 1650 (amide carbonyl), 1H NMR (free base, CDCl3) 5 8 37 (d, 1H, 2-Ar-H, J= 4 3 Hz), 7 47 (bs, 1H, NH), 7 10 (d, 1H, 3-Ar-H, J= 4.3 Hz), 6.44 (s, 1H, 7-Ar-H), 4.18 (m, 1H, N-CH), 3 95 (s, 3H, OCH3), 3.87 (t, 2H, OCH2, J= 6.9 Hz), 3.71 (s, 1H, N-CH), 3.47 (s, 4H, 2 x NH2), 3 24 (m, 4H, 2 x CH2), 2 92 (s, 2H, N-CH2), 1.8-1.3 (m, 18H, 9 x CH2), 1.24 (m, 6H, 2 x CH3), 0 94 (t, 3H, CH3, J= 7.9 Hz); 13C NMR (free base, CDC13): 8 177.0, 170.3, 151 2, 149.7,
144 4, 141 9, 133 9, 123 7, 122.5, 94.5, 74 2, 56.9, 53 1, 48.1, 39 8, 38 9, 34 3, 33 7, 31 2, 29 7, 28 2, 25 6, 24 9, 22 6, 21 8, 21 5, 20.5, 15.5, 14.1; HRMS (APCI). m/z 516 (M+l) Example 59
N1-[4-(4-Ethyl-5-heptoxy-6-methoxy-8-quinolylaniino)pentyl]-(25)-2,6-diamino-hexanamide
Yield: 100%, mp (salt). 102-105 °C (dec), IR (KBr): 3410 cm-1 (NH2), 1712 (amide carbonyl), 1H NMR (free base, CDC13). 5 8 37 (d, 1H, 2-Ar-H, J= 3.6 Hz), 8 11 (bs, 1H, NH), 7 11 (d, 1H, 3-Ar-H, J= 3 6 Hz), 6 44 (s, 1H, 7-Ar-H), 3 96 (s, 3H, OCH3), 3 84 (t, 2H, OCH2, J= 6 8 Hz), 3.73 (m, 1H, N-CH), 3.48 (m, 1H, N-CH), 3.27 (m, 4H, 2 x CH2), 2.89 (m, 2H, N-CH2), 1.88-1 48 (m, 22H, 10 x CH2, NH2), 1 24 (m, 6H, 2 x CH3), 1 04 (t, 3H, CH3, J= 6.6 Hz); l3C NMR (free base, CDC13): 5 177.7, 157 2, 151.1, 149 7, 144 4, 141 7,
132 5, 128.5, 123.7, 122.5, 94.5, 74.0, 60.1, 53.8, 49.2, 47.9, 39.9, 38.9, 34 1, 33.8, 28.6,
25 6, 24 9, 23 3, 22.6, 21.5, 20.3, 17.8, 15 5, 10.6; HRMS (APCI): m/z 530 (M+l).
Example 60
N1-[4-(4-Ethyl-6-methoxy-5-octoxy-8-quinolyIamino)pentyI]-(2S)-2,6-diamino-hexanamide
Yield: 99%; mp (salt): 99-101 °C (dec); IR (KBr): 3409 cm1 (NH2), 1583 (amide carbonyl); 1H NMR (free base, CDC13): 6 8.36 (d, 1H, 2-Ar-H, J= 3.5 Hz), 7.10 (d, 1H, 3-Ar-H, J= 3 5 Hz), 6.62 (bs, 1H, NH), 6.43 (s, 1H, 7-Ar-H), 3.94 (s, 3H, OCH3), 3 86 (t, 2H, OCH2, J= 7.3 Hz), 3.61 (m, 1H, N-CH), 3.48 (m, 1H, N-CH), 3 23 (m, 4H, 2 x CH2), 2.90 (m, 2H, N-CH2), 1.81-1.46 (m, 24H, 11 x CH2, NH2), 1.28 (m, 6H, 2 x CH3), 0 88 (t, 3H, CH3, J= 6.8 Hz); 13C NMR (free base, CDC13)- 5 177.4, 170.6, 151 1, 149 6, 144 4, 141 9,
133 9, 132.3, 123 7, 122 5, 94.6, 74.3, 56.9, 53 1, 49 4, 48.1, 39.8, 38.8, 34 3, 33 8, 31.4,
29 3, 28.6, 26 1, 24 9, 22.7, 22.3, 20.5, 17.8, 15 5, 14.1; HRMS (ESI): m/z 544 (M+l).
Example 61
N1 -[4-(4-Ethyl-6-methoxy-5-propoxy-8-quinolylamino)pentyl]-(25)-2,5-diamino-pentanamide
Yield: 90%, mp (salt). 125-127 °C (dec), IR (KBr): 3460 cm-1 (NH2), 1667 (amide carbonyl); lH NMR (free base, CDC13): 5 8.37 (d, 1H, 2-Ar-H, J= 4 1 Hz), 7 61 (bs, 1H, NH), 7.11 (d, 1H, 3-Ar-H, ,J= 4.1 Hz), 6.44 (s, 1H, 7-Ar-H), 3.95 (s, 3H, OCH3), 3 85 (t, 2H, OCH2, J= 6.3 Hz), 3.62 (s, 1H, N-CH), 3.23 (m, 6H, 3 x CH2), 2.96 (bs, 2H, NH2), 1.85-1.31 (m, 12H, 5 x CH2, NH2), 1.28 (d, 3H, CH3, J= 5.0 Hz), 1.15 (t, 3H, CH3, J= 6.4 Hz); 1 04 (t, 3H, CH3, J= 7.5 Hz); I3C NMR (free base, CDCl3): 5 177.3, 157.5, 151 2, 149.7,
144 4, 141 9, 134 1, 128 5, 123 7, 122.5, 94 7, 75 8, 56.9, 49 4, 48 1, 33 8, 28 6, 26 1, 25 6. 24 9, 23.3, 22 0, 20 6, 15 5, 10 6, HRMS (ESI)- m/z 460 (M+l) Example 62
N1-[4-(5-Butoxy-4-ethyl-6-methoxy-8-quinolylamino)pentyl]-(2S)-2,5-diamino-pentanamide
Yield 100%, mp (salt) 121-123 °C (dec); IR (KBr) 3439 cm'1 (NH2), 1720 (amide carbonyl), lH NMR (free base, CDC13): 5 8.37 (d, 1H, 2-Ar-H, J= 4.4 Hz), 7 11 (d, 1H, 3-Ar-H, J= 4 4 Hz), 6.43 (s, 1H, 7-Ar-H), 6 34 (bs, 1H, NH), 3 94 (s, 3H, OCH3), 3 88 (t, 2H, OCH2, J= 6.3 Hz), 3.61 (s, 1H, N-CH), 3.41 (bs, 2H, NH2), 3.21 (m, 4H, 2 x CH2), 2.94 (m, 2H, N-CH2), 1.80-1.30 (m; 14H, 6 x CH2, NH2), 1.28 (m, 6H, 2 x CH3), 0.88 (t, 3H, CH3, J= 6 8 Hz); 13C NMR (free base, CDC13) 5 176.8, 151.1, 149.6, 144.4, 141 9, 134 0, 123 7, 122 5, 95 0, 94.5, 74 0, 58.9, 48.0, 34 2, 33.8, 32.1, 29.7, 28 6, 25.6, 24.9, 23 8, 21 2, 20.6, 19.3, 15 5, 14.0; HRMS (ESI): m/z 474 (M+l). Example 63
N1-[4-(4-Ethyl-6-methoxy-5-pentoxy-8-quinolylamino)pentyl]-(2S)-2,5-diamino-pentanamide
Yield; 100%; mp (salt): 116-118 °C (dec); IR (KBr)- 3378 cm'1 (NH2), 1643 (amide carbonyl); 1H NMR (free base, CDCl3): 8 8.36 (d, 1H, 2-Ar-H, J= 4.2 Hz), 8 2 (bs, 1H, NH), 7.11 (d, 1H, 3-Ar-H, J= 4.2 Hz), 6.44 (s, 1H, 7-Ar-H), 3.95 (s, 3H, OCH3), 3 88 (t, 2H, OCH2, J= 6 9 Hz), 3.70 (s, 1H, N-CH), 3 61 (s, 1H, N-CH), 3.46 (bs, 2H, NH2), 3 22 (m, 4H, 2 x CH2), 2.97 (m, 2H, N-CH2), 1.90-1.41 (m, 16H, 7 x CH2, NH2), 1.29 (m, 6H, 2 x CH3), 0.94 (t, 3H, CH3, J= 6.9 Hz); 13C NMR (free base, CDCl3): 5 177 2, 170 4, 151.2, 149.8, 144.5, 141.7, 134.0t 123.7, 122.5, 95.1, 94.7, 74.3, 56.9, 50.6, 48 1, 39.4, 34.3, 33 8, 29 7, 28 6, 28.2, 24.9, 22.6, 21.8, 20 8, 15.5, 14.1; HRMS (APCI)- m/z 488 (M+l) Example 64
N1-[4-(4-Ethyl-5-hexoxy-6-methoxy-8-quinolyIamino)pentyI]-(2S)-2,5-diamino-pentanamide
Yield: 80%, mp (salt): 109-112 °C (dec); IR (KBr): 3372 cm'1 (NH2), 1645 (amide carbonyl), 1H NMR (free base, CDC13)- δ 8.37 (d, 1H, 2-Ar-H, J= 4.3 Hz), 8 16 (bs, 1H, NH), 7 11 (d, 1H, 3-Ar-H, J= 4.3 Hz), 6.44 (s, 1H, 7-Ar-H), 4.18 (m, 1H, N-CH), 3 96 (s, 3H, OCH3), 3.87 (t, 2H, OCH2, J= 5.4 Hz), 3.62 (s, 1H, N-CH), 3.49 (bs, 2H, NH2), 3.24 (m, 4H, 2 x CH2), 2.96 (s, 2H, N-CH2), 1.79-1.35 (m, 18H, 8 x CH2, NH2), 1.26 (m, 6H, 2 x CH3), 0.92 (t, 3H, CH3, J= 7.6 Hz); l3C NMR (free base, CDC13): 5 177.1, 170.0, 151.1,
149 9, 144.5, 141 2, 133.2, 123.1, 122.2, 94 4, 74 8, 57 2, 53 0, 48.5, 39 4, 38 7, 34 2, 33 5, 31 6, 29 7, 28 6, 25.8, 24.9, 22.6, 21 9, 20.6, 15 6, 14.1, HRMS (APCI): m/z 502 (M+l) Example 65
N1-[4-(4-Ethyl-5-heptoxy-6-methoxy-8-quinolylamino)pentyl]-(2S)-2,5-diamino-pentanamide
Yield. 91%, mp (salt). 98-101 °C (dec), IR (KBr)- 3396 cm'1 (NH2), 1623 (amide carbonyl), 1H NMR (free base, CDC13) δ 8.37 (d, 1H, 2-Ar-H, J= 3 8 Hz), 8 18 (bs, 1H, NH), 7 12 (d, 1H, 3-Ar-H, J= 3.8 Hz), 6 45 (s, 1H, 7-Ar-H), 3.96 (s, 3H, OCH3), 3 85 (t, 2H, OCH2, J= 6.9 Hz), 3 61 (m, 1H, N-CH), 3 45 (bs, 4H, 2 x NH2), 3.24 (m, 4H, 2 x CH2), 2 97 (m, 2H, N-CH2), 1.90-1.67 (m, 18H, 9 x CH2), 1.23 (m, 6H, 2 x CH3), 1.04 (t, 3H, CH3, J= 6 4 Hz), 13C NMR (free base, CDCl3): 5 177 4, 169 9, 151 1, 149.8, 144 3, 141 9, 133.9, 132 3, 123 7, 122.4, 94 6, 75 8, 56.9, 52.7, 50 4, 49.4, 48 0, 39.8, 38.8, 34.2, 33 6, 28.6, 25 9, 25.5, 24.8, 23 2, 21.8, 20.5, 15 5, 10.5; HRMS (APCI): m/z 516 (M+l).
Example 66

N1-[4-(4-Ethyl-6-methoxy-5-octoxy-8-quinolyIamino)pentyl]-(25)-2,5-diamino-
pentanamide
Yield: 99%; mp (salt): 98-103 °C (dec); IR (KBr): 3410 cm-1 (NH2), 1591 (amide carbonyl); 1H NMR (free base, CDC13). 5 8.36 (d, 1H, 2-Ar-H, J= 3.5 Hz), 7 10 (d, 1H, 3-Ar-H, J= 3.5 Hz), 6.46 (bs, 1H, NH), 6 43 (s, 1H, 7-Ar-H), 3.94 (s, 3H, OCH3), 3.88 (t, 2H, OCH2, J= 6.1 Hz), 3.62 (m, 1H, N-CH), 3.23 (m, 4H, 2 x CH2), 2.94 (bs, 2H, NH2), 2.17 (bs, 2H, NH2), 1.81-1 46 (m, 20H, 10 x CH2), 1.28 (m, 6H, 2 x CH3), 0.89 (t, 3H, CH3, J= 6.6 Hz); I3C NMR (free base, CDC13)- 5 177.3, 170.6, 151.1, 149.7, 144.3, 141 9, 133 9, 132 3, 123.7, 122 5, 95.0, 74.2, 56 8, 52 9, 49.4, 48.1, 39.9, 38 9, 34.3, 33 8, 30 9, 29 5, 28 6, 26 1, 24.9, 22.7, 22 2, 20.5, 15 5, 14.1, HRMS (ESI): m/z 530 (M+l). Example 67
A1-[4-(4-EthyI-6-methoxy-5-propoxy-8-quinoIylamino)pentyl]-(25)-2-amino-3-methylbutanamide
Yield: 100%; mp (salt): 135-137 °C (dec); IR (KBr): 3456 cm-1 (NH2), 1583 (amide carbonyl), 1H NMR (free base, CDC13)- 5 8 39 (d, 1H, 2-Ar-H, J= 4 1 Hz), 7 94 (bs, 1H, NH), 7 12 (d, 1H, 3-Ar-H, J= 4.1 Hz), 6.46 (s, 1H, 7-Ar-H), 3.96 (s, 3H, OCH3), 3 85 (t, 2H, OCH2, J= 6.9 Hz), 3 62 (m, 1H, N-CH), 3 46-3.23 (m, 4H, 2 x CH2), 2.01 (bs, 2H, NH2), 1.89-1 68 (m, 6H, 3 x CH2), 1.30 (m, 6H, 2 x CH3), 1.05 (m, 4H, CH and CH3), 0.94 (m, 6H, 2 × CH3); l3C NMR (free base, CDCl3): 5 177.3, 171.8, 157.7, 151.2, 149.8, 144.4,
141 9, 134 1, 123 7, 122 5, 94 8, 75.8, 56 9, 49 4, 48.2, 38 4, 33 7, 28 6, 26 4, 24 7, 23 3. 21 8, 20 6, 13.5, 10.6; HRMS (ESI)- m/z 445 (M+l). Example 68
N1-[4-(5-Butoxy-4-ethyl-6-methoxy-8-quinolyIamino)pentyl]-(25)-2-amino-3-methylbutanamide
Yield: 100%, mp (salt)- 125-127 °C (dec), IR (KBr)- 3434 cm-1 (NH2), 1673 (amide

carbonyl); 1H NMR (free base, CDC13) 5 8.39 (d, 1H, 2-Ar-H, J= 4 0 Hz), 7 34 (bs, 1H, NH), 7 12 (d, 1H, 3-Ar-H, J= 4.0 Hz), 6.45 (s, 1H, 7-Ar-H), 3.97 (s, 3H, OCH3), 3.89 (t, 2H, OCH2, J= 6.8 Hz), 3.66 (m, 1H, N-CH), 3.49 (bs, 1H, NH), 3 25 (m, 4H, 2 x CH2), 2.08 (bs, 2H, NH2), 1 95-1.36 (m, 8H, 4 x CH2), 1 30 (m, 6H, 2 x CH3), 1 01 (m, 4H, CH and CH3), 0 85 (m, 6H, 2 x CH3); 13C NMR (free base, CDC13). 5 176.2, 173 8, 157.5, 151.1, 149 7, 144.4, 142.0, 134.0, 123.7, 122 5, 94 5, 74.0, 60.1, 56.9, 49 4, 48.0, 39 1, 33 8, 31 9, 29 4, 25 6 20.7, 19 3, 15.5, 14.0; HRMS (APCI): m/z 459 (M+l) Example 69
N1-[4-(4-Ethyl-6-methoy-5-pentoxy-8-quinoIylamino)pentyI]-(25)-2-amino-3-methylbutanamide
Yield: 100%, mp (salt): 118-122 °C (dec); IR (KBr): 3379 cm-1 (NH2), 1643 (amide carbonyl); 1H NMR (free base, CDC13): 5 8.39 (d, 1H, 2-Ar-H, J= 3 3 Hz), 7 44 (bs, 1H, NH), 7 12 (d, 1H, 3-Ar-H, J= 3.3 Hz), 6.45 (s, 1H, 7-Ar-H), 3 96 (s, 3H, OCH3), 3.88 (t, 2H, OCH2, J= 6.7 Hz), 3.72 (m, 2H, 2 x N-CH), 3.48 (bs, 1H, NH), 3.24 (m, 4H, 2 x CH2), 2 06 (bs, 2H, NH2), 1.94-1.35 (m, 10H, 5 x CH2), 1.31 (m, 6H, 2 x CH3), 0.95 (m, 7H, CH and 2 x CH3), 0.88 (m, 6H, 2 x CH3); 13C NMR (free base, CDC13): 5 176 6, 173.2, 151.2, 149.7, 144 4, 142.0, 134.1, 132.4, 123.7, 122.5, 94.6, 74.3, 60.0, 56.9, 48.1, 39.3, 34.2, 30.8, 29 7, 28 3, 26.3, 24 9, 22.6, 20.7, 19 4, 16.7, 15.5, 14.1; HRMS (APCI). m/z 473 (M+l). Example 70
N1-[4-(4-Ethyl-5-hexoxy-6-methoxy-8-quinoIyIamino)pentyl]-(25)-2-amino-3-methylbutanamide
Yield- 100%; mp (salt) 98-99 °C (dec); IR (KBr): 3432 cm'1 (NH2), 1589 (amide carbonyl); lH NMR (free base, CDC13)- 5 8.40 (d, 1H, 2-Ar-H, J= 3.6 Hz), 7.45 (bs, 1H, NH), 7.13 (d, 1H, 3-Ar-H, J= 3.6 Hz), 6 45 (s, 1H, 7-Ar-H), 3.96 (s, 3H, OCH3), 3.90 (t, 2H, OCH2, J= 6.9 Hz), 3.72 (m, 2H, 2 x N-CH), 3.47 (bs, 1H, NH), 3 25 (m, 4H, 2 x CH2), 2.2 (bs, 2H, NH2), 1.95-1.59 (m, 12H, 6 x CH2), 1.35 (m, 6H, 2 x CH3), 1.15 (m, 7H, CH and 2 x CH3), 0.93 (m, 6H, 2 × CH3); l3C NMR (free base, CDC13): 8 177.4, 172.3, 151.1, 149.6,
144 3, 141 6, 133.2, 132.0, 125 2, 122.9, 94.8, 74 1, 59 7, 56 2, 48.5, 39 0, 33 1, 30 1, 29 2,
28 3, 25 8, 24 8, 23 2, 22 8, 20.1, 18 1, 16.4, 15.4, 14.2, HRMS (ESI), m/z 487 (M+l)
Example 71
N1-[4-(4-Ethyl-5-heptoxy-6-methoxy-8-quinolylamino)perityl]-(25)-2-amino-3-methylbutanamide
Yield, 99%, mp (salt). 87-89 °C (dec ); IR (KBr)- 3435 cm-1 (NH2), 1666 (amide carbonyl), 1H NMR (free base, CDC13): 5 8.39 (d, 1H, 2-Ar-H, J= 4 3 Hz), 7 38 (bs, 1H, NH), 7 12 (d, 1H, 3-Ar-H, J= 4.3 Hz), 6.45 (s, 1H, 7-Ar-H), 3.96 (s, 3H, OCH3), 3 88 (t, 2H, OCH2, J= 7.0 Hz), 3.65 (m, 1H, N-CH), 3 48 (bs, 1H, NH), 3.36 (m, 1H, N-CH), 3 24 (m, 4H, 2 x CH2), 2 04 (bs, 2H, NH2), 1 94-1 47 (m, 14H, 7 x CH2), 1.30 (m, 6H, 2 x CH3), 1.16-0.84 (m, 10H, CH and 3 x CH3); 13C NMR (free base, CDCl3): 5 176.9, 172.9, 151 1, 149.7, 144 4, 141.9, 134.0, 132.4; 123.7, 122.5, 94.5, 75.3, 59.8, 56.9, 49.4, 48.1, 39 3, 34.2, 31.9, 30.0, 29 2, 26.2, 23.7, 21.4, 20.7, 19.3, 16.8, 15.5, 14.1; HRMS (APCI): m/z 501 (M+l). Example 72
N1-[4-(4-Ethyl-6-methoxy-5-octoxy-8-quinoIylamino)pentyI]-(25)-2-amino-3-methylbutanamide
Yield, 97%; mp (salt): 76-78 °C (dec); IR (KBr): 3414 cm-1 (NH2), 1589 (amide carbonyl), 1H NMR (free base, CDCl3): 5 8.40 (d, 1H, 2-Ar-H, J= 4 3 Hz), 7 13 (d, 1H, 3-Ar-H, J= 4 3 Hz), 6.76 (bs, 1H, NH), 6.45 (s, 1H, 7-Ar-H), 3.96 (s, 3H, OCH3), 3.88 (t, 2H, OCH2, J= 6.9 Hz), 3.65 (m, 2H, 2 x N^CH), 3 49 (bs, 1H, NH), 3 39 (m, 2H, CH2), 3.25 (m, 4H, 2 x CH2), 2 22 (bs, 2H, NH2), 1.95-1 48 (m, 16H, 8 x CH2), 1.29 (m, 6H, 2 x CH3), 1.19 (m, 4H, CH and CH3), 0.88 (m, 6H, 2 x CH3); 13C NMR (free base, CDC13): 5 176.8, 172.5, 151.2, 149.6, 144.3, 141.9, 134.2, 132.6, 123.6, 122.5, 94.5, 74.3, 59.9, 56.9, 49.5, 48.1, 39 3, 34.3,
29 5, 26.1, 25.6, 24.9, 22.7, 21 2, 20 7, 19.3, 16 8, 15 6, 14.1; HRMS (ESI): m/z 515 (M+l)
(100%).
General method for the synthesis of N1-[4-(5-alkoxy-4-ethyl-6-methoxy-8-quinolylamino)pentyl]-3-(2,4-dimethyI-3,6-dioxo-l,4-cyclohexadienyl)-3-methyl-butanamides
To a mixture of 3-(2,4-dimethyl-3,6-dioxo-l,4-cycIohexadienyl)-3-methylbutanoic acid (4, 1 06 mmol) and N8-(4-amino-l-methylbutyl)-5-alkoxy-4-ethyI-6-methoxy-8-quinohnamine (0.96 mmol) in anhydrous dichloromethane (15 mL), 1,3-dicyclohexylcarbodnmide (1 06 mmol) and 4-(dimethylamino)pyndine (0.02g) was added and the reaction mixture stirred for 4 h at room temperature under nitrogen atmosphere. The solvent was removed, and to
the residue was added ethyl acetate (10 mL). Reaction mixture was kept in refrigerator overnight and the separated dicyclohexylurea was removed by filtration Filtrate was concentrated under reduced pressure to yield crude product, which was purified by flash column chromatography over silica gel (230-400 mesh) using 0 2% methanol/chloroform to yield N1-[4-(5-aIkoxy-4-ethyI-6-methoxy-8-quinoIyIamino)-pentyl]-3-(2,4-dimethyl-3,6-dioxo-l,4-cyclohexadie-nyl)-3-methylbutanamides which on treatment with a solution of ethereal HC1 gave the corresponding hydrochloride salt. Example 73
N1-[4-(4-Ethyl-6-methoxy-5-propoxy-8-quinolylamino)pentyl]-3-(2,4-dimethyl-3,6-dioxo-l,4-cyclohexadienyl)-3-methylbutanamide
Yield. 43%, mp (salt). 140-143 °C (dec); IR (KBr): 3410 cm-1 (NH), 1798 (quinone), 1590 (amide carbonyl); 1H NMR (free base, CDC13): 5 8.40 (d, 1H, 2-Ar-H, J= 4.3 Hz), 7.13 (d, 1H, 3-Ar-H, J= 4 3 Hz), 6 50 (s, 1H, 5-Ar-H), 6.43 (s, 1H, 7-Ar-H), 5 55 (bs, 1H, NH), 4 22 (bs, 1H, NH), 3 96 (s, 3H, OCH3), 3 86 (t, 2H, OCH2) J= 6.9 Hz), 3.62 (s, 1H, N-CH), 3 49 (m, 2H, N-CH2), 3 23 (m, 4H, 2 x CH2), 2.77 (s, 2H, CH2), 2.17 (s, 3H, 2-CH3), 1.95 (s, 3H, 4-CH3), 1.89-1.62 (m, 6H, 3 X CH2), 1.38 (s, 6H, 2 x CH3), 1.28 (m, 6H, 2 x CH3), 1.05 (t, 3H, CH3, J= 7.4 Hz); ?C! NMR (free base, CDC13): 8 190.0, 188.3, 171 8, 152.5, 151.1, 149.7, 144.4, 143.4, 141.9', 138.7, 135.3, 134.0, 132.4, 123.7, 122.5, 94.5, 75.8, 56 9, 49 4, 48 0, 39.3, 34.2, 33 9, 29.1, 28.6, 26.3, 25.6, 24.9, 23.3, 20.8, 15.5, 14 3, 10.6, HRMS (ESI)- m/z 564 (M+l). Example 74
N1-[4-(5-Butoxy-4-ethyl-6-methoxy-8-quinoIylamino)pentyl]-3-(2,4-dimethyl-3,6-dioxo-l,4-cyclohexadienyI)-3-methylbutanamide
Yield: 91%, mp (salt): 135-139 °C (dec); IR (KBr): 3375 cm"' (NH), 1795 (quinone), 1648 (amide carbonyl); 1H NMR (free base, CDC13): 8 8.39 (d, 1H, 2-Ar-H, J= 4 2 Hz), 7 12 (d, 1H, 3-Ar-H, J= 4 2 Hz), 6 48 (s, 1H, 5-Ar-H), 6.42 (s, 1H, 7-Ar-H), 5 60 (bs, 1H, NH), 4 12 (bs, 1H, NH), 3.97 (s, 3H, OCH3), 3 89 (t, 2H, OCH2, J= 6.9 Hz), 3 61 (m, 1H, N-CH), 3.23 (m, 4H, 2 x CH2), 2.76 (s, 2H, CH2), 2.20 (s, 3H, 2-CH3), 1.95 (s, 3H, 4-CH3), 1 83-1 40 (m, 8H, 4 x CH2), 1 36 (s, 6H, 2 x CH3), 1 24 (m, 6H, 2 x CH3), 0 97 (t, 3H, CH3, J= 6 9 Hz); l3C NMR (free base, CDC13): 8 190.2, 188.0, 171.4, 152.9, 151.0, 149 3, 144 3, 143 2, 141.7, 138.5, 135.1, 134'.1, 132.3, 123.5, 122.3, 94 9, 74.1, 56.7, 49 5, 48.1, 38.5, 34.3, 33.0, 29 3, 29.0, 28.2, 26.1, 25 5, 22.8, 20.5, 15.4, 14.1, 14.0; HRMS (APCR: m/z 578 (M+l) Example 75
N1-[4-(4-Ethyl-6-methoxy-5-pentoxy-8-quinolylamino)pentyl]-3-(2,4-dimethyl-3,6-dioxo-l,4-cyclohexadienyl)-3-methylbutanamide
Yield 95%, mp (salt) 126-128 °C (dec ), IR (KBr) 3380 cm-1 (NH), 1797 (quinone), 1641 (amide carbonyl); 1H NMR (free base, CDC13). 5 8 39 (d, 1H, 2-Ar-H, J= 4 3 Hz), 7 13 (d, 1H, 3-Ar-H, J= 4 3 Hz), 6 49 (s, 1H, 5-Ar-H), 6 43 (s, 1H, 7-Ar-H), 5 57 (bs, 1H, NH), 4 10 (bs, 1H, NH), 3 96 (s, 3H, OCH3), 3 88 (t, 2H, OCH2, J= 6 8 Hz), 3.60 (m, 1H, N-CH), 3 24 (m, 4H, 2 x CH2), 2.73 (s, 2H, CH2), 2.21 (s, 3H, 2-CH3), 1 94 (s, 3H, 4-CH3), 1.85-1.43 (m, 10H, 5 x CH2), 1.37 (s, 6H, 2 x CH3), 1.25 (m, 6H, 2 x CH3), 0.94 (t, 3H, CH3, J= 6 8 Hz), 13C NMR (free base, CDCl3): δ 190.0, 188.3, 1717, 152.5, 151.1, 149 7, 144.4, 143 4, 141 9, 138.7, 135.3, 134.0, 132 4, 123.7, 122.5, 94.5, 74 2, 56.9, 49.4, 48.0, 38 6, 34 2, 33 9,
29.7, 29.1, 28.6, 26 3, 25.6, 24 9, 22.6, 20.7, 15.6, 14 2, 14.1; HRMS (APCI) m/z 592
(M+l)
Example 76
N1-[4-(4-Ethyl-5-hexoxy-6-methoxy-8-quinoIyIamino)pentyl]-3-(2,4-dimethyl-3,6-dioxo-l,4-cyclohexadienyI)-3-methylbutanamide
Yield. 93%, mp (salt): 124-127 °C (dec); IR (KBr): 3403 cm-1 (NH), 1795 (quinone), 1643 (amide carbonyl); lH NMR (free base, CDC13)- 5 8.40 (d, 1H, 2-Ar-H, J= 4.4 Hz), 7 14 (d, 1H, 3-Ar-H, J= 4.4 Hz), 6 50 (s, 1H, 5-Ar-H), 6.43 (s, 1H, 7-Ar-H), 5.51 (bs, 1H, NH), 4 11 (bs, 1H, NH), 3.95 (s, 3H, OCH3), 3.87 (t, 2H, OCH2, J= 6.7 Hz), 3.61 (s, 1H, N-CH), 3.23 (m, 4H, 2 x CH2), 2.75 (s, 2H, CH2), 2.13 (s, 3H, 2-CH3), 2.05 (s, 3H, 4-CH3), 1 85-1.51 (m, 14H, 6 x CH2), 1.37 (s, 6H, 2 x CH3), 1 26 (m, 6H, 2 x CH3), 0.97 (t, 3H, CH3, J= 7.9 Hz), 13C NMR (free base, CDC13): 5 190.0, 171.8, 168.7, 152.5, 151.1, 149 7, 144 4, 143.4, 141.9, 136.5, 135.3, 134.6, 134.0, 132.4, 123.7, 122.5, 122.1, 115.9, 94.5, 74 3, 60.4, 56 9, 49 4, 48.0, 47.4, 42.9, 39.3, 34.2, 31.5, 30.0, 29 7, 29.1, 29.0, 28.6, 26.3, 25 8, 24 7, 22 7,
20.8, 15.6, 14.1, HRMS (APCI): m/z 606 (M+l).
Example 77
N1-[4-(4-Ethyl-5-heptoxy-6-methoxy-8-quinolylamino)pentyl]-3-(2,4-dimethyl-3,6-dioxo-l,4-cyclohexadienyl)-3-methylbutanamide
Yield: 98%, mp (salt)- 122-125 °C (dec); IR (KBr)- 3384 cm-1 (NH), 1722 (quinone), 1641 (amide carbonyl); 1H NMR (free base, CDCl3): 5 8.40 (d, 1H, 2-Ar-H, J= 4 2 Hz), 7.14 (d, 1H, 3-Ar-H, J= 4.2 Hz), 6.50 (s, 1H, 5-Ar-H), 6.44 (s, 1H, 7-Ar-H), 5.56 (bs, 1H, NH), 4.12 (bs, 1H, NH), 3.97 (s, 3H, OCH3), 3.85 (t, 2H, OCH2, J= 6.8 Hz), 3.61 (m, 1H, N-CH), 3.21 (m, 4H, 2 x CH2), 2.74 (s, 2H, CH2), 2.17 (s, 3H, 2-CH3), 2.12 (s, 3H. 4-CH3), 1.85-1.62 (m.
14H, 7 x CH2), 1 38 (s, 6H, 2 x CH3), 1 28 (m, 6H, 2 x CH3), 1 05 (t, 3H, CH3, J= 7 3 Hz), 13C NMR (free base, CDC13): 5 190.0, 188 3, 1718, 152 5, 151.2, 149 7, 144 4, 143 4, 141 9, 138.8, 135 3, 134.1, 132.3, 129 0, 128.2, 122.5, 121.1, 94 6, 75 8, 56 9, 49 2, 48 1, 39 3, 38 6, 35 1, 34 2, 29 7, 29 4, 29 3, 26 8, 25 6, 25.0, 24 1, 20 8, 15 6, 14 3, 10 6, HRMS (APCI) m/z620(M+l). Example 78
N1-[4-(4-Ethyl-6-methoxy-5-octoxy-8-quinolylamino)pentyl]-3-(2,4-dimethyl-3,6-dioxo-l,4-cyclohexadienyl)-3-methylbutanamide
Yield: 57%, mp (salt) 121-123 °C (dec); IR (KBr): 3430 cm-1 (NH), 1798 (quinone), 1646 (amide carbonyl); 1H NMR (free base, CDCl3): 5 8.40 (d, 1H, 2-Ar-H, J= 4 3 Hz), 7 13 (d, 1H, 3-Ar-H, J= 4 3 Hz), 6.50 (s, 1H, 5-Ar-H), 6 43 (s, 1H, 7-Ar-H), 5.56 (bs, 1H, NH), 4.15 (bs, 1H, NH), 3.96 (s, 3H, OCH3), 3 88 (t, 2H, OCH2) J= 6.9 Hz), 3 62 (s, 1H, N-CH), 3 49 (m, 2H, N-CH2), 3.23 (m, 2H, CH2), 2.75 (s, 2H, CH2), 2.21 (s, 3H, 2-CH3), 2.03 (s, 3H, 4-CH3), 1.83-1.63 (m, 16H, 8 x CH2), 1.38 (s, 6H, 2 x CH3), 1.28 (m, 6H, 2 x CH3), 0.89 (t, 3H, CH3, J= 7.9 Hz); TNMR (free base, CDCl3): 5 190.0, 171.8, 156.8, 152.5, 151.2, 149 7, 144.4, 143.4, 141.9, 138.8, 135.3, 134.0, 132.5, 127.3, 123 7, 122.5, 94.6, 74.3, 56.9, 49.4, 49.2, 48.0, 45.6, 39 3, 38.6, 34.2, 33 6, 31 8, 30.0, 29.3, 27 5, 26.1, 24.1, 22.7, 20 8, 15.6, 14 3, 14 1; HRMS (APCI): m/z 634 (M+l).
General Method for the synthesis of 2-{2-[4-(5-alkoxy-4-ethyl-6-methoxy-8-quinoIylamino)pentacarbamoyl]-l,l-dimethylethyl}-3,5-dimethylphenyl acetate
To a mixture of 3-(2,4-dimethyl-6-methylcarbonyloxyphenyl)-3-methylbutanoic acid (5, 1.2
mmol) and N8-(4-amino-l-methylbutyl)-5-alkoxy-4-ethyl-6-methoxy-8-quinohnamine (1.1
mmol) in anhydrous dichloromethane (15 mL), was added 1,3-dicyclohexylcarbodnmide
(1 18 mmol) and 4-(dimethylamino)pyndine (0 02g), and reaction mixture was stirred for
10 h at room temperature under nitrogen atmosphere. The solvent was removed in vacuo,
and to the residue was added ethyl acetate (10 mL). Reaction mixture was kept in
refrigerator overnight and the separated 1,3-dicyclohexylurea was removed by filtration
Filtrate was concentrated under reduced pressure to yield crude product, which was punfied
by flash column chromatography over silica gel (230-100 mesh) using 0 3% methyl
alcohol/chloroform to afford oil, which on treatment with a solution of ethereal HCI
provided 2-{2-[4-(5-alkoxy-4-ethyl-6-methoxy-8-quinolylamino)pentacarbamoyl]-l,l-
dimethylethyl}-3,5-dimethyl-phenyl acetates as the hydrochloride salt.
Example 79
2-{2-[4-(4-ethyl-6-methoxy-5-propoxy-8-quinoIylamino)pentacarbamoyl]-l,l-dimethylethyl}-3,5-dimethyIphenyl acetate
Yield: 99%, mp (salt). 124-129 °C (dec), IR (KBr)- 3397 cm'1 (NH), 1710 (C=O), 164L (amide carbonyl), 1H NMR (free base, CDC13): 5 8 52 (d, 1H, 2-Ar-H, J= 3.2 Hz), 7 93 (d, 1H, 4-Ar-H, J= 7.9 Hz), 7.30 (dd, 1H, 3-Ar-H, J= 4.4 and 8.3 Hz), 6 49 (s, 1H, 6-Ar-H), 6 43 (s, 1H, 4-Ar-H), 6.34 (s, 1H, 7-Ar-H), 6 27 (s, 1H, 5-Ar-H), 5.62 (bs, 1H, NH), 4.65 (bs, 1H, NH), 3.89 (s, 3H, OCH3), 3 85 (t, 2H, OCH2, J= 6.3 Hz), 3.63 (s, 1H, N-CH), 3 42 (s, 2H, CH2), 3 27 (m, 2H, N-CH2), 2 08 (s, 3H, 5-CH3), 1.94 (s, 3H, COCH3), 1 62 (s, 3H, 3-CH3), 1.31 (m, 7H, 2 x CH2 and CH3), 1.14 (m, 6H, 2 x CH3); 1 05 (t, 3H, CH3, J= 7 2 Hz); HRMS (APCI): m/z 592 (M+l).
Example 80
2-{2-[4-(5-Butoxy-4-ethyI-6-methoxy-8-quinolyIamino)pentacarbamoyl]-l,l-dimethylethyl}-3,5-dimethylphenyl acetate
Yield: 85%, mp (salt): 133-137 °C (dec); IR (KBr): 3390 cm'1, 1715, 1645; 1H NMR (free base, CDCl3): 5 8.51 (d, 1H, 2-Ar-H), 7.95 (d, 1H, 4-Ar-H), 7.30 (dd, 1H, 3-Ar-H), 6.47 (s, 1H, 6-Ar-H), 6.41 (s, 1H, 4-Ar-H), 6.37 (s, 1H, 7-Ar-H), 6.29 (s, 1H, 5-Ar-H), 5.53 (bs, 1H, NH), 4.68 (bs, 1H, NH)i 3].90 (s, 3H, OCH3), 3.87 (t, 2H, OCH2), 3.61 (s, 1H, N-CH), 3 41 (s, 2H, CH2), 3.27 (m, 2H, N-CH2), 2.07 (s, 3H, 5-CH3), 1.92 (s, 3H, COCH3), 1 60 (s, 3H, 3-CH3), 1 31 (m, 11H, 4 x CH2 and CH3), 1.14 (m, 6H, 2 x CH3); 1.05 (t, 3H, CH3); HRMS (APCI): m/z 606 (M+l).
Biological Activity
Assessment of in vitro susceptibility of an isolate of Plasmodium falciparum to tested
compounds
Different drug dilutions [test compounds and chloroqume (positive control)] were prepared in complete RPMI (medium RPMI 1640 + 10% AB+ human serum, CRPMI) Fifty ul of each dilution was transferred to respective well of a microtiter plate in triplicates Parasitized erythrocytes (PE, mainly rings; 4 % parasitaemia; 5% hematoknt) were added to each well. Volume in each well was made up to 200 µl with CRPMI. The plates were incubated at 37°C in a candle/jar. After 24-48 hours of incubation, thin smears from each well were made and stained with Giemsa. The number of PE/10,000 cells was counted. Percent inhibition by the drug over the control (well which do not contain any drug) was plotted against the respective logarithmic concentration of the drug. Using non-linear regression analysis, the IC50 of the test compounds was then calculated.
Table 1. In vitro susceptibility of an isolate of Plasmodium falciparum to compound NP-90, NP-8 and chloroquine
(Table Removed)
Blood schizontocidal activity evaluation of potential antimalarial compounds against Plasmodium berghei (sensitive strain) and P. yoelii nigeriensis (resistant strain) infection in mice
Test Procedure: On day '0', groups of 6 mice each were inoculated, intrapentoneally, with 1x10 mfected-erythrocytes, from a donor mouse. Four hours later, mice were administered test compounds/chloroquine pnmaquine/vehicle, orally. A total of 4 doses were given on days D'0', D+l, D+2, and D+3. The tail blood smears were made on day D+4 and D+7, stained with Geimsa, and examined microscopically The minimum dose which completely suppressed parasitaemia on days D+4 and D+7 was designated 'minimum effective dose (MED)' and, the minimum dose, which cleared the parasitaemia for up to 28 days, was termed 'curative dose' All compounds found curative at 10 mg/kg against P berghei infected mice model were then tested against resistant P yoelii nigeriensis strain in mice at various doses and results are summarized in Table 3
Table 2. In vivo blood-schizontocidal activity of compounds against P. berghei infection in mice
(Table Removed)
Table 3. In vivo blood-schizontocidal activity of compounds against P yoehi mgenensis infection in mice

(Table Removed)
The biological activity results obtained are indicating folio wings:
Six compounds [NP-97, NP-254, NP-255, 258, NP-262, and NP-270] have shown curative blood-schizontocidal activity at a dose of 100 mg/kg in P. berghei mice model On the other hand, five compounds [NP-98, NP-193, NP-195, NP-196, and NP-257] have shown suppressive blood-schizontocidal activity at a dose of 10 mg/kg in P. berghei mice model. Eleven (11) compounds [NP-8, NP-90, NP-167, NP-190, NP-191, NP-194, NP-249, NP-250, NP-251, NP-260 and! NP-265] have shown curative blood-schizontocidal activity at a dose of 10 mg/kg m P. berghei mice model. It is important to note that the standard drug chloroquine is curative only at 12 mg/kg in the same test model. Compounds NP-8 and NP-90 have minimum effective dose (MED) of 5 mg/kg as compared to 8 mg/kg for chloroquine. When evaluated at lower doses, compounds NP-167 and NP-190 were found
to be curative at a dose of 5 mg/kg, whereas, compounds NP-194 and NP-260 were found to
have suppressive activity (MED) at 5 mg/kg in P. berghei mice model. All these results are
indicting the superior activity profile of these compounds as compared to chloroquine and
make them very attractive candidates as future antimalarial agents
When tested against P. falciparum in vitro test both NP-8 and NP-90 demonstrated IC50 of
33 nM and 169 nM [chloroquine has IC50 of 13 nM].
Compound [NP-8] is active at a dose of 50 mg/kg, whereas compounds [NP-90, NP-191,
NP-194 and NP-265] are curative at a dose of 100 mg/kg against P. yoelu nigeriensis in
vivo test in mice. The standard drug chloroquine is ineffective in this model at a dose of 156
mg/kg and the strain is naturally resistant to chloroquine.
The most effective compounds were further evaluated for acute toxicity studies in Swiss
mice. A group of six mice with equal ration of male and female were subjected to a single
dose of 50 mg/kg. The compounds were evaluated for acute toxicity as per the protocols of Schedule 'Y" of Drug and Cosmetic Act, 1988, Govt, of India, Ministry of Health and Family Welfare, except the number of animals used in the present investigation and results are given in Table 4.
Table 4. Acute toxicity studies in Swiss Mice (50 mg/kg)

(Table Removed)
To summanze it all, as evident from the biological activity results obtained so far, majonty
of the new 8-aminoquinolines have shown excellent in vivo antimalanal activity against P.

berghei infected mice model supenor to that of chloroqmne. On the other hand, many of these compounds have also demonstrated excellent antimalanal activity in resistant P. yoelu nigeriensis infected mice model. The basic sub-structure in our study is pnmaquine (clinically used radical curative drug), we anticipate observing the same (as pnmaquine) or increased degree of tissue-schizontocidal activity for all of these molecules. It is expected that this unique blend of broad-spectrum of antimalanal activity against blood stages, tissue stages, and resistant strains of the human malana parasites may make these compounds very attractive in the cure and prevention of malaria. It is further expected that the development of these compounds may offer the possibility of a single drug that can cure all of the relapsing and non-relapsing forms of malana.


























We claim:
1. Novel 4-ethyl-5-alkoxyprimaquine compounds represented by Formula I and its pharmaceutically acceptable salts having broad-spectrum anti-malarial activities.
(Formula Removed)
wherein, R1 represents straight-chain alkyl groups containing 1 to 10 carbon atoms, R2 represents hydrogen, all (R)- and (S)-enantiomers of proteiogenic amino acids, L- unnatural amino or anchors of formulae 2 and 3 respectively.
2. 4-Ethyl-5-alkoxy primaquine compounds as claimed in claim 1, wherein R1 and R2 are as below:
(Table Removed)
3. The compounds as claimed in claims 1 and 2 which are effective in vivo and in vitro systems against parasites Plasmodium berghei, Plasmodium yoelli nigerienss and Plasmodium falciparum, said compounds are more effective than chloroquine phosphate and primaquine phosphate.
4. The compounds as claimed in claim 1 and 2, wherein the pharmaceutically acceptable salts are selected from a group consisting of hydrochloride, sulphonate, citrate, maleate or camphor sulphonate salts.
5. A process for the preparing the compounds as claimed in claim 1 of formula (1), the said process comprising steps of:
a) treating compound of formula (Ia) as herein described with suitable N-
protected ammo acid or propionic acid derivative of formula (4 or 5) as herein described in an organic solvent in presence of a condensing agent, optionally an organic base at a temperature range of 0°C to room temperature for a period of 2 hrs to 12 hrs.
b) bringing the reaction mixture of step (a) to room temperature, if required filtering to obtain a clear filtrate,
c) concentrating the clear filtrate of step(b) to obtain a residue,
d) adding ethyl acetate to the residue of step (c), cooling it to a temperature range of 5 to 10°C; separating precipitated solid from the cooled solution to obtain a clear solution,
e) washing the clear solution of step(d) with saturated bicarbonate solution, followed by water, drying over anhydrous sodium sulphate, filtering and evaporating to afford a residue, and
f) purifying the residue of step (e) over silica gel column using chloroform/methanol mixture as an eluant to yield the required product of formula (I) wherein R2 is as defined above,
g) deprotecting product of formula (1) of step (f), when protected amino acid is used as one of the reactants used in step (a), and
h) optionally converting compound of step (g) to its pharmaceutically
acceptable salts by treating with an acid.
6. A process as claimed in claim 5, wherein in step (a), the protected amino acid is selected from a derivative consisting of N-tert-butoxycarbonyl and N-carbobenzyloxy derivatives of R or S enantiomers of proteiogenic amino acids or L- unnatural amino acids.
7. A process as claimed in claim 5, wherein in step (a) the anchor propionic acid derivative used is selected from a group consisting of 3-(3',6'-dioxo-2l,4'-dimethylcyclohexa-1,4' -diene)-3,3-dimethylpropionic acid (2) or 3-(2'-acetoxy-4' ,6'dimethylphenyl)-3,3-dimethylpropionic acid (3).
8. A process as claimed in claim 5, wherein in step (a) the organic solvent is selected from a group consisting of carbon tetrachloride, dichloromethane, chloroform, toluene or mixtures thereof.
9. A process as claimed in claim 5, wherein in step (a) the condensing agent used is selected from a group consisting of 1,3-dicyclohexylcarbodiimide (DCC) or l,T-carbonyldimidazole.
10. A process as claimed in claim 5, wherein in step (a) the organic base used is selected from pyridine, piperidine, N-methyl piperidine or 4-dimethy laminopyridine.
11. A process as claimed in claim 5, wherein in step (g), the deprotection of N-tert-butoxycarbonyl group is performed by treating with methanolic hydrochloric acid for 10-12 h and deprotection in the case of N-carbobenzyloxy group with 10% Pd-C in the presence of H2 for 2 to 12 h.
12. A process as claimed in claim 5, wherein in step (h) the acid used is selected from a group consisting of hydrochloric acid, sulphonic acid, maleic acid, succinic acid, fumaric acid, or camphor sulphonic acid.
13. The compound as claimed in claim 1 and 2, as and when used for preparing a pharmaceutical composition along with pharmaceutically acceptable excipients.

Documents:

1112-DEL-2002-Abstract-(12-07-2010).pdf

1112-del-2002-abstract.pdf

1112-DEL-2002-Claims-(01-12-2010).pdf

1112-DEL-2002-Claims-(12-07-2010).pdf

1112-DEL-2002-Claims-(22-11-2010).pdf

1112-del-2002-claims.pdf

1112-DEL-2002-Correspondence-Others-(12-07-2010).pdf

1112-DEL-2002-Correspondence-Others-(22-11-2010).pdf

1112-del-2002-correspondence-others.pdf

1112-del-2002-description (complete).pdf

1112-DEL-2002-Form-1-(12-07-2010).pdf

1112-del-2002-form-1.pdf

1112-del-2002-form-18.pdf

1112-DEL-2002-Form-2-(12-07-2010).pdf

1112-del-2002-form-2.pdf

1112-del-2002-form-26.pdf

1112-DEL-2002-Form-3-(12-07-2010).pdf

1112-del-2002-form-3.pdf

1112-del-2002-form-5.pdf

1112-DEL-2002-GPA-(12-07-2010).pdf

1112-DEL-2002-Petition 137-(22-11-2010).pdf


Patent Number 248025
Indian Patent Application Number 1112/DEL/2002
PG Journal Number 24/2011
Publication Date 17-Jun-2011
Grant Date 09-Jun-2011
Date of Filing 06-Nov-2002
Name of Patentee NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER)
Applicant Address SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB-160 062, INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 RAHUL JAIN DEPARTMENT OF MEDICINAL CHEMISTRY, NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER), SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB-160 062, INDIA.
2 SURYANARAYANA VANGAPANDU POST-DOCTORAL RESEARCH ASSOCIATE AT UNIVERSITY OF MISSISSIPPI, P.O. 4356, MS 38677, USA.
3 PRATI PAL SINGH DEPARTMENT OF MEDICINAL CHEMISTRY, NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER), SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB-160 062, INDIA.
4 ARVIND GUNWANT KINHIKAR DEPARTMENT OF MEDICINAL CHEMISTRY, NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER), SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB-160 062, INDIA.
5 SAVITA SINGH DEPARTMENT OF MEDICINAL CHEMISTRY, NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER), SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB-160 062, INDIA.
6 MEENAKSHI JAIN DEPARTMENT OF MEDICINAL CHEMISTRY, NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER), SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB-160 062, INDIA.
7 SANDEEP SACHDEVA DEPARTMENT OF MEDICINAL CHEMISTRY, NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER), SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB-160 062, INDIA.
8 VIJAI MISRA DEPARTMENT OF MEDICINAL CHEMISTRY, NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER), SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB-160 062, INDIA.
9 PODURI RAMA RAO DEPARTMENT OF MEDICINAL CHEMISTRY, NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER), SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB-160 062, INDIA.
10 CHAMAN LAL KAUL NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER), SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB 160062, INDIA.
PCT International Classification Number A61K 31/4706
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA