WO2002026713A1 - Antiparasitic compounds - Google Patents

Antiparasitic compounds Download PDF

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WO2002026713A1
WO2002026713A1 PCT/GB2001/004337 GB0104337W WO0226713A1 WO 2002026713 A1 WO2002026713 A1 WO 2002026713A1 GB 0104337 W GB0104337 W GB 0104337W WO 0226713 A1 WO0226713 A1 WO 0226713A1
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group
unsubstituted
aryl
alkyl
substituted
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PCT/GB2001/004337
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French (fr)
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Keith Jones
Philip John Whitfield
Sharon Rossiter
Michael Derek Matthewson
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King's College London
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/14—Ectoparasiticides, e.g. scabicides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/40—Nitrogen atoms attached in position 8
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the adults of S. mansoni live in the mesenteric blood vessels associated with the gut of the human host and lay large numbers of eggs.
  • the eggs have a sharp spine that can break through blood vessels into body tissues, or they can be carried along the hepatic portal vein to the liver, where they cause an immune reaction leading to the formation of granulomata.
  • liver and spleen enlargement ensues, which can be fatal if treatment is not received in time.
  • anthelmintics can be broadly classified by their modes of action. Piperazine salts, avermectins, levamisole, and organophosphates interfere with 25 the neuromuscular coordination ofthe parasites, whereas benzimidazoles such as thiabendazole and albendazole interfere with the assembly of parasitic microtubules.
  • a further object of the present invention is to provide compounds having improved anthelmintic activity.
  • a still further object of the present invention is to provide further compounds having activity against parasitic nematodes.
  • a yet further object of the present invention is to provide compounds having activity against parasitic trematodes and cestodes, many of which have hitherto been resistant to chemical control.
  • R 1 represents H, C, to C 5 alkyl or benzyl
  • C, to C 6 alkyl which may be branched, or unbranched and unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of C 5 to C 10 aryl, CN, F, CI, Br, I, OH, SH, N0 2 , OR 9 , SR 9 , COR 9 , COOR 10 and NR 10 R 11 ;
  • R 2 groups are: (i) unsubstituted C 1 to C 6 alkyl, which may be branched or unbranched; (ii) C 6 to C 10 aryl, which may be unsubstituted or substituted by 1-5 substituents independently selected from the group consisting of C, to C e alkyl, C s to C 1fl aryl, CF 3 , OCF 3 , OR 9 or SR 9 ; (iii) OR 12 ; (iv).. a halo group selected from F, CI, Br or I;
  • R 12 is as defined as above, and preferably R 12 represents unsubstituted C, to C 6 alkyl, which may be branched, or unbranched; or
  • R 7 represents hydrogen, unsubstituted C, to C 6 alkyl, or a halo group selected from F, CI Br and I. Even more preferably, R 7 represents hydrogen.
  • R 1 are the same or different and each is independently selected from the group consisting of H and C, to C 6 alkyl.
  • R 12 preferably represents unsubstituted C, to C 6 alkyl.
  • Administration of the compounds to treat plant nematode infections may be carried out by spraying a solution of one or more of the active compounds on the plant, or by introducing pellets or powder containing the active agent(s) into the soil.
  • Aryl represents a carbocyclic group containing 6-15, preferably 6 to 10, carbon atoms and having at least one aromatic ring, and which may be substituted by 1 -5 substituents independently selected from the group consisting of C, to C 6 alkyl, C 1 to C s aryl, OR 9 , SR 9 , CN, F, CI, Br, I, OH, SH, N0 2 , COR 9 , C0 2 R 10 , OCF 3 , CF 3 and
  • Substituted quinoline derivatives can be formed from an appropriately substituted aniline starting material.
  • a two- or three- carbon fragment is condensed onto the nitrogen atom of the aniline.
  • a subsequent cyclisation reaction step forms the quinoline ring.
  • This procedure has wide applicability to the formation of substituted quinoline derivatives.
  • ortho- and para- substituted anilines may be used to produce 8- and 6-substituted quinolines, respectively; mete-substituted anilines give mixtures of 5- and 7-substituted quinolines. Where mixtures of positional isomers are formed, these may be separated by, for example, chromatographic procedures such as flash chromatography and HPLC.
  • m/z 180 (80%, M + ), 164 (100%, M + - NH 2 ), 134 (17%, M + - N0 2 ), 89 (63%).
  • C. elegans were maintained in culture of agar plates seeded with Escherischia coli bacteria. The nematodes were harvested 7 days after inoculation, into 0.05 M phosphate buffer - pH 7, and counted. The volume of the suspension was adjusted to give about 500 nematodes/ml. Aliquots of 1.98 ml were dispensed into glass vials and 20 ⁇ l of drug stock solution added. After 60 minutes, five samples of 100 ⁇ l were removed, and in each of these, the total number of nematodes and the number that were inactive were counted. From these five replicated values the mean percentage of immobile, presumed dead, nematodes associated with each concentration could be estimated. Results from dilution series were used to estimate the LD S0 (60 minutes) for each compound. The results from this assay are shown in Table 3.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Disclosed are antiparasitic compounds of Formulae (I, IA and IB). These compounds are useful in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of infections caused by helminths or arthropod ectoparasites.

Description

Antiparasitic Compounds
This invention relates to the technical field of compounds that have antiparasitic activity. In particular, this invention pertains to compounds that have potential use in therapy for the treatment of disease caused by parasitic helminths. This invention also relates to compounds having activity against ectoparasites.
There are three main classes of parasitic worms or helminths - nematodes (round worms), trematodes (digeaπians or flukes) and cestodes (tapeworms).
Parasitic helminths can infect vertebrates, invertebrates and plants, causing many diseases of medical, veterinary and agricultural importance. In plants, parasitic nematodes can cause severe mechanical damage to the roots, stems, leaves and flowers of many plants, as well as causing losses in plant crops by opening a path for the entry of bacteria, fungi and other nematodes. Diseases caused by parasitic helminths in humans and other mammals can cause a wide range of pathological effects and symptoms, including abdominal pain, abcesses, anaemia, appendicitis, bronchial asthma, chyluria, conjunctivis, dermatitis, diarrhoea, oedema, elephantiasis, eosinophilia, eosinophilic meningitis, leukocytosis, lymphangitis, myocarditis and neurological effects. Parasitic infections can lead to malnutrition, weight loss, weakness and severe damage to the tissues and organs of the infected host.
Infections by parasitic worms can be extremely debilitating, and in severe cases, may be fatal if left untreated. It is estimated that over one billion people are infected by nematodes worldwide. Most of the infections are in the developing countries of the tropics and sub-tropics. Also of importance are the parasitic helminths that infect livestock. For example, cattle and sheep harbour a number of nematodes, with Trichostrongylυs, Dictyocaulus, Ostertagia, Coope a and Haemonchus being the most important. Medically important nematodes include
Nematodirus, Ascaris, Bunostomum, Oesophagostomum, Chabertia, Trichuris, Strongyiυs, Trichonema, Dictyocaulus, Capillaria, Heterakis, Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris, Parascaris and Wuchereria.
The pathological effects and symptoms of the veterinary diseases depend on the identity of the parasitic helminth and the site of the helminth infection. For example, certain of these such as Nematodirus, Coopeha and Oesphagostomum attack the intestinal tract, whereas Haemonchus and Ostertagia primarily attack the stomach. Dictyocaulus is more prevalent in the lungs. Other parasitic helminths may be located in other tissues and organs of the body, such as the heart, blood vessels, subcutaneous and lymphatic tissue.
In humans, the parasitic disease schistosomiasis (bilharzia, bilharziosis), is a widespread disease in many parts of the world, particularly Africa and South America. It is caused by trematode parasites of the schistosome family, of which Schistosoma mansoni, is the most widespread.
The adults of S. mansoni live in the mesenteric blood vessels associated with the gut of the human host and lay large numbers of eggs. The eggs have a sharp spine that can break through blood vessels into body tissues, or they can be carried along the hepatic portal vein to the liver, where they cause an immune reaction leading to the formation of granulomata. In severe cases, liver and spleen enlargement ensues, which can be fatal if treatment is not received in time.
Other schistosomes cause different forms of illness in humans - for example. S. haematobium infects the blood vessels of the bladder, and can cause damage to the urinary system, whereas S. japonicum also infects the mesenteric veins around the small intestine.
The life cycle of S. mansoni is complex. The eggs of S. mansoni are excreted from the body with human faeces, and if they make their way into water, the first larval stages (miracidia), can hatch from the eggs to infect an intermediate host, a water snail. Eventually, subsequent larval stages (cercariae) develop and are released into the water, where they can infect humans by burrowing through the skin, and subsequently are carried through the circulation info the liver. The adults then migrate to the mesenteric blood vessels where they stay for life.
Infection can occur in any standing or slow-flowing water, where the water snails -5 live. It-is- estimated-that-Gver-500 million people in over seventy countries are at-- risk from the various forms of schistosomiasis, with around 200 million actual infections worldwide, making schistosomiasis a disease of global significance.
It will therefore be appreciated that early treatment is necessary to manage
10 schistosomiasis, and other diseases caused by parasitic helminths. The drug praziquantel is the current drug of choice used to eradicate the adult worms of S. mansoni. However, recent studies have shown low cure rates in particular parts of the world, suggesting that the S. mansoni parasite is becoming resistant to this drug. Measures to control the population ofthe schistosome-carrying water snails
.5 have had some effect. However, the use of molluscicides on a large scale is difficult logistically and not desirable for ecological reasons. Research to find a vaccine against particular schistosomes, has proved to be difficult because, for example, adult S. mansoni are able, by a variety of mechanisms, to evade immune responses. Thus, at present, chemotherapeutic control of parasitic
20 helminths is a favoured approach.
Although the mechanism of action of most anthelmintics are not fully understood in detail, anthelmintics can be broadly classified by their modes of action. Piperazine salts, avermectins, levamisole, and organophosphates interfere with 25 the neuromuscular coordination ofthe parasites, whereas benzimidazoles such as thiabendazole and albendazole interfere with the assembly of parasitic microtubules.
Certain substituted quinoline derivatives are disclosed to possess anthelmintic 30 activity against specific helminths. Atanine (3-dimethylallyl-4-methoxy-2- quinolinone), an alkaloid isolated from the dried, unripe fruits of Evodia rutaecarpa (Rutaceae), and having the following chemical structure:
Figure imgf000005_0001
has been shown to be active against cercarial and miracidial larvae of S. mansoni,. and adults and larvae of the non-parasitic soil nematode, Caenorhabditis elegans (Planta Medica, (1995), 61, 276-278).
Heterocyclic compounds, including quinoline-based analogues having anthelmintic and fungicidal activity are disclosed in US 3,624,088. The compounds disclosed therein all possess a trichloroethylidine amine functionality i.e. -N=CHCCI3, attached to the heterocyclic ring.
US 3,879,549 discloses a process for the treatment of bilharziosis and filariasis using antimony. According to the disclosed process, the antimony is administered as a salt of a substituted 8-hydroxyquinoline.
US 5,227,387 discloses a method of inhibiting a nematode population in plants comprising applying to the locus of a nematode, a compound of the formula Het-X-CH2CH2-Ar, wherein "Het" can include 4-quinolinyl or 8-fluoro-4-quinolinyl, and X can be O, NH or CH2. The compounds are said to possess nematocidal activity against certain agricultural nematodes compared with the known agricultural nematocides, aldicarb, carbofuran and fenamiphos.
US 5,541 ,195 discloses a class of 2-substituted quinoline derivatives for the treatment of leishmaniasis, a group of parasitic conditions caused by the Leishmania protozoal parasite of the family Trypanosomatidae. This document does not disclose compounds having anthelmintic activity.
The development of drug resistance is a major problem with chemical control measures. For example, benzimidazole and ievamisole resistance has appeared in Trichostrongyle infections of sheep. Because anthelmintic resistance remains a threat to the main form of control of parasitic helminths, there exists an urgent need for the development of new, alternative anthelmintic drugs.
Advantageously, an anthelmintic should have a broad spectrum of activity and have a wide safety margin. Preferably, an anthelmintic -agent -should -be- therapeutically effective against all pathogenic stages of a parasitic helminth, including the larvae. Ideally, an anthelmintic should be rapidly metabolised and excreted and be easy to administer.
It is an object of the present invention to provide further anthelmintic compounds, especially compounds that have a broad spectrum of activity, and compounds that are effective against organisms that are resistant to available drugs. A further object of the present invention is to provide compounds having improved anthelmintic activity. A still further object of the present invention is to provide further compounds having activity against parasitic nematodes. A yet further object of the present invention is to provide compounds having activity against parasitic trematodes and cestodes, many of which have hitherto been resistant to chemical control.
The present invention is directed to substituted quinoline derivatives having anthelmintic activity, pharmaceutical uses thereof and synthetic methods for their production.
In accordance with a first aspect of the invention, there is provided the use of a compound of Formula (I), (IA) or (IB):
Figure imgf000007_0001
in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of helminth infections, wherein:
R1 represents H, C, to C5 alkyl or benzyl;
R2, R3, R4, R5, R6 R7 and R8 are each independently selected from the group consisting of: (i) hydrogen; (ii) Ct to C20 alkyl, which may be branched, or unbranched and unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of: C6 to C10 aryl, CN, F, CI, Br, I, OH, SH, N02, OR9, SR9, COR9, COOR10 and NR10R11; (iii) C2 to C20 alkenyl, which may be unsubstituted or substituted by 1 -3 substituents independently selected from the group consisting of C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10 and NR10R11; (iv) C2 to C10 alkynyl, which may be unsubstituted or substituted by 1 -3 substituents independently selected from the group consisting of C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10and NR 0R11; (v) C6 to C1S aryl, which may be unsubstituted or substituted by 1 -5 substituents independently selected from the group consisting of C, to C6 alkyl, C6 to C16 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10, CF3, OCF3 and NR10R11; (vi) C3 to C8 cycloalkyl, which may be unsubstituted or substituted by 1-5 substituents independently selected from the group consisting of C, to C6 alkyl, C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10, CF3, OCF3 and NR10R11; (vϋ) a heter.ocycli.c-gr.o.up.which„may-be aromatic or non-aromatic having from 5 to 10 ring atoms wherein 1 , 2 or 3 of the ring atoms are selected from nitrogen, oxygen or sulfur atoms and the remainder are carbon atoms; (viii) OR12;
(ix) a halo group selected from F, CI, Br or I; (x) NR10R11;
(xi) COOR10; (xii) N02; (xiii) SR12; (xiv) CONR10R11; (xv) COR9;
(xvi) CN; (xvii) OH; or (xviii) SH,
wherein:
R9 represents C1 to Cβ alkyl or C6 to C1S aryl;
R10 and R11 are the same or different and each is independently selected from the group consisting of hydrogen, C1 to C6 alkyl and C6 to C15 aryl; and
R12 represents C1 to C6 alkyl, which may be branched or unbranched and unsubstituted or substituted by 1 -3 substituents independently selected from the group consisting of C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10and NR10R11;
or an N-oxide derivative thereof, wherein the quinoline ring nitrogen forms an N-oxide group, or a pharmaceutically acceptable salt, solvate or quaternary ammonium salt thereof, with the proviso that (a) at least one of R2 and R4 is other than hydrogen and (b) for the compounds of Formula (IA) wherein R3 represents dimethylallyl and R4 represents ethoxy, at least one of R5, Rs, R7 and R8 is other than hydrogen.
Preferably, in the compounds of Formula (I), (IA) or (IB) R2 represents
(i) C, to C6 alkyl, which may be branched, or unbranched and unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of C5 to C10 aryl, CN, F, CI, Br, I, OH, SH, N02, OR9, SR9, COR9, COOR10 and NR10R11;
(ii) C6 to C10 aryl, which may be unsubstituted or substituted by 1 -5 substituents independently selected from the group consisting of C, to C6 alkyl, Cs to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10, CF3, OCF3 and NR 0R11; (iii) C3 to C8 cycloalkyl, which may be unsubstituted or substituted by 1 -5 substituents independently selected from the group consisting of C, to C6 alkyl, C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10, CF3, OCF3 and NR10R11;
(iv) OR12; (v) a halo group selected from F, CI, Br or I;
(vi) NR10R11;
(vii) COOR10;
(viii) SR12;
(ix) CONR10R11; (x) COR9; or
(xi) CN wherein R9, R10, R11 and R12 are as defined as above.
Particularly preferred R2 groups are: (i) unsubstituted C1 to C6 alkyl, which may be branched or unbranched; (ii) C6 to C10 aryl, which may be unsubstituted or substituted by 1-5 substituents independently selected from the group consisting of C, to Ce alkyl, Cs to C1fl aryl, CF3, OCF3, OR9 or SR9; (iii) OR12; (iv).. a halo group selected from F, CI, Br or I;
(v) COOR10; or (vi) COR9 wherein R9, R10 and R12 are as defined as above.
Especially preferred are compounds of Formula (I), (IA) or (IB) wherein R2 represents: (i) OR12, wherein R12 is as defined as above, and is preferably unsubstituted, branched or unbranched C1 to C6 alkyl; or (ii) a halo group selected from F, CI, Br or I.
In the compounds of Formula (I), (IA) or (IB), R2 is preferably methoxy or halo.
Preferred groups for R3 in the compounds of Formula (I), (IA) or (IB) are: (i) hydrogen; (ii) C, to C2o alkyl, which may be branched, or unbranched and unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of C6 to C10 aryl, CN, F, CI, Br, I, OH, SH, N02, OR9, SR9, COR9, COOR10 and NR10R11; (iii) C2 to C2Q alkenyl, which may be unsubstituted or substituted by 1 -3 substituents independently selected from the group consisting of C, to C6 alkyl, C5 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10 and NR10R11; (iv) C6 to C15 aryl, which may be unsubstituted or substituted by 1 -5 substituents independently selected from the group consisting of C, to C6 alkyl, C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, NO2, COR9,
COOR10, CF3, OCF3 and NR10R11; (v) C3 to C8 cycloalkyl, which may be unsubstituted or substituted by 1 -5 substituents independently selected from the group consisting of C, to C6 alkyl, C8 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10, CF3, OCF3 and NR10R11; (vi) • OR12 wherein R12 represents C1 to- C6 alkylr which--may--be branched or unbranched and unsubstituted or substituted by 1 -3 substituents independently selected from the group consisting of OR9, SR9, CN, F, CI, Br, I, OH, SH, N02 and NR10R11 wherein R10 and R11 are the same or different and each is independently selected from the group consisting of hydrogen, C, to C6 alkyl and Cs to C15 aryl; or
(vii) a halo group selected from F, CI, Br or I, wherein unless stated otherwise, R9, R10, R11 and R 2are as defined above.
More preferably R3 represents: (i) hydrogen;
(ii) unsubstituted C, to C6 alkyl, which may be branched or unbranched
(iii) unsubstituted C6 to C15 aryl;
(iv) OR12 wherein R12 represents C, to C6 alkyl; or
(v) a halo group selected from F, CI, Br, I.
Especially preferred compounds of Formula (I), (IA) or (IB) are those wherein R3 represents hydrogen or halo, and preferably hydrogen.
For the compounds of Formula (I), (IA) or (IB), R is preferably selected from: (i) C, to C20 alkyl, which may be branched, or unbranched and unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, NO2, COR9, COOR10 and NR10R11; (ii) Cs to C15 aryl, which may be unsubstituted or substituted by 1 -5 substituents independently selected from the group consisting of O, to C6 alkyl, C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10, CF3, OCF3 and NR10R11; (iii) C3 to C8 cycloalkyl, which may be unsubstituted or substituted by 1-5 substituents independently selected from the group consisting of C, to C6 alkyl, Ce to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10, CF3, OCF3 and NR10R11; (iv) OR12 -wherein R12-represents~Grt0»G2-raSkylT~which may be branched, or • unbranched and unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10 and NR10R11;
(v) a halo group selected from F, CI, Br or I; (vi) NR10R11;
(vii) COOR10;
(viii) SR12;
(ix) CONR1αR11;
(x) COR9; or (xi) CN, wherein R9, R10, R and R12 are as defined as above.
Preferred R4 groups are selected from:
(i) unsubstituted , to C6 alkyl, which may be branched or unbranched; (ii) unsubstituted C6 to C10 aryl;
(iii) OR12;
(iv) a halo group selected from F, CI, Br or I;
(v) COOR10; and
(vi) COR9, wherein R9, R 0 and R12 are as defined as above.
Especially preferred are compounds of Formula (I), (IA) or (IB) wherein R4 represents
(i) OR12 wherein R12 is as defined as above, and preferably R12 represents unsubstituted C, to C6 alkyl, which may be branched, or unbranched; or
(ii) a halo group selected from F, CI, Br or I. Most preferred are compounds of Formula (I), (IA) or (IB) wherein R4 represents methoxy or halo.
In preferred compounds of Formula (I), (IA) or (IB), R5, Rs, R7 and R8 are each 5. independefitly-seleeted r-Θm -he-group consisting of:
(i) hydrogen;
(ii) C1 to C20 alkyl, which may be branched, or unbranched and unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, 0 COOR10, and NR10R11;
(iii) C6 to C,5 aryl, which may be unsubstituted or substituted by 1 -5 substituents independently selected from the group consisting of C, to C6 alkyl, C6 to C1Q aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10, CF3, OCF3 and NR10R11; 5 (iv) C3 to C8 cycloalkyl, which may be unsubstituted or substituted by 1 -5 substituents independently selected from the group consisting of C, to C6 alkyl, C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10, CF3, OCF3 and NR10R11; (v) a heterocyclic group having from 5 to 10 ring atoms wherein 1 , 2 or 3 of the 0 ring atoms are selected from nitrogen, oxygen or sulfur atoms and the remainder are carbon atoms; (vi) OR12;
(vii) a halo group selected from F, CI, Br or I; (viii) COR9; 5 (ix) CN; and
(x) OH, wherein R9, R10, R11 and R12 are as defined as above.
Further preferred compounds for use in the present invention are those wherein 0 R5, 6, R7 and R8are each independently selected from the group consisting of:
(i) hydrogen (ii) unsubstituted C1 to C6 alkyl, which may be branched or unbranched; (iii) C6 to C10 aryl, which may be unsubstituted or substituted by 1-5 substituents independently selected from the group consisting of C, to C6 alkyl, C6 to C10 aryl, OR9, SR9, CF3 and OCF3;
(iv) the group OR12; and (-v.).- — a-hatø-grøup selected from F, CI, Br and I.
Particularly preferred R5, R6, R7 and R8 groups are independently selected from the group consisting of: (i) hydrogen (ii) CB to C10 aryl, which may be unsubstituted or substituted by 1-5 substituents independently selected from the group consisting of C, to C6 alkyl, Cβ to C10 aryl, OR9, SR9, CF3 and OCF3; and (iii) a halo group selected from F, CI, Br or I.
Especially preferred are compounds of Formula (I), (IA) or (IB) wherein R6, R6, R7 and R8are each independently selected from hydrogen, Cβ to C10 aryl, which may be unsubstituted or substituted by 1-3 alkoxy groups OR9, wherein R9is as defined as above.
Particularly preferred compounds of Formula (I), (IA) or (IB) for use in the present invention are those wherein R2 and R4 both represents methoxy.
For the above compounds of Formula (I), (IA) or (IB), R5 preferably represents (i) hydrogen (ii) C, to C6 alkyl which may be branched or unbranched and unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of C6 to C10 aryl, OR9, SR9 or a halo group selected from F, CI, Br and I; (iii) Ce to C10 aryl which may be unsubstituted or substituted with 1 -5 substituents independently selected from the group consisting of C, to C6 alkyl, Cs to C10 aryl, OR9, SR9 F, CI, Br, I, CF3 and OCF3; or (iv) a halo group selected from F, CI, Br and I. Even more preferred R5 groups are selected from hydrogen, unsubstituted C, to C6 alkyl, or a halo group selected from F, CI, Br and I. Preferably, in the compounds of Formula (I), (IA) or (IB), R5 represents hydrogen.
In the compounds of Formula (I), (IA)-or (IB) R0~preferably-- reρreserτ-S' a- substituent selected from the group consisting of:
(i) hydrogen,
(ii) C, to C6 alkyl which may be branched or unbranched and unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of OR9, SR9, F, CI, Br and I;
(iii) C6 to C10 aryl which may be unsubstituted or substituted with 1-5 substituents independently selected from the group consisting of C1 to C6 alkyl, Cβ to C10 aryl, OR9, SR9, F, CI, Br, I, CF3 and OCF3; and
(iv) a halo group selected from F, CI, Br and I.
In preferred compounds of Formula (I), (IA) or (IB), R7 represents hydrogen, unsubstituted C, to C6 alkyl, or a halo group selected from F, CI Br and I. Even more preferably, R7 represents hydrogen.
Also preferred compounds of Formula (I), (IA) or (IB) are those wherein one of
Rs, R6, R7 and R8 is other than hydrogen, and the remaining three represent hydrogen.
In preferred compounds of Formula (I), (IA) or (IB), R9 represents unsubstituted C to C6 alkyl. Also, in preferred compounds of Formula (I), (IA) or (IB), R10 and
R1 are the same or different and each is independently selected from the group consisting of H and C, to C6 alkyl. R12 preferably represents unsubstituted C, to C6 alkyl.
Preferably, of the compounds of Formula (I), (IA) or (IB), the group R12 represents unsubstituted C, to Cβ alkyl. Particularly preferred compounds of Formula (IA) or (IB) are those wherein R1 represents H.
Especially preferred compounds for use in the present invention are those having the-following str-tietwe&r
Figure imgf000016_0001
Further preferred compounds for use in the present invention are those having the following structures:
Figure imgf000016_0002
In a further aspect of the present invention, there is provided novel compounds of Formula (II), (IIA) or (IEB):
Figure imgf000017_0001
Figure imgf000017_0002
wherein:
R1a represents H, C, to Cβ alkyl or benzyl
R2a represents OR12 or SR12;
R4a represents OR12 or SR12;
R3a, R5a, R6a, R7a and R8a is selected from the group consisting of:
(i) hydrogen;
(ii) C, to C6 alkyl, which may be branched or unbranched and unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of C6 to C10aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10 and NR 0R11;
(iii) C2 to C20 alkenyl, which may be unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of C, to C6 alkyl, C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10 and NR10R11;
(iv) C2 to C10 alkynyl, which may be unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10 and NR10R11;
(v) Cs to C15 aryl, which may be unsubstituted or substituted by 1-5 substituents independently selected from the group consisting of C, to C6 alkyl, C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, NR10R11, COOR10, COR9, OCF3 and CF3;
(vi) C3 to C8 cycloalkyl, which may be unsubstituted or substituted by 1-5 substituents independently selected from the group consisting of C1 to C6 alkyl, C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, OH, SH, NO2, NR10R11,
COOR10, COR9, OCF3 and CF3; (vii) a heterocyclic group, which may be aromatic or non-aromatic, having from
5 to 10 ring atoms wherein 1 , 2 or 3 of the ring atoms are selected from nitrogen, oxygen or sulfur atoms and the remainder are carbon-atoms*;
(viii) OR12; or (ix) a halo group selected from F, CI, Br or I;
with the proviso that at least one of RSa, R6a, R7a and Raa is selected from the group consisting of:
(i) C2 to C10 alkenyl, which may be unsubstituted or substituted by 1 -3 substituents independently selected from the group consisting of C1 to Cs alkyl, C6 to C10 aryl, OR9 or SR9, CN, F, CI, Br, I, OH, SH, N02, COR9,
COOR10 and NR10R11; (ii) C2 to C10 alkynyl, which may be unsubstituted or substituted by 1 -3 substituents independently selected from the group consisting of C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10 and NR 0R11; (iii) C6 to C15 aryl, which may be unsubstituted or substituted by 1 -5 substituents independently selected from the group consisting of C, to Cβ alkyl, C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR8,
COOR10, NR10R1\ OCF3 and CF3; (iv) the group OR12; and (v) a halo group selected from F, CI, Br or I,
wherein R9 represents C, to C6 alkyl or Cβ to C15aryl;
R10 and R 1 are the same or different and each is independently selected from the group consisting of hydrogen, C1 to C6 alkyl and C6 to C15 aryl; and
R12 represents C, to C6 alkyl, which may be branched or unbranched and unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10 and NR10R11;
or an N-oxide derivative thereof, wherein the quinoline ring nitrogen forms an N- oxide group, or a pharmaceuticall-y-acceptable-saltror~solvate;-or addition salt-or a quaternary ammonium salt thereof.
Preferably for the compounds of Formula (II), (IIA) or (IIB), R a, R5a, R6a, R7a and R8a are independently selected from the group consisting of: (i) hydrogen;
(ii) C1 to C6 alkyl, which may be branched or unbranched and unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9,
COOR10 and NR10R11; (iii) C2 to C6 alkynyl, which may be unsubstituted or substituted by 1 -3 substituents independently selected from the group consisting of C6 to C10 aryl, OR9 or SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10 and
NR10R11; (iv) C6 to C10 aryl, which may be unsubstituted or substituted by 1 -5 substituents independently selected from the group consisting of C1 to Ce alkyl, C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9,
COOR10, OCF3, CF3 and NR10R11; (v) OR12 wherein R12; or (vi) a halo group selected from F, CI, Br and I,
wherein R9, R10, R11 and R12are as defined as above.
Particularly preferred compound of Formula (II), (IIA) or (IIB) are those wherein R3a represents hydrogen.
Further preferred compounds of Formula (II), (IIA) or (IIB) are those wherein R5a, R6a, R7a and R8a are selected from the group consisting of: (i) hydrogen;
(ii) unsubstituted C1 to C6 alkyl which may be branched or unbranched;
(iii) unsubstituted , to C6 alkynyl, which may be branched or unbranched;
(iv) unsubstituted C6to C10 aryl; (v) OR12; and
(vi) a halo group selected from F, CI, Br or I.
Even more preferred are compounds wherein one of R5a, R6a, R7a and R8a is other than hydrogen and the remaining three represent hydrogen. Of these compounds of Formula (π), (IIA) or (IIB), it is preferred that one of R5a,
R6a, R7a and RSa represents a group selected from:
(i) Cβ to C10 aryl, which may be unsubstituted or substituted by 1-5 substituents independently selected from the group consisting of C, to C6 alkyl, C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10, OCF3, CF3 and NR10R11;
(ii) OR12; and
(iii) a halo group selected from F, CI or Br, and the remaining three represent hydrogen, wherein R9, R10, R11 and R12 are as defined as above.
Especially preferred compounds are those wherein one of R5a, R6a, R7a and R8a represents C6 to C10 aryl, which may be unsubstituted or substituted by 1-5 substituents independently selected from the group consisting of C, to C6 alkyl, C5 to C10aryl, OR9, SR9, OCF3, CF3, F, CI, Br and I; and the remaining three represent hydrogen.
Also preferred are compounds of Formula (II), (IIA) or (IIB) wherein at least one of R6a and R8a represents a group selected from: F, CI, Br, I and OR12 wherein R12 as defined as above.
Further preferred are compounds of Formula (II), (IIA) or (IIB) wherein at least one of R5a and R8a is selected from phenyl which may be unsubstituted or substituted by 1-5 substituents independently selected from the group consisting of C1 to C6 alkyl, C6 to C10 aryl, F, CI, Br, I, OCF3, CF3, OR9 and SR9 wherein R9 represents C1 to C6 alkyl. Preferably, at least one of R6a and R8a is selected from phenyl which may be substituted by 1-3 methoxy groups.
Of the compounds of Formula (II), (IIA) or (IIB), especially preferred are those wherein R5a represents hydrogen.
Also, in preferred compounds of Formula (II), (IIA) or (IBB), R7a represents hydrogen. Especially preferred are compounds of Formula (II), (IIA) or (IIB) wherein both R5a and R6a represent hydrogen.
For the compounds of Formula (II), (IIA) or (IBB), R9 preferably represents unsubstituted C, to C6 alkyl. Preferably, R 0and R11 are the same or different and each is independently selected from the group consisting of H and C, to Cβ alkyl.
Especially preferred compounds of Formula (IIA) or (IBB) are those wherein R a represents H.
Preferred novel compounds of the present invention include those having the following structures:
Figure imgf000022_0001
Further preferred novel compounds of the present invention include those selected from the group consisting of:
Figure imgf000022_0002
According to another aspect of the present invention there is provided a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula (π), (IIA) or (IIB) in a pharmaceutical carrier.
The compounds of Formula (I), (IA), (IB), (II), (IIA) and (IIB) are useful in the manufacture of a medicament for the treatment or prophylaxis of parasitic helminth infections, caused by nematodes, trematodes or cestodes, in humans and veterinary animals, particularly agricultural livestock including cattle, sheep, goats, pigs, equine and poultry. Such diseases include ascariasis, filariasis, loaiasis, onchocerciasis, schistosomiasis, trichinelliasis and hydatid disease. Examples of parasitic nematodes include, but are not limited to, Ostertagia lyrata, O. ostertagi, O. circumcincta, Coope a oncophora, C. pectinata, C. punctata, C. surnabada, C. curticea, Haemonchus contortus, H. placei, T chostrongylus axei, T. colubriformis, T. vet nus, Bunostomum phlebotomum, B. trigonocephalum, Oesophagostomum radiatum, O. c.en-a-um,._O. venutosum, O. columbianum,
Strongyloides papillosus, S. westeri, S. stercoralis, Nematodirus helvetianus, N. spathiger, N. filicolis, Trichuris spp., Strongylus vulgaris, S. edentatus, S. equinus, Triodontophorus spp., Oxyuris equi, Parascaris equorum, Habronema muscae, Oncocerca spp., Dirofilaria immitis, Toxocara canis, Toxascaris leonina, Ancylostoma caninum, A. braziliense, A. duodenale, Thelazia spp., Uncina a stenocephala, Chaberia ovina, Ascaris lumbήcoides, Dictyocaulus vivaparus, D. arnfieldi, D. filaria, Brugia malayi, B. timori, Dioctophyma renale, Entβrobius vermicularis, Loa loa, Mansonella ozzardi, M. perstans, M. streptocerca, Necator americanus, Onchocerca volvulus, Stronglyloides stercoralis, Trichinella spiralis, T. triciura and Wuchereria bancrofti)
Examples of plant-damaging nematodes include, but are not limited to, the following genera: Meloidogyne, Heterodera, Ditylenchus, Aphelenchoides, Radopholus, Globodera, Pratylenchus, Longidorus and Xiphenema.
Examples of parasitic cestodes include, but are not limited to: Diphyllobothrium latum, D. caninum, Echinococcus granulosus, E. multilocularis, Hymenolepsis diminuta, Taenia multiceps, T. saginatus, T. serialis, T. solium and Vampirolepis nana.
Examples of parasitic trematodes include, but are not limited to Clonorchis sinensis, Dicrocoelium dendriticum, an echinostome, Fasciolopsis buski, Fasciola hepatica, a heterophyid, Nanophyetus salmincola, Opisthorchis felineus, O. viverrini, Paragonimus kellicotti, P. westermani, Schistosoma haematobium, S. japonlcum, S. mansoni, S. intercalatum and S. mekongi. The compounds of the invention are also useful in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of infections of arthropod ectoparasites, such as flies, lice, keds, fleas, ticks, mites and certain copepod of fish. The activity of the compounds may be against all or individual development stages.
The compounds of the present invention are also particularly useful for the treatment or prophylaxis of infections caused by ticks, which include, but are not limited by Boophilus spp, Rhipicephalus spp, Ixodes spp, Hyalomma spp, Amblyomma spp, Dermacentor spp and Argas spp; mites, which include, but are not limited by Psoroptes spp, Chorioptes spp, Sarcoptes spp and Demodex spp; flies, which include, but are not limited by Musca spp, Stomoxys spp, Oestrus spp, Culicoides spp, Tabanus spp, Phlebotomus spp, Simulium spp, Lucilia spp, Calliphora spp, Dermatobia spp and Hypoderma spp; lice, which include, but are not limited by Linognathus spp, Bovicola spp, Haematopinus spp and Solenopotes spp; keds, such as Melophagus ovinus; fleas, which include, but are not limited by Ctenocephalides spp and ectoparasites of fish, such as the copepod parasites Lepeophtheirus salmonis and Caligus elongatus.
Formulations suitable for agricultural use include granules, pastes, sprays, powders, solutions and dusts. Formulation auxiliaries for such use include: solvents such as oils, alcohols, esters and water; carrier materials such as talc, kaolin, calcite, montmorillinite and attapulgite and dispersing agents.
The formulations may also contain further additives, such as stabilisers, antifoaming agents, viscosity regulators, binders and adhesives, as well as fertilisers or other active agents.
The compounds of Formula (I), (IA), (IB), (II), (IIA) and (IIB) may be administered to a vertebrate either alone, or preferably, in combination with pharmaceutically acceptable carriers or diluents, and optionally with known adjuvants. Such pharmaceutical compositions may comprise one or more antiparasitic compounds of the invention. The compounds can be administered by oral, parenteral, intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, vaginal and topical routes of administration. The route of administration depends upon the site of the parasite infection and the mammal to be treated.
For administration to humans and animals, the compounds of the invention may be formulated in a variety of ways, depending upon biological and physicochemical parameters. Such formulations include, but are not limited by, tablets, chews, gels, pastes, granules, boluses, drenches, pour-ons, injectable suspensions or solutions, emulsions, solutions, water or oil dispersions, granules, microcapsules and waxes. Formulation auxiliaries including inert materials, surfactants, solvents and other additives known in the art may be suitably employed.
For example, the active compound may be administered by the oral route in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers that are commonly employed include lactose and cornstarch, and lubricating agents such as magnesium stearate, may be employed. For oral administration in capsule form, the formulation may comprise diluents such as lactose, starch, dried cornstarch, dicalcium phosphate. These unit dosage forms may be prepared by intimately and uniformly mixing the active ingredient with suitably finely divided diluents, fillers, disintegrating agents, and/or binders such as starch and vegetable gums. A particularly suitable mode of administration for the treatment of parasitic helminth infections of livestock is by the use of pellets or powders for adding to the animal feedstuff or drinking water.
The unit dosage formulations may be varied widely with respect to their total weight and content of the anthelmintic agent depending upon factors such as the host animal to be treated, the severity and type of infection and the weight of the host animal. For example, a composition for a single dose oral administration may comprise from 0.001 to 10, and preferably, 0.02 to 5 mg per kg of animal body weight. The compositions of the invention are also suitable for administration in a controlled release dosage form. Such dosage forms are particularly useful for administering to agricultural livestock because of the requirement for repeated therapeutic treatment in such animals due to the likelihood of the re-exposure of the animals to the parasite.
Where aqueous suspensions are employed, the active compound may be combined with known emulsifying and suspending agents and stabilisers. For parenteral administration, the active compound may be dissolved or dispersed in a carrier vehicle, such as a vegetable oil, glycerol formal or water. Such compositions suitably comprise 0.005 to 30%, preferably 0.005 to 5% by weight, of the active agent.
For intramuscular, intraperitoneal, subcutaneous and intravenous use, the compounds may be formulated into sterile solutions and the pH of the solution controlled as necessary with buffers. For intravenous use, the total concentration of the solutes should be controlled in order to render the preparation isotonic.
The compounds of the invention may also be prepared as a drench. The drench is normally a solution, suspension or dispersion of the active ingredient, and is usually aqueous. The drench may contain a suspending agent such as bentonite and a wetting agent or a similar excipient, and may further contain an antifoaming agent. Preferably, drench formulations comprise 0.001 % to 10%, and more preferably, 0.01 to 5% by weight of the active agent.
The compounds of the invention may also be used as prophylactic agents.
Prophylactic use of an antiparasitic agent is based on the epidemiology of the parasite. For example, a treatment regime comprising administering the active agent to agricultural livestock or plants at strategic times of the year may be advantageous in preventing infection.
Administration of the compounds to treat plant nematode infections may be carried out by spraying a solution of one or more of the active compounds on the plant, or by introducing pellets or powder containing the active agent(s) into the soil.
The compounds of the invention may also be used in the manufacture of a medicament for use in treating parasitic helminth infections in animals comprising a further pharmaceutically active agent, including other known anthelmintics and immunomodulators, such as levamisole. A particularly useful pharmaceutical agent for use in combination with the compounds of the invention is a laxative, which may be useful in assisting the elimination of the parasites from the body. As used herein, the following terms are used as defined below, unless otherwise indicated.
"Alkyl" represents straight or branched carbon chains, containing 1 -20 carbon atoms, preferably 1 -6 carbon atoms (for example, methyl, ethyl, propyl, iso-propyl, n-butyl, t-butyl, n-pentyl, isopentyl and hexyl). The term "alkyl" also includes straight or branched carbon chains, containing 1-20, and preferably 1 -6 carbon atoms and which are substituted with 1-3 substituents independently selected from the group consisting of: C, to C6 aryl, CN, F, CI, Br, I, OH, SH, N02, OR9, SR9, CORs, C02R10 and NR10R11 wherein R9 represents C, to Cs alkyl or Ceto C15 aryl, and R10 and R11 may be the same or different and each is independently selected from the group consisting of H, C. to C6 alkyl and C8 to C15 aryl.
Representative examples of substituted alkyl groups include -CH2CI, -CHCI2, -CCI3, -CF3, -(CH2)3OH, and -(CH2)2OR9. Particularly preferred are substituents for alkyl groups are selected from CN, F, CI, OR9 and NR10R11. In preferred embodiments of the invention, the term "alkyl" represents unsubstituted
Figure imgf000027_0001
carbon chains.
"Alkenyl" represents straight or branched carbon chains having at least one carbon-carbon double bond and containing 2-20 carbon atoms, preferably 2-10 carbon atoms, and more preferably 2-6 carbon atoms. The term alkenyl also includes straight or branched carbon chains having at least one carbon-carbon double bond and containing 2-20, preferably 2-10 and more preferably 2-6 carbon atoms and which are substituted with 1-3 substituents independently selected from the group consisting of C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, C02R1D and NR10R11 wherein R9 represents C, to Cβ alkyl and or Ceto C15 aryl, and R10 and R11 may be the same or different and each is independently selected from the group consisting of H, C, to C6 alkyl and C6 to C15 aryl. Representative examples of substituted alkenyl -groups -include~GH=GHF,
-CF=CCI2, -(CH3)C=CF2and -(HO)CH=CH(CH2CH3). Preferably, the term "alkenyl" refers to unsubstituted straight or branched carbon chains having one carbon- carbon double bond, representative examples of which include -CH=CH2, -C(CH3)=CHCH3 and -CH2CH=C(CH3)2.
The term "alkynyl" represents straight or branched carbon chains having at least one carbon-carbon triple bond and containing from 2-10 carbon atoms, preferably 2-6 carbon atoms, which may be unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of Cs to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, C02R10 and NR10R1\ wherein R9 represents
C, to C6 alkyl and or C6 t0 C15 aryl, and R10 and R11 may be the same or different and each is independently selected from the group consisting of H, C, to C6 alkyl and Ce to C15 aryl. Preferably, the substituents are selected from the group consisting of CN, F, Br, CI, I, OH, OR9 and SR9, wherein R9 represents C, to C3 alkyl or halo. Particularly preferred substituents are selected from OR9, F and CI, wherein R9 represents C, to C3 alkyl (preferably methyl). Representative examples of substituted alkynyl groups include -CH(CH3)CF2CH2≡CH and -CH(CH3)CH(OMe)CH2C≡H, Preferably, the term "alkynyl" refers to unsubstituted C2to C6 carbon chains which may be branched or unbranched, including -C≡CH, - CH2CH2C≡CH, -CH2CH(CH3)CH2C≡H.
"Aryl" represents a carbocyclic group containing 6-15, preferably 6 to 10, carbon atoms and having at least one aromatic ring, and which may be substituted by 1 -5 substituents independently selected from the group consisting of C, to C6 alkyl, C1 to Cs aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, C02R10, OCF3, CF3 and
NR10R11, wherein R9 represents C, to C6 alkyl and or C6toC15 aryl, and R10 and R11 may be the same or different and each is independently selected from the group consisting of H, C^ to C6 alkyl and C6 to C15 aryl. Preferably, the term "aryl" refers to a carbocyclic group containing 6-10 carbon atoms and which may be unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of C, to C6 alkyl, C6 to C10 aryl (such as phenyl), OR9 and halo (F, CI, Br and I), wherein Rs represent-s-unsubstituted-Crto-Cs alkyl. In particularly preferred embodiments of the invention, the term "aryl" refers to phenyl substituted by 1-3 substituents independently selected from the group consisting of C, to C3 alkyl and OR9, wherein R9 represents C1 to C3 alkyl. In especially preferred embodiments of the invention, the term "aryl" refers to phenyl substituted by 1-3 substituents independently selected from C, to C3 alkyl
(preferably CH3) or OR9 wherein R9 represents C, to C3 alkyl (preferably methyl).
"Cycloalkyl" represents a carbocyclic group containing from 3-8 carbon atoms forming at least one saturated ring, and which may be unsubstituted or substituted by 1-5 substituents on the ring carbon atoms, the substituents being independently selected from the group consisting of C, to C6 alkyl, C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, OCF3, CF3, C02R10 and NR10R11 wherein R9 represents C, to C6 alkyl and or C6to C15 aryl, and R10 and R11 may be the same or different and each is independently selected from the group consisting of H, C, to Cβ alkyl and C6 to C15 aryl. For substituted cycloalkyl groups, particularly preferred substituents are selected from the group consisting of C, to C3 alkyl, C6 to C10 aryl, OR9 (wherein R9 represents C1 to C3 alkyl) and halo (F, CI, Br). Particularly preferred compounds are those wherein the term "cycloalkyl" represents cyclopentyl or cyclohexyl, which may be unsubstituted or substituted with the above groups.
The term "heterocyclic group" refers to an aromatic (heteroaryl) or heterocycloalkyl group having from 5 to 10 ring atoms wherein 1 , 2 or 3 of the ring atoms are independently selected from nitrogen, oxygen or sulfur atoms and the remainder are carbon atoms, wherein any one of the ring atoms is a point of attachment.
Preferred heteroaromatic groups include pyridyl, thiazolyl, thiophenyl, furanyl, benzotriazolyl, quinolyl, isoquinolyl, pyrimidinyl, pyrrolyl, oxazolyl, indolyl and imidazolyl. Especially preferred heteroaromatic groups include pyridyl, thiazolyl, thiophenyl, furanyl, indolyl and imidazolyl. Representative non-aromatic heterocyclic substituents include piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, 2- or 4-dioxanyl and 1 -, 2- or 3-morpholino.
Unless otherwised indicated as being substituted, the terms "alkyl", "alkenyl", "alkynyl", "aryl", "cycloalkyl" and "heterocyclic group" referto unsubstituted groups.
The term "halo" represents F, CI, Br or I.
The term "quarternary ammonium salt" in the context of quinoline rings refers to compounds wherein the nitrogen atom of the quinoline ring is alkylated , e.g. with and alkyl halide, R-X, to form an N-alkylated analogue:
Figure imgf000030_0001
The term "N-oxide" refers to compounds wherein the nitrogen atom of the quinoline ring forms an N→O group.
Bonds drawn into the ring systems indicate that the indicated bond may be attached to any of the available substitutable ring atoms.
Certain compounds of the invention may exist in different isomeric (e.g. enantiomers and diastereoisomers) forms. The present invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Enol forms and other tautomeric forms are also included. It will be appreciated, for example, that for compounds wherein the carbon atoms of the quinoline 2- or 4- positions are directly bonded to an oxygen atom to form the group C=0 (i.e. a quinolin-2-one or a quinolin-4-one), the quinolin-2-one or quinolin-4-one co-exists with the tautomeric 2- and 4-hydroxyquinoline, respectively:
Figure imgf000031_0001
or
Figure imgf000031_0002
Usually, for the 2-hydroxyquinolines, the quiπolinone form is thermodynamically favoured, whereas for the 4-hydroxyquinolines, the quinolinol form is favoured.
Certain compounds will be acidic in nature, such as those compounds that possess a carboxyl or a phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminium, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines including as ammonia, alkyl amines, hydroxyalkylamines and N-methylglucamine.
It will be appreciated that basic compounds can also form pharmaceutically acceptable salts, such as acid addition salts. For example, the quinoline nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups may also form salts with weaker acids. Examples of suitable acids for salt formation include hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known in the art.
Methods of preparation of acid addition salts will be apparent to those skilled in the art. For example, the salts may be prepared by contacting the free base form with a sufficient amount, e.g. a stoichoimetric amount, of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution, such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia or sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base forms are otherwise equivalent to their respective free base forms for the purposes of the invention.
All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for the purposes of the invention.
The compounds for use in the present invention may be synthesised by methods of quinoline synthesis known in the art, (see for example, Cheng, Y. Org. React. 1982, 28, 37-201 and Jones, G. in "Comprehensive Heterocyclic Chemistry II"; Katritzky, A.R., Rees, CW. and Scriven, E.F.V., Eds., Pergamon, Oxford, 1996, Vol. 5, pp 167-243, and references cited therein.
A wide range of methods are known for the construction of the quinoline nucleus to form compounds useful in the present invention. Examples of synthetic routes to produce substituted quinolines will be apparent to a person of skill in the art. These include the Skraup, Dόbner-von Miller, Conrad-Limpach, Friedlaenderand
Pfitzinger syntheses.
Substituted quinoline derivatives can be formed from an appropriately substituted aniline starting material. In a typical procedure, a two- or three- carbon fragment is condensed onto the nitrogen atom of the aniline. A subsequent cyclisation reaction step forms the quinoline ring. This procedure has wide applicability to the formation of substituted quinoline derivatives. For example, ortho- and para- substituted anilines may be used to produce 8- and 6-substituted quinolines, respectively; mete-substituted anilines give mixtures of 5- and 7-substituted quinolines. Where mixtures of positional isomers are formed, these may be separated by, for example, chromatographic procedures such as flash chromatography and HPLC. A wide range of substituted aniline compounds suitable for use in the above synthesis of substituted quinolines are commercially available. The commercially available substituted anilines can also be dehvatised to form the appropriate aniline derivative for use in the above synthesis. Substituted- anilines for use in the above process may also be synthesised by procedures known in the art.
According to a further aspect of the present invention, there is provided process for the production of a compound of Formula (II):
Figure imgf000033_0001
or an intermediate thereof, wherein R2a and R4a represent OR12 or SR12; R12 represents C, to C6 alkyl; and R3a, R5a, R6a, R7a and R8a are as defined as above and are other than C2 to C10 alkenyl, C2 to C10 alkynyl, or C6 to C15 aryl, comprising the steps of: (a) subjecting a compound of Formula (III)
wherein R5 , R6b, R7b and R8b respectively represent the groups R5a, Rea, R7a and R8a or precursors thereof, to reaction with malonic acid in the presence of phosphorus oxychloride to produce a compound of Formula (IV):
Figure imgf000033_0003
(b) subjecting the compound of Formula (IV) to reaction with NaXR12, wherein X represents oxygen or sulphur to form a compound of Formula (V):
Figure imgf000034_0001
The process is illustrated in the following scheme:
Figure imgf000034_0002
III IV
NaXMe wherein X=0 or S
Figure imgf000034_0003
Preferably, step (a) is carried out using neat reagents, i.e. in the absence of solvent. Thus, in a typical procedure, the compound of Formula (III) is heated with an excess of malonic acid and phosphorus oxychloride under reflux. In some cases, mixtures of positional isomers ofthe quinolines may be formed, depending on the substitution pattern of the aniline starting material. Such mixtures may be separated after step (a) by conventional chromatographic techniques, e.g. by column chromatography. Alternatively step (b) may be carried out using the mixture of quinoline isomers from step (a), and the separation step carried out subsequently. In the above process, R5 , R6b, R7b and R8b respectively represent precursors to the groups R5a, R6a, R7a and R8a. Alternatively, the groups R5 , R6b, R7b and R8b can be protected groups corresponding to R5a, R6a, R7a and R8a or precursors thereof. Suitable protecting groups are well known in the art (see e.g. "Protective Groups in OrganiαS-yntbesis!,J !:eene, T.W., Witts, P.G.M., John Wiley, N.Y. 1999). The precursors or protected intermediates may be subsequently converted to the respective substituents R5a, R6a, R7a and R8a by known procedures (see Comins, D.L and Joseph, S.P. in "Comprehensive Heterocyclic Chemistry II"; Katritzky, A.R., Rees, CW. and Scriven, E.F.V., Eds. Pergamon, Oxford, 1996, Vol. 5, pp 167-243 and Dennis, N. in "Comprehensive Heterocyclic Chemistry II"; Katritzky,
A.R., Rees, CW. and Scriven, E.F.V., Eds. Pergamon, Oxford, 1996, Vol. 5, pp 91-134, and references cited therein).
In a typical procedure for step (b) of the above process, the substituted quinoline, or mixture of substituted quinoline isomers from step (a) is heated with the compound NaXR12 under reflux. Where a mixture of substituted quinoline starting materials is used, the mixture from step (b) may be separated using standard chromatographic techniques.
In the above process, the compounds of Formula (II) that are substituted in the quinoline 3-position (i.e. R3a is other than hydrogen), may be produced by a subsequent reaction step comprising subjecting the compound of Formula (V) to a deprotonation reaction at the quinoline 3-position using a strong base, such as an alkyllithium, and quenching the anion with an electrophile to form the group R3a or a precursor thereof:
Figure imgf000035_0001
Suitable electrophiles for the above reaction include ketones, aldehydes, halogens, halogen-producing agents (such as 1 ,2-dibromotetrafluoroethaπe), pseudohalogens (such as phenylthio compounds) and epoxides. The 3- substituted compounds may be further derivatised to form further compounds of Formula (II), (IIA) or (IIB).
Jt-wilLbe-apparent from the above that a variety of methods known in the-art-may- be suitable for producing substituted quinoline derivative useful in the present invention. As a illustrative example, the synthesis of a 2,4,8-trisubstituted quinoline is shown in the following scheme:
NaOMe
Figure imgf000036_0001
Figure imgf000036_0002
1. n-BuLi
2. >=^Br
Figure imgf000036_0003
According to a still further aspect of the present invention, there is provided a process for producing a compound of Formula (II) or an intermediate thereof, wherein at least one of R6a, R6a, R7a and R8a represents a substituent selected from substituted or unsubstituted C2to C10alkenyl, substituted or unsubstituted C2to C10 alkynyl, or substituted or unsubstituted C6 to C15 aryl wherein the substituents are as defined above, comprising reacting a compound of Formula (II) wherein one of R5a, R6a, R7a and R8a represents Br, I or triflate with a boronic acid derivative of Formula (VI):
(OH)2B-ψ (VI) wherein ψ represents a substituted or unsubstituted C2 to C10 alkenyl, substituted or unsubstituted C2 to C10 alkynyl, substituted or unsubstituted C6 to C1S aryl or substituted or unsubstituted C5 to C10 heteroaryl group as defined above; in the presence of a base and a palladium or nickel catalyst under Suzuki coupling conditions. The reaction may be represented thus:
Figure imgf000037_0001
. /-i nr i ..r Ψ = unsubstituted or
OSO2CF3 substituted aryl, alkenyl or alkynyl
Thus, as indicated above, the appropriate quinolyl bromide, iodide or triflate is reacted with a boronic acid in the presence of a palladium (0) catalyst and a suitable base to form the substituted quinoline derivatives ofthe invention wherein one of R5a, R8a, R7a and R8a represents a C2 to C10 alkenyl, C2 to C10 alkynyl or C6 to C1S aryl group, since a large number of aryl, alkenyl, alkynyl and heteroaryl boronic acids are commercially available or can be readily synthesised [see Lancaster Synthesis Catalogue 2000-2001 , Appendix 5, pp. A39-A46, and references cited therein, Stanforth, S.P., Tetrahedron, (1998), 54, 263; Ishiyama, T., Murata, M., Miyaura, N., J. Org. Chem. (1995), 60, 7508].
Suitable catalysts for this process include the following: Pd(PPh3)4) Ni(dppf)CI2 Pd(dba)2 (dba = dibenzilidene acetone), Pd(OAc)2, Pd(OAc)2/(o-tol)3P [(o-tol)3Ph = tri(o-tolyl)phosphine], Pd(OAc)2/dppf [dppf = 1 ,1 '-bis(diphenylphosphino)- ferrocene] , (PhCN2PdCI2/Ph3As (Ph3As = triphenyl arsine), (CH3CN)2PdCI2, Pd-C, (Ph3P)2NiCI2, Pd(dppb)CI2, bis(tricyclohexylphosphine)palladium(ll) chloride, (Ph3P)2PdCI2 and trans-di-μ-acetatobis[2-(di-o-tolylphosphino)benzyl]- dipalladium(ll) (see Appendix 5, page A41 , Lancaster Synthesis Catalogue
2000-200 , and references cited therein). Particularly preferred are palladium catalysts comprising phosphine ligands, such as Pd(PPh3)4 and Pd(PPh3)2CI2. These catalysts are suitable for high reaction temperatures because of their stability. Alternatively, phosphine-free catalysts such as palladium acetate may be used, and advantageously, can give a more rapid conversion.
Suitable bases for the Suzuki coupling reaction include sodium carbonate, NaHC03, K2C03τ~Cs2C03, K R0lfr-Eit3N- -Ag2Or--Ba(OH-)?-and CsF. Sodium carbonate is a particularly preferred base.
Typically the reaction is carried out in an inert solvent comprising a hydrocarbon, such as benzene or toluene. Preferably, the reaction is carried in the presence of a solvent containing water.
As an illustrative example, the synthetic route to form 2,4-dimethoxy-6- phenylquinoline is shown below:
Figure imgf000038_0001
NaOMe MeOH
Figure imgf000038_0002
Compounds wherein the 2-position of the quinoline ring represents the group =0, i.e. substituted quinolinones of Formula (IIA), can be produced, for example, from the corresponding 2-alkoxy derivative by reaction with thmethylsilyl iodide.
Alternatively, quinolin-2-one derivatives can be produced from the corresponding 2,4-dimethoxy derivatives by a two step reaction procedure comprising (a) cleavage of both methoxy groups using a Grignard reagent, such as MeMgl, followed by (b) methylation at the 4-position to reinstall the methoxy group:
Figure imgf000039_0001
Substituted quinolin-4-ones corresponding to Formula (IIB) may be produced by treatment of the corresponding 2,4-dimethoxyquinoline derivative with sodium isopropyl thiolate in DMF, resulting in the selective demethylation of the 4- methoxy group:
Figure imgf000039_0002
N-oxide derivatives ofthe compounds of the present invention may be formed by methods of quinoline N-oxidation known in the art. As an example, a substituted quinoline intermediate or final compound may be treated with hydrogen peroxide or peracids, such as meta-chloroperoxybenzoic acid (MCPBA) to form the corresponding substituted quinoline-N-oxide analogue.
Compounds of Formula (IIA) or (IIB) wherein R1a represents a C, to C6 alkyl group or a benzyl group, may be formed by reaction of the corresponding substituted quinoline or intermediate thereof, wherein R1 represents hydrogen, with suitable alkylating agents, e.g. alkyliodides or benzyl iodide by procedures known in the art.
EXAMPLES
The following Examples 1 to 72 illustrate the preparation of various quinoline derivatives of Formulae (I), (IA), (IB), (II), (IIA) or (IIB) and intermediates useful in the preparation.of compounds of the invention. The procedures described for synthesising known compounds may be adapted for the preparation of compounds according to the invention by an appropriate selection of substituents and procedures for functional group conversions known in the art. Thus, Examples 1 and 2 illustrate procedures for the synthesis of substituted aniline intermediates useful for producing the compounds of the invention. Examples 3 to
19 illustrate the synthesis of known compounds useful in the invention and Examples 20 to 72 illustrate procedures for synthesising novel compounds of Formula (II), (IIA) and (IIB).
General experimental conditions
All moisture or oxygen sensitive reactions were carried out under argon. All glassware, syringes and needles were pred ed in an oven (110°C) and cooled in an anhydrous atmosphere prior to use. Organic phases were dried with magnesium sulfate or sodium carbonate.
Diethyl ether, tetrahydrofuran (THF), diisopropyl ether and toluene were distilled from sodium with benzophenone ketyl as indicator immediately before use. Dichloromethane was refluxed over calcium hydride and distilled directly into the reaction vessel. Dimethylformamide was heated to reflux over calcium hydride, distilled and stored over activated 3A molecular sieves prior to use. Sodium hydride was washed with hexane before use.
Purification was carried out by flash column chromatography using Merck 7734 or Merck 60 (230-400 mesh) silica gel.
All melting points were determined on a Gallenkamp or Electrothermal melting point apparatus and are uncorrected. Infrared spectra were recorded on a Perkin Elmer Paragon 1000 FT-IR spectrophotometer using NaCI plates. 1 H NMR and 13C NMR spectra were recorded on a Bruker AM360 spectrometer operating at 360 MHz for proton and 90 MHz for carbon. NMR spectra were recorded in deuteriochloroform (CDCI3) as solvent, unless otherwise stated.
<.
Tetramethylsilane (TMS) was adopted as the internal standard for 1 H NMR spectra and the solvent peaks were adopted as the internal standard for 13C NMR spectra . Chemical shifts (δμ and δc) are quoted as parts per million downfield from tetramethylsilane. The multiplicity of a 1H NMR signal is designated by one 0 of the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, br = broad and m = multiplet. Coupling constants (J) are expressed in Hertz.
Mass spectra were recorded on either a Kratos MS89MS with Kratos DS90 software or a Jeol AX505W with Jeol complement data system. Samples were 5 ionised electronically (El), with an accelerating voltage of a6 kV. Analytical data are presented as ±0.01 %.
EXAMPLE 1. 3-Methyl-2-nitrobenzamide
Figure imgf000041_0001
CβH7N04 c n N o
Mol Wt - 181 1 <--8HaN2s->3 0 Mol. wr 1802
A mixture of 3-methyl-2-nitrobenzoic acid (3.0 g, 17 mmol) and triethylamine (1.7g, 17 mmol) in THF (50 ml) was cooled to 0°C Isobutyl chloroformate (2.3 g, 17 mmol) was added, and the mixture stirred at 0°C for 5 minutes, then allowed to 5 warm to room temperature and stirred for a further 2 hours. Concentrated ammonia solution (30 ml of 35% ammonia) was then added in one portion, and the mixture stirred overnight. The flask contents were transferred to a separating funnel, water (30 ml) was added, and the aqueous layer extracted with ethyl acetate (2 x 30 ml). The combined organic layers were dried with MgSO-j, and the solvent removed under reduced pressure to give the crude product as a cream solid. Recrystallisation (EtOH) gave the product as cream needles, Rf (EtOAc)
0.56. Yield 2.4 g, 78%. Melting point 188-190°C Found M+: 180.0531 . C8H8 2θ3 requires 180.0535 δH (DMSO d6): 8.20 (1 H, br s, NH), 7.69 (1 H, br s, NH), 7.60-7.52 (3H, m, Ar-
H), 2.28 (3H, s, Me). δc (DMSO d6): 166.1 (C=0), 149.1 (C-N02) 133.5 (CH), 130.3 (CH), 129.9,
129.4, 126.2 (CH), 16.6 (Me). nmax /cm-1: 3337, 3183 (w, N-H), 1688 (s, C=0), 1525 (s, N=0). m/z: 180 (80%, M+), 164 (100%, M+ - NH2), 134 (17%, M+ - N02), 89 (63%).
EXAMPLE 2. 3-Methyl-2-nitroaniline Method A - by Hofmann rearrangement
Figure imgf000042_0001
CaH8N203 C7HaN202
Mol. Wt: 180.2 Mo-wt: 152.2
Bromine (1.8 g, 11 mmol) was added to an ice-cold solution of potassium hydroxide (3.1 g, 55 mmol) in water (40 ml), and the resultant yellow solution stirred at 0°C for 10 minutes. 3-Methyl-2-nitrobenzamide (2.0 g, 11 mmol) was added in one portion, and the mixture heated at 65°C for 2 hours. After cooling, the product, a yellow precipitate, was filtered off and dried. The filtrate was extracted with ethyl acetate (3 x 30 ml), the combined organic extracts dried (MgSO- and the solvent removed in vacuo to give more of the product. Total yield 0.60 g, 36%. Melting point 103-105°C
Found M+: 152.0583. C7H8N2θ2 requires 152.0586. δH: 7.14 (1 H, dd, J 8.2, 7.3, H5), 6.65 (1 H, d, J8.2, C4), 6.58 (1 H, d, J 7.3, C6),
5.17 (2H, br s, NH2), 2.46 (3H, s, Me). δc: 143.3, 135.5, 135.5 (C-NH2, CN02, CMe), 133.2 (C5), 121.1 (C4), 1 16.5
(C6), 21 .4 (Me). nmax/cm-i: 3490, 3376 (w, N-H), 1610, 1584, 1552 (s, C=C, C=N, N=0). m/z: 152 (98%, M+), 135 (100%, M+ - OH), 106 (36%, M+ - N02), 77 (66%, C6H5 +).
Method B - by Schmidt rearrangement
Figure imgf000043_0001
CβH7N04 C7HβN2θ2
3-Methyl-2-nitrobenzoic acid (5.0 g, 28 mmol) was suspended in concentrated sulfuric acid (50 ml) and cooled to -5°C, with stirring. Sodium azide (1.8 g, 28 mmol) was added in small portions over 10 minutes, and the resulting deep violet mixture stirred at -5°C for 20 minutes and then allowed to warm to room temperature over 30 minutes. The mixture was then heated on a water bath at 60°C for approximately 3 hours, until the evolution of gas ceased and the violet colouration of the acyl azide had disappeared. After cooling, the pale brown liquid was poured onto crushed ice and made alkaline with NH4OH. The resultant yellow precipitate was filtered off and dried. Yield 4.2 g, 100%. Melting point 105-
107°C
Spectral data was in agreement with product isolated from Method A.
EXAMPLE 3. 2,4-DSchloroquinoline
Figure imgf000044_0001
CβH-N C9H5CI2N Mol. WU 93.1 Mol. Wt.; 198.1
Aniline (6.7 g, 72 mmol) and malonic acid (1 1 .7 g, 112 mmol) were heated under reflux in phosphorus oxychloride (60 ml), with stirring, for 5 hours. The mixture was cooled, poured into crushed ice with vigorous stirring and then made alkaline with 5M sodium hydroxide. Filtration gave the crude product as a brown solid. A four hour continuous (Soxhlet) extraction with hexane followed by evaporation of solvent under reduced pressure yielded a pale yellow powder. Tic (95:5 hexane/ethyl acetate) gave two spots; Rf=0.51 and Rf=0.05. Column chromatography with 95:5 hexane:EtOAc as eluent yielded the pure product (Rf=0.51) as off-white needles, yield 6.8 g, 48%, m.p. 66-67°C
Found M+: 196.9792. C9H5CI2N requires 196.9799. δH: 8.18 (1 H, dd, J 8.4, 1.3, H5), 8.03 (1 H, dd, J 8.5, 1.0, H8), 7.79 (1 H, ddd,
J 8.5, 7.0, 1 .3, H7), 7.65, (1 H, ddd, J 8.4, 7.0, 1 .0, H6), 7.50 (1 H, s, H3). δc: 149.8 ( C2), 148.1 (C8a), 144.4 (C4), 131.5 (C7), 129.0 (C8), 127.9 (C6),
125.2 (C4a), 124.2 (C5), 121.9 (C3). nmax /cm-i: 1580 (s, C=N), 720 (m, C-CI). m/z: 201 (15%, M+ 37d2), 199 (72%, M+ 3 c|35ci), 197 (100%, M+ 35ci2), 162
(69%, M+ - CI).
EXAMPLE 4A. 2,4-Dimethoxyquinoline and EXAMPLE 4B. 4-chloro-2-methoxyquinoline
Figure imgf000045_0001
C9H5CI2N CnH„N02 C10H8CINO Mol. Wt.: 198.1 Mol. Wt: 189.2 Mol. Wt.: 193.B
2,4-Dichloroquinoline (2.8 g, 14 mmol) was heated under reflux in methanolic sodium methoxide solution (from 2.0 g, 86 mmol Na in 50 ml MeOH) for 24 hours.
The reaction mixture was cooled and poured into ice-cold water, and the resulting white precipitate was filtered off. Tic (95:5 hexane:EtOAc) gave two spots, Rf 0.61 and 0.48. Column chromatography with 9:1 hexane:EtOAc yielded the two products 2,4-dimethoxyquinoline (Rf 0.48), 1 .85 g, 70% and 4-chloro-2- methoxyquinoline (Rf 0.61 ), 0.32 g, 12%, both as white needles.
Data for 2,4-dimethoxyquinoline (EXAMPLE 4A)
Melting point 78-80°C Found M+: 189.0797. CnHnN02 requires 189.0790. δH: 8.04 (1 H, dd, J 8.2, 1.5, H5), 7.78 (1 H, dd, J 8.5, 1.2, H8), 7.60 (1 H, ddd, J
8.5, 7.0, 1.5, H7), 7.33 (1 H, ddd, J 8.2, 7.0, 1.2, H6), 6.21 (1 H, s, H3), 4.05 (3H, s, 2-OMe), 3.97 (3H, s, 4-OMe). δc : 163.9 (C4), 163.84 (C2), 147.1 (C8a), 130.0 (C7), 126.9 (C8), 123.3 (C6), 12 .8 (C5), 119.3 (C4a), 90.7 (C3), 55.7 (4-OMe), 53.4 (2-OMe).
N.O.E: Irradiation at d3.97 ppm gave enhancement of H3 (6.21 ppm).
Irradiation at d4.05 ppm gave weak enhancement of H3 (6.21 ppm). nmax /cm-1: 1640, 1580 (s, C=N, C=C) m/z 189 (100%, M+), 188 (93%, M+ - H). Data for 4-chloro-2-methoxyquinoline (EXAMPLE 4B)
Melting point 70-72°C
Found M+: 193.0298. C10H8 35CINO requires 193.0294. δH: 8.10 (1 H, dd, 8.2, 1.3, H5), 7.86 (1 H, dd, J 8.0, 1.2, H8), 7.67 (1 H, ddd, J
8.0, 7.0, 1.3, H7), 7.46 (1 H, ddd, J 8.2, 7.0, 1.2, H6), 7.03 (1 H, s, H3), 4.06 (3H, s, -OCH3). δc: 161.9 (C2), 147.0 (C8a), 143.7 (C4), 130.5 (C7), 127.6 (C8), 124.8 (C6),
124.1 (C5), 123.3 (C4a), 112.9 (C3), 53.8 (OCH3).
"max /cm-1: 1610, 580 (s, C=N and C=C). m/z: 195 (33%, M+ 37d), 193 (100%, M+ 35ci), 192 (67%, M+ 35ci - H), 163
(33%, M+ - CH 0).
EXAMPLE 5. 2-Chloro-4-methoxyquinoline
Figure imgf000046_0001
C9H5Cl2N C10H8CINO Mol Wt 198 1 Mol. Wt 193 6
2,4-Dichloroquinoline (1.5 g, 7.5 mmol) was heated under reflux in methanolic sodium methoxide (from 0.80 g, 34 mmol Na in 30 ml methanol) for 30 minutes.
The mixture was cooled, poured into ice-cold water and then filtered to give a pale yellowish solid. Tic (4:1 hexane: EtOAc) showed three spots; Rf 0.73 (4-chloro 2- methoxyquinoline), 0.55 (starting material), 0.36 (2-chloro 4-methoxyquinoline).
Column chromatography (4:1 hexane: EtOAc) yielded 0.35 g, 25% of the desired product as white needles, plus 0.5 g, 36% of 4-chloro-2-methoxyquinoline and
0.3 g of starting material. Melting point 73-75°C.
Found M+: 193.0298. C10H835CINO requires 193.0294. δH: 8.12 (1 H, dd, J 8.5, 1 .5, H5), 7.93 (1 H, dd, J 8.2, 1 .2, H8), 7.70 (1 H, ddd, J
8.2, 6.9, 1.5, H7), 7.50 (1 H, ddd, 8.5, 6.9, 1 .2, H6), 6.73 (1 H, s, H3), 4.05 (3H, s, OCH3). δc: 163.8 (C4), 151 .6 (C2), 148.1 (C8a), 130.9 (C7), 128.1 (C8), 126.1 (C6),
122.0 (C5), 120.4 (C4a), 101 .2 (C3), 56.2 (MeO). nmaχ /cm-1 : 1630, 1590, 1570 (s, C=N and C=C). /z: 195 (33%, M+ 3 ci), 193 (100%, M+ 35C|), 179 (M+ 35ci - CH2), 158 (M+ - C1).
EXAMPLE 6. 4-Chloro-1//-quinolin-2-one
Figure imgf000047_0001
C10HβCINO CgH6CINO Mol Wf 179 6
4-Chloro-2-methoxyquinoline (EXAMPLE 4B) (0.30 g, 1.6 mmol) was heated under reflux in 5M HCI (30 ml) for 45 minutes and then left to stand overnight. A small amount of white precipitate formed. After neutralisation with aqueous sodium carbonate the mixture was filtered to give the product (0.10 g, 36%) as a white powder which was insoluble even in polar solvents. Melting point 248-
250°C.
Found M+: 179.0143. C9H6CINO requires 179.0138. nmax /cm-1: 3300 (m, N-H), 1670 (s, amide C=0). m/z: 181 (33%, M+, 37C1), 179 (100%, M+, 35ci), 151 (75%, M+ - CO), 89 (62%,
C3H2 35CIO+).
EXAMPLE 7. 4-Hydroxy-2 -methoxy 3-(3-methylbut-2-enyl)quinoline
Figure imgf000047_0002
C16H10NO2 C1εH17N02 Mol. Wt.: 257.3 Mol. Wt . 243.3
Sodium hydride (0.67 g of a 60% mineral oil dispersion, washed with hexane, 17 mmol) was suspended in dimethylformamide (10 ml). 2-Propanethiol (0.51 g, 6.7 mmol) was added and the mixture was stirred for 10 minutes. Then a solution of 2,4-dimethoxy-3-(3-methylbut-2-enyl)quinoline (0.7 g, 2.7 mmol) in DMF (10 ml) was added, and the mixture heated under reflux for 4 hours. After cooling and neutralisation with 2M HCI the solution was extracted with ether (4 x 50 ml), the combined ether extracts were dried over MgSO-t , and the solvent removed in vacuo to give a brown oil. Tic (4:1 hexane:EtOAc) revealed the presence of both starting material (Rf 0.57) and a product (Rf 0.30). Column chromatography (4:1 hexane:ethyl acetate) followed by recrystallisation (ethanol) yielded the pure product (0.25 g, 38%) as off-white needles. Melting point: 154-155°C Found M+: 243.1246. Cι5H17N02 requires 243.1259. δ : 7.98 (1 H, dd, J 8.2, 1.3, H5), 7.75 (1 H, dd, J 8.2, 1 .2, H8), 7.56 (1 H, ddd, J
8.3, 6.9, 1.3, H7), 7.32 (1 H, ddd, J 8.2, 6.9, 1 .2, H6), 5.38 (1 H, tq, J 7.3, 1.2, CH=), 4.06 (3H, s, OCH3), 3.51 (2H, d, J 7.3, CH2CH=), 1 .86 (3H, s, CH=CCH3) 1.81 (3H, d, J 1.2, CH=CCH3). OH not observed in CDCI3. δc: 161 .4 (C2), 145.0 (C8a), 137.0 (=C(CH3)2), 129.3, 126.5, 123.2, 121.6, 121 .1 (C-5,6,7,8 and =CH), 1 19.0 (C4a), 105.2 (C3), 53.9 (OMe), 25.9 (CH3),
23.0 (CH2), 18.0 (CH3), no signal observed for C4.
NOESY (DMSO d6): correlation between the OH proton at d11.5 ppm and the C5 proton at δ7.98 ppm. nmaχ /cm-1: 3200-3000 (br, O-H), 1627, 1580 (s, C=C, C=N) m/z: 243 (26%, M+), 228 (12%, M+ - CH3), 188 (5%, M+ - CH=C(CH3)2 ), 83
(100%).
EXAMPLE 8. 4-Methoxy-1 H-quinolin-2-one
Figure imgf000048_0001
CilHnNO- C10H9NO2 Mol. Wt: 189.2 Mol. Wt.: 175.2
2,4-Dimethoxyquinoline (EXAMPLE 4A) (2.0 g, 1 1 mmol) was dissolved in 3% HBr in a :1 mixture of H 0/THF (100 ml). The solution was heated under reflux for 3 hours, then cooled and neutralised with aqueous NaHCO3. The THF was removed under reduced pressure, precipitating a white solid, which was filtered and dried under suction. Tic (4:1 hexane: EtOAc) showed the presence of starting material and a polar material (baseline). A 5 hour Soxhlet extraction with hexane separated these two compounds. The starting material was extracted into the reaction flask leaving the product, cream needles, in the thimble. Yield 1.0 g,
54%. Melting point 249-252°O
Found M+: 175.0629. C10H9NO2 requires 175.0633. δH: 7.90 (1 H, dd, J 8.1 , 1.1 , H5), 7.52 (1 H, dd, J 8.1 , 1.1 , H7), 7.40 (1 H, dd, J 8.1 , .1 , H8), 7.20 (1 H, dd, J 8.1 , 1 .1 , H6), 6.03 (1 H, s, H3), 3.99 (3H, s, OMe). δc: 166.3 (C2), 165.0 (C4), 138.4 (C8a), 131.2 (C7), 122.8 (C8), 122.2 (C6),
116.1 (C5), 1 15.6 (C4a), 96.0 (C3), 56.0 (OMe). nmax /cm-1: 3100 (w, N-H), 1674 (s, C=0), 1634, 1607 (s, C=C). m/z: 175 (100%, M+), 132 (63%, M+ - CONH), 76 (28%, C6H4 +).
EXAMPLE 9. 2,4-Dichloro-8-methylquinoline
Figure imgf000049_0001
C7HSN C10H7CI2N
Mol. Wt.: 107.2 Mol. Wt : 212.1
o-Toluidine (5.0 g, 47 mmol), malonic acid (7.3 g, 70 mmol) and POCI3 (40 ml) were heated under reflux for 5 hours. Aqueous workup was as for other dichloroquinolines to give the crude product as a brown powder. After continuous extraction of the crude product (hexane, 4h) the pure quinoline was obtained as a yellow powder. Yield 5.3 g, 53%. Rf (9:1 hexane:EtOAc) 0.70. Melting point 80-82°O
Found M+: 210.9956. C10H7 35CI2N requires 210.9955. δπ: 7.95 (1 H, d, J 8.3, H5), 7.54 (1 H, d, J 7.1 , H7), 7.44 (1 H dd, J 8.3, 7.1 , H6), 7.40 (1 H, s, H3), 2.68 (3H, s, 8-Me). δc: 147.6 (C2), 146.3 (C8a), 143.3 (C4), 136.2 (C8), 130.6 (C7), 126.5 (C6), 124.2 (C4a), 121.0 (C5), 120.7 (C3), 17.1 (8-Me). nmax /cm-1 : 1610, 1573 (s, C=C and C=N) 680 (w, C-CI). m/z: 215 (13%, M+ 37d2), 213 (79%, M+ 37c|35ci), 211 (100%, M+ 35d2), 176 (22%, M+ - CI), 148 (14%), 140 (24%, M+ - 2CI).
EXAMPLE 10. 2,4-Dichloro-6-methylquinoline
Figure imgf000050_0001
C7H9N C10H7CI2N
Mol. Wt: 107.2 Mol. Wt.: 212.1
Malonic acid (7.3 g, 70 mmol) and p-toluidine (5.0 g, 47 mmol) were heated under reflux in phosphorus oxychloride (40 ml) for 5 hours. After cooling, the reaction mixture was poured onto crushed ice and neutralised (NaOH). The crude brown precipitate was filtered off and then and purified by Soxhlet extraction (hexane), to give the title compound as a pale yellow powder. Yield 5.1 g, 51 %. Melting point
91-93°C.
Found M+: 210.9955. C-|0H735ci2N requires 210.9955. δH: 7.91-7.88 (2H, m, H5 and H8), 7.60 (1 H, dd, J 8.6, 1.9, H7), 7.44 (1 H, s,
H3), 2.56 (3H, s, 6-Me). δc: 148.8, 146.7 (C2. C4), 143.6 (C8a), 138.3 (C6), 133.7 (CH), 128.7 (CH),
125.1 (C4a), 123.1 (CH), 121 .9 (CH), 21.9 (6-Me). nmaχ /cm-1 : 573, 1558 (m, C=C, C=N). m/z: 215 (14%, M+, 37CI2), 213 (34%, M+, 37c|35c[), 211 (100%, M+, 35ci2), 176
(28%, M+ - CI), 140 (29%). EXAMPLE 11. 2,4-Dimethoxy-6-methylquinoline
Figure imgf000051_0001
2,4-Dichloro-6-methylquinoline (EXAMPLE 10) (2.0 g, 9.4 mmol) was heated under reflux in methanolic sodium methoxide (2.0 g Na in 100 ml MeOH), for 40 hours, then cooled, poured into cold water and filtered to give the product as off-white needles. Yield 1 .6 g, 84%. Melting point 53-55°C Found M+: 203.0947. C12H13N02 requires 203.0946. δπ: 7.81 ( H, d, J 1.9, H5), 7.67 (1 H, d, J 8.5, H8), 7.41 (1 H, dd, J 8.5, 1.9, H7),
6.18 (1 H, s, H3), 4.03 (3H, s, OMe), 3.95 (3H, s, OMe), 2.46 (3H, s, Me), δc: 163.9, 163.7 (C2. C4), 145.7 (C8a), 133.3 (C6), 132.2, 127.0, 121.4, (C5, C7, C8), 119.4 (C4a), 91.0 (C3), 56.0 (OMe), 53.7 (OMe), 21.8 (Me). nmaχ /cnτ1 : 1631 , 1609, 1581 (s, C=C and C=N). m/z: 203 (93%, M+), 202 (100%, M+ - H), 174 (22%, M+ - OMe), 173 (36%,
M+ - OMe, H).
EXAMPLE 12. 2,4-Dichloro-8-methoxyquinoline
Figure imgf000051_0002
o-Anisidine (3.0 g, 24 mmol) and malonic acid (3.7 g, 36 mmol) were heated under reflux in phosphorus oxychloride (35 ml) for 5 hours, followed by aqueous alkaline workup and filtration to give a brown solid. Soxhlet extraction ofthe crude product with hexane gave the title compound as an off-white powder. Yield 1.45 g, 26%. Melting point 132-135°C.
Found M+: 226.9909. C10H735CI2NO requires 226.9905. δH: 7.74 (1H,dd, 8.5, 1.1, H5), 7.55 (1H, dd, J 8.5, 7.0, H6), 7.53 (1H, s, H3),
7.14 (1H, dd, J7.0, 1.1, H7), 4.07 (3H,s, OMe). . δc: 154.8, 148.9, 144.3, 139.9 (C2, C4, C8, C8a), 128.1, 126.3 (C4a), 122.7,
115.7, 109.8, 56.3 (OMe). nmax/cnrr1: 1616, 1576, 1559 (s, C=C, C=N). m/z: 231 (19%, M+37CI2), 230(16%, M+37CI2-H), 229(68%, M+3 c|35d), 228
(84%, M+ 3 CI35CI - H), 227 (92%, M+ 5Cl2), 226 (100%, M+ 35ci2 - H), 198
(94%), 162(59%).
EXAMPLE 13. 2,4.8 -Trimethoxyquinoline
Figure imgf000052_0001
C10H7CI2NO C12H13N03 Mol. Wt.: 228.1 Mol. Wt: 219.2
2,4-Dichloro-8-methoxyquinoline (EXAMPLE 12) (1.0 g, 4.4 mmol) was heated under reflux in methanolic sodium methoxide (1.0 g Na in 50 ml MeOH) for 48 hours. After cooling, the mixture was poured into cold water and the product, white fluffy needles, obtained by filtration. Yield 0.67 g, 70%. Melting point
149-150° C.
Found M+: 219.0899. C12Hι3N03 requires 219.0895. δπ: 7.65 (1H, dd, 8.2, 0.8, H5), 7.26 (1H, dd, J 8.2, 7.8, H6), 7.03 (1H, dd, J 7.8, 0.8, H7), 6.26 (1H, s, H3), 4.12 (3H, s, 8-OMe), 4.04 (3H, s, OMe), 3.98 (3H, s, OMe). δc: 164.4, 163.9 (C2,C4), 154.3 (C8), 138.7 (C8a), 123.6 (C6), 120.9 (C4a), 114.2, 109.9 (C5,C7), 91.5 (C3), 56.7, 56.153.8 (3 x OMe). nmaχ/cm-1: 1621 , 1603, 1580 (s, C=C, C=N), 1082, 1044 (s, C-O-C). m/z: 219 (10%, M+), 218 (90%, M+ - H), 204 (36%, M+ - Me), 189 (44%, M+ -
2Me).
EXAMPLE 14. 2,4-Dich~lόro-6-methoxyquinoline
Figure imgf000053_0001
C7HgNO C10H7GI2NO Mol. Wt: 123.2 Mol. Wt: 228.1
p-Anisidine (5.0 g, 41 mmol), malonic acid (6.5 g, 63 mmol), and phosphorus oxychloride (40 ml) were heated under reflux for 4 hours. Standard workup gave the crude product as a black solid, from which Soxhlet extraction with hexane yielded 5.1 g, 55% of the title compound as white needles. Melting point:
168-170°C
Found M+: 226.9917. C10H735CI2NO requires 226.9905. δH: 7.84 (1 H, d, 9.1 , H8), 7.40 (1 H, s, H3), 7.35 (1 H, dd, 9.1 , 2.7, H7), 7.31
( H, d, J 2.7, H5), 3.89 (3H, s, OMe). δc: 158.9, 147.0, 144.1 , 142.7 (C2, C4, C6, C8a), 130.5 (CH), 126.3 (C4a),
124.1 (CH), 122.0 (CH), 102.0 (C3), 55.8 (OMe). nmaχ/cm-1: 1622, 1563 (s, C=C and C=N). m/z: 229 (36%, M+ 35c|3 ci), 227 (49%, M+ 5ci2), 143 (41 %), 113 (66%).
EXAMPLE 15. 2,4,6-Trichloroquinoline
Figure imgf000054_0001
4-Chloroaniline (7.0 g, 54 mmol), malonic acid (8.5 g, 82 mmol) and phosphorus oxychloride (50 ml) were heated under reflux for 6 hours. Standard aqueous workup gave the crude product as a red-brown solid. Soxhlet extraction with hexane gave the pure product as a yellow powder. Yield 3.0 g, 24%. Melting point 116-118°C Found M+: 230.9417. C9H435ci3 requires 230.9409. δH: 8.17 (1 H, d, J 2.3, H5), 7.97 (1 H, d, J 8.9, H8), 7.73 (1 H, dd, J 8.9, 2.3, H7), 7.54 (1 H, s, H3). δc: 150.2 (C2), 146.5 (C4), 143.3 (C8a), 134.2 (C6), 132.5 (C8), 130.6 (C7), 125.9 (C4a), 123.3 (C5), 122.8 (C3). nmax /cm-1: 1571 (s, C=C or C=N). m/z 235 (36%, M+ 37CI235CI), 233 (97%, M+ ci35ci2), 231 (100%, M+ 35d3), 196 (54%, M+ - CI), 163 (13%, C9H437CIN+), 161 (38%, C9H435ciN+).
EXAMPLE 16. 2,4-Dichloro-5,7-dimethoxyquinoline
Figure imgf000054_0002
CaH^NOa C11HBCI2N02 Mol Wt 153 2 Mol Wt 258 1
3,5-Dimethoxyaniline (3.0 g, 20 mmol) and malonic acid (3.1 g, 30 mmol) were heated under reflux in phosphorus oxychloride (30 ml) for 5 hours. The mixture was poured into crushed ice and made alkaline with 5M NaOH, then filtered to give the crude product as a black solid. Soxhlet extraction with hexane furnished the product as pale yellow needles. Yield 0.9 g, 18%. Melting point: 160-162°C dec.
Found M+: 257.0007. CnH935CI2N02 requires 257.0010. δH: 7.22 (1 H, s, H3), 6.94 (1 H, d, J 2.3, H8), 6.53 (1 H.-d, ,J 2.3, H6), 3.92 (3H, s, OMe), 3.91 (3H, s, OMe). δc: 162.5, 157.5, 152.4, 150.7 (C2, C4, C5, C7), 143.3 (C8a), 121.4 (C3), 113.3
(C4a), 100.7, 100.5, (C5, C7) 56.3 (OMe), 56.1 (OMe). nmaχ / cnr1: 1617, 1577, 1558 (s, C=C, C=N). m/z: 261 (11%, M+ 37d2), 259 (54%, M+ 3 C|35CI), 257 (100%, M+ 35d2), 212
(8%), 149 (9%).
EXAMPLE 17. 2,4-Dichloro-5-methylquinoline
Figure imgf000055_0001
8-Amino-2,4-dichloro-5-methylquinoline (EXAMPLE 45) (0.10 g, 0.44 mmol) was added to 49% sulfuric acid (6.0 ml) at 0°C, with stirring. Powdered sodium nitrite (35 mg, 0.50 mmol) was added and the mixture maintained at 0°C for 15 minutes before pouring into 30% hypophosphorous acid (20 ml) at 0°C. The reaction mixture was then slowly warmed to 40°C, until evolution of nitrogen ceased. The mixture was poured into crushed ice, neutralised with 2M NaOH, and extracted with diethyl ether (3 x 50 ml). The combined ether layers were dried over MgSO-j., and the solvent evaporated under reduced pressure to give a pale orange solid, Rf (9:1 hexane:EtOAc) 0.52. Yield 75 mg, 80%. Melting point: 126-129°C
Found M+: 210.9998. C10H735ci2N requires 211 .0081. δH: 7.89 ( H, d, J 8.4, H8), 7.60 (1 H, dd, J 8.4, 7.2, H7), 7.46 (1 H, s, H3), 7.37
(1 H, d, J 7.2, H6), 3.01 (3H, s, 5-Me). δc: 150.2, 149.0, 144.5, 135.7, 131.2, 130.7, 128.2, 124.6, 123.7, 25.2
(5-Me). nmaχ /crτr1: 1570, 1557 (s, C=C, C=-N) m/z: 215 (11%, M+ 37ci2), 213 (64%, M+ 7c|35cf), 211 (100%, M+ 35d2), 176
(34%, M+ - CI), 140 (25%).
EXAMPLE 18. 2-Methoxyquinoline
Figure imgf000056_0001
C10rleCINO C10H9NO Mol. Wt - 193 6 Mol. Wt 159 2
4-Chloro-2-methoxyquinoline (EXAMPLE 4B) (0.40 g, 2.1 mmol), zinc dust
(0.70 g, 11 mmol) and ammonium chloride (0.70 g, 13 mmol) were heated under reflux in 50% aqueous ethanol (30 ml) for 2 hours. After cooling, the mixture was extracted with diethyl ether (3 x 30 ml), the combined organic extracts were dried
(MgSθ4), and the solvent removed in vacuo to give a brown oil which was purified by column chromatography (9:1 hexane:EtOAc). The title compound (Rf 0.35) was obtained as a sweet-smelling colourless oil. Yield 0.25 g, 75%.
Found M+: 159.0674. C10H9NO requires 159.0684. δH: 7.95 (1 H, d, J 8.8, H4), 7.85 (1 H, d, 8.4, H8), 7.70 (1 H, d, 8.0, H5), 7.61
(1 H, dd, J 8.4, 7.0, H7), 7.36 (1 H, dd, J 8.0, 7.0, H6), 6.89 (1 H, d, J 8.8, H3),
4.07 (3H, s, OMe). δc: 162.8 (C2), 147.0 (C3), 139.1 (C4), 129.9, 127.9, 127.6, 125.5 (C4a), 124.4,
113.5 (C3), 53.8 (OMe). nmaχ/cm-1: 3060, 3010, 2944 (m, C-H), 1619, 1571 (s, C=C, C=N), 1026
(s, C-O). m/z: 159(100%, M+), 158 (98%, M+ - H), 129 (80%, C9H7N+). EXAMPLE 19. 3-Bromo 2,4-dimethoxyquinoline
Figure imgf000057_0001
CnH„N02 C11H10BrNO2 Mol. Wt: 189.2 Mol. Wt: 268.1
2,4-Dimethoxyquinoline (EXAMPLE 4A) (1 .5 g, 7.9 mmol) was dissolved in dry
THF (25 ml) and cooled to 0°C under argon. Then n-butyllithium (4.8 ml of a 2.5M solution in hexanes, 12 mmol) was added dropwise and the mixture was stirred at 0°C for 45 minutes. 1 ,2-Dibromo-tetrafluoroethane (3.3 g, 12.6 mmol) in THF (10 ml) was added slowly over 5 minutes. Stirring was continued at 0°C for 30 minutes and then with warming to room temperature for 1 hour. The colour changed from purple to black/brown. The mixture was poured into water and extracted with ether (4 x 100 ml). The organic extracts were dried (MgSθ4) and the solvent removed in vacuo to leave a black sticky residue. Tic (9:1 hexane:EtOAc) showed 2 spots; Rf 0.45 and baseline (highly coloured). Column chromatography (9:1 hexane:EtOAc) furnished the pure product (Rf 0.45) as off- white plates. Yield 0.9 g, 43%. Melting point: 67-69°C Found M+: 266.9895. C1 1 H10 79BrNO2 requires 266.9894. δH: 7.97 (1 H, dd, 8.2, 1 .1 , H5), 7.84 (1 H, dd, J 8.5, 1 .1 , H8), 7.64 (1 H, ddd, J 8.5, 7.0, 1.1 , H7), 7.41 (1 H, ddd 8.2, 7.0, 1.1 , H6), 4.14 (3H, s, OMe), 4.08 (3H, s, OMe). δc: 162.4 (C2), 159.0 (C4), 145.9 (C8a), 130.2, 127.3, (C7, C8), 124.5, 122.0, (C5, C6), 100.4 (C4a), 61 .6 (MeO), 54.8 (MeO). No signal observed for C3. nmax /cm-1 : 1580, 1568 (s, C=C, C=N). m/z 267 (93%, M+ 79Br), 266 (95%, M+ - H), 239 (62%, M+ - OMe), 237 (56%, M+ - OMe) (N.B. M+, 81 Br lost due to coincidence with PFK internal reference). EXAMPLE 20. 2,4 -Dimethoxy-3-(3methylbut-2-enyl)quinoline
Figure imgf000058_0001
Cl 6H1gN02
Figure imgf000058_0002
Mol. Wt: 257.3
2,4-Dimethoxyquinoline (EXAMPLE 4A) (2.0 g, 1 1 mmol) in dry THF ( 0 ml) was cooled to 0°C under argon and n-butyllithium (6.2 ml of a 2.5M solution in hexane) was added dropwise, with stirring. The mixture was stirred at 0°C under argon for 30 minutes, then 1-bromo-3-methylbut-2-ene (2.8 g, 19 mmol) was added dropwise over 5 minutes. The mixture was stirred at 0°C for 30 minutes and then allowed to warm to room temperature with stirring for a further hour. The reaction mixture was poured into water and extracted with ether (4 x 30 ml) to give the crude product as a yellow/brown oil. Column chromatography (4:1 hexane:EtOAc) yielded the pure product (Rf 0.57) as a yellow-brown oil. Yield 2.4 g, 88%. Found M+: 257.1417. Cι6H-ιgN0 requires 257.1416. δH: 7.92 (1 H, ddd, J 8.2, 1.5, 0.5, H5), 7.82 (1 H, ddd, J 8.5, 1.2, 0.5, H8), 7.56 (1 H, ddd, J 8.5, 6.9, 1.5, H7), 7.35 (1 H, ddd, J 8.2, 6.9, 1 .2, H6), 5.22 (1 H, br t, J 6.9, C=CH), 4.08 (3H, s, 2-OMe), 3.95 (3H, s, 4-OMe), 3.45 (2H, d, J 6.9, C±>), 1.81 (3H, d, J 0.7, =CCH3), 1.69 (3H, d, J 1 .2, =CCH3). δc: 162.5 (C4), 161.6 (C2), 146.1 (C8a), 132.3 (=CMe2), 128.9, 127.3, (C7,
C8) 123.6, 121.9, 121.8, (C5, C6 and =CH), 121.2 (C3), 1 16.9 (C4a), 62.3 (OMe), 53.8 (OMe), 25.8 (CH3), 23.3 (CH2), 18.0 (CH3). nmaχ /cπr1 : 3070 (s, C-H), 1620, 1605, 1575 (s, C=C and C=N). m/z : 257 (100%, M+), 242 (82%, M+- Me), 202 (52%, M+ - Me2C=CH). EXAMPLE 21. 3-(1 -Hydroxy-3-methyl-but-2-enyl)-4-methoxy-1 H- quinolin-2-one
Figure imgf000059_0001
4-Methoxyquinolin-2-one (0.80 g, 4.6 mmol) in THF (20 ml) was cooled to -78°C, and π-butyllithium (9.2 mmol) was added slowly, with stirring. The mixture was stirred at -78°C for 15 minutes, then allowed to warm to room temperature for 15 minutes, before cooling to -78°C once more. 3-Methylbut-2-enal (0.77 g, 9.2 mmol) in THF (5 ml) was added dropwise, and the mixture was stirred for 15 minutes before being allowed to warm to room temperature and stirred for a further hour. The yellow solution was poured into water, and extracted with ether (3 x 50 ml). The combined organic layers were dried over MgSθ4, and the solvent removed in vacuo to give a white powder, Rf (1 :1 hexane:ethyl acetate) 0.30. Yield 0.18 g, 15%. Melting point 128-130°C.
Found M+: 259.1 179. C15H17N03 requires 259.1208. δπ: 12.73 (1 H, s, NH/OH), 7.73 (1 H, d, J 8.1 , H5), 7.47 (1 H, m, H7), 7.38 (1 H, d, J 8.0, H8), 7.20 (1 H, m, H6), 5.77 (1 H, d, J 9.2, CH-OH), 5.69 (1 H, dd, J 10.5, 9.2, CHOH), 5.30 (1 H, d, J 10.5, =CH), 3.92 (3H, s, OMe), 1.81 (3H, s, Me), 1.66 (3H, s, Me). δc: 166.2, 161.5 (C2, C4), 137.7, 135.5 (088^^=), 130.9, (CH) 125.9 (CH), 123.4 (CH), 123.1 (CH), 117.1 (C4a), 116.4 (CH), 64.9 (OMe), 62.5 (OMe), 26.0 (Me), 18.3 (Me). No signal observed for C3. nmax / cm-1: 3462 (m, OH), 1644 (s, C=0), 1608 (s, C=C). m/z (C\): 259 15%, M+), 242 (43%, M+ - OH), 241 (17%, M+ - H20), 88 (49%),
175 (100%, M+ - Me2C=CHCHOH). EXAMPLE 22. 2,4-Dimethoxy-8-methylquinoline
Figure imgf000060_0001
2,4-Dichloro-8-methylquinoline (EXAMPLE 9) (2.0 g, 9.4 mmol) was heated under reflux in methanolic sodium methoxide (from 4.0 g Na in 100 ml MeOH) for 40 hours, then cooled and poured into ice-cold water. The product was obtained by filtration as off-white needles. Yield 1.7 g, 89%. Melting point: 52-54°C. Found M+: 203.0911. C12H13N02 requires 203.0946. δH: 7.89 (1 H. d, 8.2, H5), 7.45 (1 H, d, 7.0, H7), 7.21 (1 H, dd, 8.2, 7.0, H6),
6.20 (1H, s, H3), 4.05 (3H, s, OMe), 3.94 (3H, s, OMe), 2.67 (3H, s, 8-Me) δc: 164.1 (C4), 162.5 (C2), 145.8 (C8a), 134.9 (C8), 130.1 (C7), 122.7 (C6), 119.4 (C5), 118.9 (C4a), 90.1 (C3), 55.6 (OMe), 53.1 (OMe), 18.0 (8-Me). nmax /cm-1: 1620, 1580 (s, C=C, C=N). m/z: 203 (51 %, M+), 202 (32%, M+ - H), 193 (17%), 188 (22%, M+ - Me), 173
(12%) 162 (16%).
EXAMPLE 23. 2,4-Dimethoxy-3-(3-methyl but-2-enyl)-8-methylquinoline
Figure imgf000060_0002
C,2H13N02 C17H21N02 Mol. Wt: 203.2 Mol. Wt: 271.4
2,4-Dimethoxy-8-methylquinoline (EXAMPLE 22) (1.0 g, 4.9 mmol) was dissolved in dry THF (10 ml) and cooled to 0°C under argon. n-Butyllithium (3.0 ml of a 2.5M solution in hexane, 7.5 mmol) was added slowly with stirring, and the mixture was stirred for 30 minutes at 0°C 1 -Bromo-3-methylbut-2-ene (1.3 g, 8.7 mmol) in THF (8 ml) was then added dropwise over 5 minutes. Stirring was continued for 30 minutes at 0°C and then the mixture was warmed to room temperature over 45 minutes. The resultant yellow-brown solution was poured into cold water and extracted with ether (3 x 50 ml). The combined ether extracts were dried over
MgSθ4. Removal of solvent in vacuo yielded the crude product, a brown oil. Column chromatography (9:1 hexane:EtOAc) furnished the pure quinoline as a yellow-brown oil. Yield 1 .1 g, 82%. Rf (9:1 hexane:EtOAc) 0.68.
Found M+: 271.1562 . C17H2 N02 requires 271.1572. δH: 7.77 (1 H, d, 8.0, H5), 7.41 (1H, d, 7.2, H7), 7.24 (1 H, dό, J7.2, 8.0, H6),
5.23 (1 H, br t, J 7.0, =CH), 4.08 (3H, s, MeO), 3.92 (3H, s, MeO), 3.45 (2H, d,
J 7.0, CH2), 2.68 (3H, s, 8-Me), 1.81 (3H, s, =CCH3 ), 1 .68 (3H, d, J 0.8,
=CCH3) δc: 161.8, 161.3 (C2 and C4), 144.8 (C9), 135.4, 132.1 (C8 and =C(CH3)2), 129.1 , 123.2, 122.0, 120.9 (C5,6,7 and =CH), 119.6 (C10), 116.3 (C3), 62.2
(MeO), 53.5 (MeO), 25.8 (CH3), 23.2 (CH2), 17.9, 17.8(8-Me, CH3). nmaχ /cm-1: 1619, 1583 (m, C=C, C=N). m/z: 271 (100%, M+), 256 (78%, M+ - Me), 224 (34%), 202 (33%,
C12H12N02 +).
EXAMPLE 24. 4-Hydroxy-2-methoxy-8-methyl-3(3-methyl-but-2- enyPquinoline
'PrSNa, DMF
Figure imgf000061_0001
Figure imgf000061_0002
C17rl21N02 C16H1gN02
Mol. Wt.271.4 Mol. Wt. 2573
Sodium hydride (0.70 g of a 60% mineral oil dispersion, 18 mmol) was suspended in DMF (20 ml) and 2-propanethiol (0.57 g, 7.5 mmol) was added. The mixture was stirred for 5 minutes. A solution of 2,4-dimethoxy-8-methyl-3-(3-methylbut-2- enyl)quinoline (EXAMPLE 23) (0.80 g, 3.0 mmol) in DMF (10 ml) was added, followed by heating under reflux for 3 hours. After cooling the reaction mixture was neutralised with 2M hydrochloric acid, and then extracted with ether (3 x 50 ml). The ether layers were dried over MgSθ4 and the solvent was evaporated to give a brown oil. Column chromatography (4:1 hexane:EtOAc) yielded 0.3 g, 39% of the product as a yellow solid. Melting point: 164-166°C Found M+: 257.1418 . C16H19N02 requires 257.1416. δH : 7.82 (1 H, d, J8.1 , H5), 7.42 (1 H, d, J7.0, H7), 7.22 (1 H, dd, J8.1 , 7.0, H6), 6.59 (1 H, brs, OH), 5.37 (1 H, brt, 7.3, =CH), 4.06 (3H, s, OMe), 3.51 (2H, d,
7.3, CH2), 2.66 (3H, s, 8-Me), 1.86 (3H, s, =CCH3 ), 1.80 (3H, d, J 0.9, =CCH3) δc: 160.0, 158.5 (C2, C4), 144.0 (C8a), 137.0, 134.9 (C8 and =CMe2), 129.4, 122.7, 121.1 , 118.9 (C5, C6, C7 and C=CH), 118.0 (C4a), 104.4 (C3), 53.5 (OMe), 25.9 (8-Me), 22.9 (CH2), 18.1 (Me), 17.8 (Me). 1 H NOESY spectrum (DMSO d6): OH at δ10.2 ppm correlates weakly with H5 at δ8.0 ppm. nmaχ /cnr1: 3445 (m, O-H), 1619, 1586, (s, C=C, C=N). m/z: 257 (100%, M+), 242 (41%, M+ - Me), 240 (55%), 202 (92%, M+ - Me2C=CH).
EXAMPLE 25A. 2,4-Dichloro-5-methylquinoline and EXAMPLE 25B. 2,4-dichloro-7-methylquinoline
Figure imgf000062_0001
C7H9N C10H7CI2N
Mol. Wt: 107.2 Mol. Wt: 212.1
m-Toluidine (5.0 g, 47 mmol) and malonic acid (7.3 g, 70 mmol) were heated under reflux in phosphorus oxychloride (40 ml) for 5 hours, yielding the crude product as an ochre solid after aqueous workup. Continuous (Soxhlet) extraction with hexane furnished 7.7 g, 77% of a mixture of the two isomeric products; Rf
(9:1 hexane: EtOAc) 0.53, one spot. The mixture was used in the next step without separation of isomers.
Found M+: 210.9954. Cι0H7 35Cl2 requires 210.9955. nmax /cm-1: 1569 (m, C=C or C=N). m/z: 215 (55%, M+, 37C|2), 213 (93%, M+, 3 c|35ci), 211 (100%, M+, 35d2), 176
(85%, M+ - CI), 140 (84%, M+ - 2CI, H).
1H NMR showed the two products in a 7:5 ratio of 5-methyl:7-methyl:
5-Methyl isomer (EXAMPLE 25A) δπ: 7.87 (1 H, dd, 7.3, 0.6, H8), 7.58 (1 H, dd, J8.2, 7.3, H7), 7.41 (1 H, s, H3),
7.35 (1 H, dd, J 8.2, 0.6, H6), 2.99 (3H, s, 5-Me).
7-Methyl isomer (EXAMPLE 25B) δH: 8.02 (1 H, d, J 8.5, H5), 7.77 (1 H, d, J 1.0, H8), 7.44 (1 H, dd, J 8.5, 1 .0, H6),
7.40 (1 H, s, H3), 2.56 (3H, s, 7-Me).
EXAMPLE 26A. 2,4-Dimethoxy-5-methylquinoline and EXAMPLE 26B. 2,4-dimethoxy-7-methylquinoline
Figure imgf000063_0001
C10rl7CI2N C12H13N02 Mol. Wt: 212.1 Mol. Wt: 203.2
The isomeric mixture of 2,4-dichloromethylquinolines (4.0 g, 19 mmol) was heated under reflux in sodium methoxide (2.0 g Na in 75 ml MeOH) for 50 hours, then cooled, poured into cold water and filtered under suction to give the product as an off-white powder, yield 2.9 g, 75%. Rf (9:1 hexane:EtOAc) 0.39, broad spot. The mixture was used in the next step. Found M+: 203.0959. C12H13N02 requires 203.0946. nmax /cm- : 1612, 590 (s, C=C, C=N), 1207 (s, C-O-C). m/z 203 ( 00%, M+), 202 (75%, M+ - H), 173 (26%, M+ - 2Me).
1 H NMR of mixture showed the two isomers in the ratio 11 :10 5-methyl:7-methyl.
5-Methyl isomer (EXAMPLE 26A) δπ: 7.61 (1 H, d, J 8.3, H8), 7.41 ( H, dd, J 8.3, 7.2, H7), 7.06 (1 H, d, J7.2, H6),
6.17 (1 H, s, H3), 4.03 (3H, s, OMe), 3.90 (3H, s, OMe), 2.78 (3H, s, 5-Me). 7-Methyl isomer (EXAMPLE 26B) δH: 7.92 (1 H, d, J 8.3, H5), 7.58 (1 H, d, J 0.6, H8), 7.15 (1 H, dd, J 8.3, 0.6, H6), 6.15 (1 H, s, H3), 4.04 (3H, s, OMe), 3.96 (3H, s, OMe), 2.49 (3H, s, 7-Me)
EXAMPLE 27A. 2,4-Dimethoxy-5-methyl-3-(3-methylbut-2-enyl)quinoline and
EXAMPLE 27B. 2,4-dimethoxy-7-methyl-3-.3-methylbut-2-enyl)quinoline
Figure imgf000064_0001
C12rl13N02 C17H21N02 Mol. Wt: 203.2 Mol. Wt: 271.4
The isomeric 2,4-dimethoxyquinoline mixture (2.0 g, 9.9 mmol) was dissolved in THF (40 ml) and cooled to 0°C n-Butyllithium (6.0 ml of 2.5M solution, 15 mmol) was added dropwise, and the deep red solution was stirred at 0°C for 30 minutes.
1-Bromo-3-methylbut-2-ene (2.7 g, 18 mmol) was added slowly, and the mixture stirred for 1 hour whilst slowly warming to room temperature. The mixture was poured into cold water, extracted with ether (3 x 30 ml), dried, and the solvent removed to give the product as a brown oil. Yield 1 .46 g, 54%. Rf (9:1 hexane:EtOAc) 0.52, broad single spot. The mixture was used in the next step without further purification.
Found M+: 271 .1572 . C17H21 N02 requires 271.1572. nmax /cm-1 : 2946 (s, C-H), 1606, 1580 (s, C=N, C=C) m/z: 271 (91 %, M+), 256 (76%, M+ - Me), 202 (27%, C12H12N02 +), 51 (100%). H NMR spectrum showed the two isomers in a 5:4 ratio; some signals coincident.
5-Methyl isomer (EXAMPLE 27A) δH: 7.66 (1 H, d, J 8.2, H8), 7.39 (1 H, d, J 8.2, 7.2, H7), 7.08 (1 H, d, J 7.2, H6),
5.27-5.20 (1 H, m, Me2C=CH), 4.06, (3H, s, OMe), 3.76 (3H, s, OMe), 3.45-3.42 (2H, m, Ar-CH2), 2.80 (3H, s, 5-Me), 1.80 (3H, s, Me), 1 .69 (3H, s, Me).
7-Methyl isomer (EXAMPLE 27B) δH: 7.78 (1 H, d, J 8.3, H5), 7.62 (1 H, s, H8), 7.17 (1 H, d, J 8.3, H6), 5.27-5.20 (1 H, m, Me2C=CH), 4.06, (3H, s, OMe), 3.91 (3H, s, OMe), 3.45-3.42 (2H, m,
Ar-CH2), 2.48 (3H, s, 7-Me), 1.80 (3H, s, Me), 1 .69 (3H, s, Me).
EXAMPLE 28A. 4-Hvdroxy-2-methoxy-5-methyl-3-(3-methylbut-2- enyl.quinoline and EXAMPLE 28B. 4-Hydroxy-2-methoxy-7-methyl-3-(3-methylbut-2- enyl.quinoline
Figure imgf000066_0001
DMF
Figure imgf000066_0002
C17H21N02 Cl6H19N02 Mol Wt: 271.4 Mol. Wt: 257.3
Sodium hydride (0.85 g of a 60% dispersion in mineral oil, 21 mmol) was washed with hexane under argon, and then suspended in dry DMF (30 ml). 2- Propanethiol (0.68 g, 9.0 mmol) was added, and the mixture stirred for 5 minutes. The mixture of isomers 28A and 28B (1.0 g, 3.7 mmol) was then added, and the mixture heated under reflux for 3 hours. After aqueous workup as for previous demethylations the crude product was obtained as a yellow solid. Tic showed 2 spots, Rf 0.30 and 0.40 (6:1 hexane: EtOAc). Column chromatography (6:1 ) yielded the two isomeric products, Rf 0.40 and Rf 0.30. NMR identified the higher Rf component as the 5-methyl isomer and the other as the 7-methyl isomer.
Data for 4-hydroxy-2-methoxy-5-methyl-3-(3-methylbut-2-enyl)quinoline
(EXAMPLE 28A)
Bright yellow solid, Rf (6:1 hexane: EtOAc) 0.40. Yield 0.1g. Melting point 118-120°C
Found M+: 257.1425. C16H19N02 requires 257.1416. δπ: 7.47 (1 H, d, J 8.2, H8), 7.24 (1 H, m, H7), 6.91 (1 H, d, J 7.0, H6), 5.14 (1 H, br t, C=CH), 3.95 (3H, s, OMe), 3.32 (2H, d, J 6.3, CH2), 2.76 (3H, s, 5-Me), 1.69 (3H, s, CH3), 1.63 (3H, s, CH3). δc: 160.3 (C2), 145.5 (C8a), 136.5, 135.8 (C5 and =CMe2), 129.3, 126.6,
123.3, 121.9 (C6, C7. C8 and C=CH), 119.4 (C4a), 106.3 (C3), 55.0 (OMe),
26.2 (Me), 24.5 (Me), 22.8 (CH2), 18.3 (Me). No signal was observed for C4. nmax /cm-1: 3400 (br, OH), 1617, 1584, 1561 (s, C=C, C=N). a. m/z: -257 (100%, M+), 242 (20%, M+ - Me), 202 (64%, M+ - CH=C(Me)2.)-
Data for 4-hydroxy 2-methoxy 7-methyl 3-(3-methylbut-2-enyl)quinoline
(EXAMPLE 28B)
Off-white powder, Rf (6:1 hexane:EtOAc) 0.30. Yield 0.15g. Melting point 149-
151°C 0 Found M+: 257.1412. C16H19N02 requires 257.1416. δH: 7.88 (1 H, d, J 8.3, H5), 7.55 (1 H, s, H8), 7.14 (1 H, d, J 8.3,
H6), 5.36 (1 H, t, 7.2, =CH), 4.04 (3H, s, OMe), 3.48 (2H, d, J7.2, CH2), 2.47
(3H, s, 7-Me), 1.84 (3H, s, CH3), 1.79 (3H, s, CH3). δc: 161.9 (C2), 139.9, 136.8 (C8a and C7), 128.7 (CH), 127.4 (Me2C=), 126.0, 5 125.5, 121.6 (CH), 117.2 (C4a), 104.7 (C3), 54.3 (OMe), 26.2 (Me), 23.6
(CH2), 22.1 (Me), 18.4 (Me). No signal was observed for C4. nmaχ cm- : 3200 (m, O-H), 1635, 1576, (s, C=C, C=N). m/z: 257 (100%, M+), 242 (39%, M+ - Me), 202.1 (56%, M+ - CH=C(Me)2).
0 EXAMPLE 29. 2,4-Dimethoxy-6-methyl-3-(3-methyl-2-butenyl)quinoline
Figure imgf000067_0001
2,4-Dimethoxy-6-methylquinoline (EXAMPLE 11) (0.80 g, 4.0 mmol) was 5 dissolved in dry THF (20 ml) and cooled to 0°C, with stirring. n-Butyllithium (3.7 ml of a 1 ,6M solution in hexanes) was added dropwise, and the mixture stirred at 0°C for 40 minutes. 1-Bromo-3-methyl-2-butene (1 .2 g, 8.1 mmol) was then added, and the resultant brown solution allowed to warm to room temperature over a period of 1 hour. The mixture was poured into cold water, and extracted with diethyl ether (3 x 30 ml). The combined organic extracts were dried over MgSθ4, and the solvent removed in vacuo to give the crude product as a brown liquid. Column chromatography (9:1 hexane:EtOAc) yielded the title compound as a pale brown oil, Rf 0.70. Yield 0.78 g, 73%.
Found M+: 272.1638. C17H22N02 requires 272.1651. δH: 7.71 (1 H, d, J 8.5, H8), 7.67 (1 H, d, J 1 .9, H5), 7.38 (1 H, dd. J 8.5, 1 .9, H7),
5.22 (1 H, t, 6.9, Me2C=CH), 4.06 (3H, s, OMe), 3.93 (3H, s, OMe), 3.43 (2H, d, 6.9, CH2), 2.49 (3H, s, 6-Me), 1.81 (3H, s, Me), 1 .68 (3H, s, Me). δc: 162.0, 161.1 (C2. C4), 144.4 (C8a), 133.1 , 132.1 (C6 and C=CMe2), 130.8,
127.0, 121.9, 121 .0 (C5, C7, C8, C=CH), 120.8 (C4a), 116.7 (C3), 62.1 (OMe),
53.6 (OMe), 25.7 (Me), 23.2 (CH2), 21 .6 (Me), 17.9 (Me). nmax /cm-1 : 2926 (s, C-H), 1609, 1572 (s, C=C, C=N). m/z: 272 (100%, M+), 271 (52%, M+ - H), 270 (51 %, M+ - 2H), 216 (33%,
C13H14N02 +).
EXAMPLE 30. 8-ter--Butyl-2,4-dichloroquinoline
Figure imgf000068_0001
C10H15N C13H13CI2 Mol. Wt: 149.2 Mol. Wt: 254.2
2-.erf-ButyIaniline (7.0 g, 47 mmol) and malonic acid (7.3 g, 70 mmol) were heated under reflux in phosphorus oxychloride (40 ml) for 6 hours. Continuous hexane extraction of the crude product obtained after aqueous alkaline workup yielded a brown oil. Tic (95:5 hexane:EtOAc) showed 3 spots; Rf 0.75, 0.12, baseline. Column chromatography (95:5 hexane:EtOAc) furnished the pure quinoline (Rf 0.75) as yellow plates. Yield 1.0 g, 8%. Melting point 56-58°C
Found M+: 253.0121. C13H1335CI2N requires 253.0425. δπ: 8.09 (1 H, dd, J 8.3, 1.3, H5), 7.75 (1H, dd, J 7.5, 1.3, H7), 7.51 (1 H. dd, -/
8.3, 7.5, H6), 7.46 (1 H, s, H3), 1.64 (9H, s, *Bu). δc: 148.2, 147.0, 146.3, 144.5 (C2, C4, C8, C8a), 128.3, 127.4, 126.2 (C4a),
122.7, 121.2, 36.7 (CMe3) 31.1 ((CH3)3). nmax /cnr1: 1578, 1562 (s C=N,.C=C) m/z: 257 (6%, M+ 37ci2), 253 (41%, M+ 35d2), 238 (89%, M+ 35d2 - Me), 211
(100%, M+ - C3H6).
EXAMPLE 31A. 8-tert-Butyl-2-chloro-4-methoxyquinoline and EXAMPLE 31 B. 8-fert-butyl-4-chloro-2-methoxyquinoline
Figure imgf000069_0001
C13H13CI2N C14H16CINO Mol Wt 254 2 Mol Wt • 249 7
8-terf-Butyl-2,4-dichloroquinoline (EXAMPLE 30) (0.7 g, 2.8 mmol) was heated under reflux in methanolic sodium methoxide (1.0 g Na in 50 ml MeOH) for 80 hours. Tic showed a mixture of products, Rf (hexane) 0.48, 0.22. Column chromatography (hexane) yielded the two isomeric chloromethoxyquinolines as white needles.
Data for 8-tert-butyl-4-chloro-2-methoxyquinoline (EXAMPLE 31A)
Yield 0.11g, 16%. Rf (hexane) 0.48. Melting point 54-56°C.
Found M+: 249.0917. C14H1635CIN0 requires 249.0920. δH: 8.03 (I H. dd. 8.2, 1.4, H5), 7.67 (1 H, dd, J 7.5, 1.4, H7), 7.38 (1 H, dd, J
8.2, 7.5, H6), 7.02 (1 H, s, H3), 4.07 (3H, s, OMe), 1.65 (9H, s, *Bu). δc: 159.1 (C2), 146.2, 145.6, 144.3 (C4, C8, C8a), 127.6, 124.4, 124.1 (C4a),
122.7, 111.8 (C3), 54.2 (OMe), 36.4 (CMe3), 30.5 ((CH3)3). nmax /cnr1: 1608, 1574 (s, C=C, C=N). m/z: 251 (16%, M+ 3 ci), 250 (16%, M+ 3 d - H), 249 (48%, M+ 35ci), 248
(27%, M+ 35CI - H), 236 (33%, M+ 37QI - Me), 234 (100%, M+ 5d - Me), 209
(34%, M+ 3 CI - C3H6), 207 (72%, M+ - C3H6).
Data for 8-ter--butyl-2-chloro-4-methoxyquinoline (EXAMPLE 31 B) Yield CL2Qg,.29% J3f (hexane) 0.22.„„Melting point 96-98°C (Found C: 67.71 , H:
6.75, N: 5.32%. C14H16CINO requires C: 67.33, H: 6.46, N: 5.61 %.)
Found M+: 249.0917. C14H16 35CINO requires 249.0920. δπ: 8.02 (1 H, dd, J 8.2, 1.4, H5), 7.66 (1 H, dd, J 7.5, 1.4, H7), 7.40 (1 H, dd, J
8.2, 7.5, H6), 6.69 (1 H, s, H3), 4.01 (3H, s, OMe), 1.63 (9H, s, *Bu). δc: 163.9 (C4), 148.0, 147.1 , 146.9 (C2, C8, C8a), 127.5, 125.5, 121.4 (C4a),
120.3, 100.4 (C3), 56.1 (OMe), 36.5 (CMe3), 31.0 ((CH3)3). nmaχ cm-1: 1588, 1575 (s, C=C, C=N) m/z: 251 (11 %, M+ 37ci), 250 (15%, M+ 3?CI - H), 249 (35%, M+ 35ci), 248
(28%, M+ 35CI - H), 236 (29%, M+ 37QI - Me), 234 (85%, M+ 35d - Me), 209 (34%, M+ 3 CI - C3H6), 207 (100%, M+ 35CI - C3H6).
EXAMPLE 32. 2,4-Dichloro-8-isopropylquinoline
Figure imgf000070_0001
C9H13N Cι2HnCI2N Mol. Wt: 135.2 Mol. Wt: 240.1
2-lsopropylaniline (7.0 g, 52 mmol) and malonic acid (8.1 g, 78 mmol) were heated under reflux in phosphorus oxychloride (40 ml) for 6 hours. Standard aqueous workup gave the crude product as a brown solid. Soxhlet extraction (hexane, 4h) ofthe crude yielded the pure product as a colourless oil. Yield 3.3 g, 26%. Found M+: 239.0250.
Figure imgf000070_0002
requires 239.0269. δH: 8.00 (1 H, dd, 8.3, 1.4, H5), 7.66 (1 H, dd, J 7.3, 1.4, H7), 7.57 (1 H, dd, J
8.3, 7.3, H6), 7.45 (1 H, s, H3), 4.22 (1 H, septet, J 6.9, CHMe2), 1.34 (6H, d, J
6.9, (CH3)2). δc: 148.5, 147.4, 146.2, 144.5 (C2, C4, C8, C8a), 127.8, 127.4, 125.3 (C4a),
121..8,_.1.2-1 -6,~.27.5 (CHMe2), 23.6 ((CH3)2). nmax /cm-1: 1607, 1564 (s, C=N, C=C). m/z 241 (26%, M+ 37c|35ci), 239 (42%, M+ 35ci2), 226 (57%, M+ 3 c|35ci
- CH3), 211 (36%, M* - C2H4).
EXAMPLE 33. 2,4-Dimethoxy-8-isopropylquinoline
Figure imgf000071_0001
C12Ht1CI2N C14H17N02 Mol. Wt: 240.1 Mol. Wt: 231.3
2,4-Dichloro-8-isopropylquinoline (EXAMPLE 32) (2.0 g, 8.3 mmol) was heated under reflux in methanolic sodium methoxide (1.5 g Na in 75 ml MeOH) for 48 hours, then cooled and poured into cold water. The product was obtained by filtration as white needles. Yield 1.1 g, 57%. Melting point 57-59°C Found M+: 231.1252. C14H17N02 requires 231.1259. δH: 7.95 (1 H, dd, J 8.2, 1.5, H5), 7.55 (1 H, dd, J 7.4, 1.5, H7), 7.34 (1 H, dd, 8.2, 7.4, H6), 6.26 (1 H. s, H3), 4.19 (1H, septet, J 6.9, ArCH(Me)2), 4.10 (3H, s, OMe), 3.99 (3H, s, OMe), 1.42 (6H, d J 6.9, CH(CH3)2). δc: 164.3, 162.4 (C2, C4), 145.0, 144.7 (C8, C8a), 125.8, 123.1 , 119.3 (C5, C6, C7), 119.1 (C4a), 90.1 (C3), 55.7 (OMe), 53.2 (OMe), 28.1 (CHMe2), 23.1 ((CH3)2). nmax /cm'1 : 1619, 1602, 1586 (s, C=C, C=N). m/z: 231 (73%, M+), 230 (56%, M+ - H), 216 (100%, M+ - Me), 203 (44%), 189
(26%). EXAMPLE 34. 2,4-Dichloro-8-phenoxyquinoHne
Figure imgf000072_0001
C12HnNO C,6H9CI2NO
Mol. Wt: 185.2 Mol. Wt: 290.1
2-Phenoxyaniliπe (3.9 g, 21 mmol), malonic acid (3.3 g, 32 mmol) and phosphorus oxychloride (30 ml) were heated under reflux for 6 hours. Standard aqueous workup gave a brown solid, which was extracted continuously with hexane for 5 hours to give a dark orange solid. Further purification by column chromatography (9:1 hexane:EtOAc) was necessary to yield the pure product
(Rf 0.65) as yellow needles. Yield 2.2 g, 36%. Melting point 90-92°C
Found M+: 289.0041. C15H9 35ci2NO requires 289.0061. δH: 7.88 (1 H, dd, 8.4, 1.2, H5), 7.57 (1 H, s, H3), 7.49 (1 H, dd, J 8.4, 7.9, H6),
7.42-7.37 (2H, m, H2' and H6'), 7.19 (1 H, tt, J 7.4, 1.1 , H4'), 7.16-7.12 (2H, m, H3' and H5'), 7.08 (1 H, dd, J 7.9, 1.2, H7). δc: 156.4 (C2), 154.0 (C4), 149.7 (C8a), 144.4, 140.6 (CT and C8), 130.0
(ArH), 127.9 (ArH), 126.7 (C4a), 124.5 (ArH), 123.0 (ArH), 120.5 (ArH), 118.1
(ArH), 1 16.9 (ArH). nmax/cnr1: 1590, 1572 (s, C=N, C=C). m/z: 293 (27%, M+ 37ci2), 292 (18%, M+ 3 ci2 - H), 291 (46%, M+ 3 c|35ci),
290 (77%, M+ 37C|35CI - H), 289 (70%, M+ 35ci2), 288 (100%. M+ 35d2 - H), 209
(27%).
EXAMPLE 35. 2,4-Dimethoxy-8-phenoxyquinoline
Figure imgf000073_0001
C15H9CI2NO C17H15l .03 Mol. Wt- 290 1 Mol. Wt' 2S1.3
2,4-Dichloro-8-pfιenoxyquinoline (EXAMPLE 34) (0.70 g, 2.4 mmol) was heated under reflux in excess methanolic sodium methoxide (from 1.0 g Na in 60 ml MeOH) for 48 hours. The mixture was poured into cold water, left to stand for 1 hour and then filtered to give the title compound as a yellow powder. Yield 0.50 g, 74%. Melting point 90-92°C. Found M+: 281.1065. Cι7H15N03 requires 281.1052. δH: 7.87 (1 H, dd, J 7.9, 1.5, H5), 7.35-7.23 (4H, m, ArH), 7.02-6.95 (3H, m, ArH), 6.20 (1 H, s, H3), 3.98 (3H, s, OMe), 3.72 (3H, s, OMe). δc: 164.0, 163.2, 159.3, 150.4 (C2, C4, C8, C1'), 140.0 (C8a), 129.3 (ArH), 123.1 (ArH), 121.9 (ArH), 121.1 (C4a), 120.9 (ArH), 1 18.0 (ArH), 1 17.3 (ArH), 91.0 (C3), 53.9 (OMe), 53.4 (OMe). nmaχ/cm-1: 3066 (m, Ar-H), 1623, 1603, 1583 (s, C=C, C=N), 1249, 1211, 1060 (s, C-O-C) m/z 281 (100%, M+), 280 (68%, M+ - H), 269(21%), 201 (19%), 169(23%), 151 (40%).
EXAMPLE 36. 2,4-Dichloro-6-hydroxyquinoline
Figure imgf000073_0002
2,4-Dichloro-6-methoxyquinoline (EXAMPLE 14) (2.0 g, 8.8 mmol) was dissolved in dry dichloromethane (80 ml) and cooled to -78°C. Boron tribromide (10 ml of a 1 M solution in dichloromethane, 10 mmol) was added dropwise over 15 minutes, with stirring. The reaction mixture was then allowed to attain room temperature overnight before shaking with ice-cold water. An ochre solid was precipitated, which was redissolved by the addition of ether ( 00 ml). The mixture was then extracted with ether (3 x 75 ml). The combined organic layers were extracted with 2M sodium hydroxide (2 x 30 ml), and then dilute HCI was added to the combined aqueous extracts until a precipitate appeared. Extraction with ether (3 x 75 ml) followed by drying of the ether extracts (MgS0 ) and removal of the solvent in vacuo yielded the pure quinoline as a pale yellow solid. Yield 1 .0 g, 53%. Melting point 182-184°C
Found M+: 212.9767. C9H5 35ci2NO requires 212.9748. δH (DMSO d6): 10.7 (1 H, s, OH), 7.93 (1 H, d, J 9.1 , H8), 7.84 (1 H, s, H3), 7.49 (1H, dd, 9.1 , 2.6, H7), 7.42 (1H, d, J 2.6, H5) δc (DMSO d6): 157.8, 145.7, 142.7, 141.6 (C2, C4, C6, C8a), 130.7, 126.4
(C4a), 124.5, 122.1 , 105.1 (C3). nmaχ /cm-1 : 3200-3000 (m br, OH), 1616, 1560 (s, C=C, C=N). m/z: 215 (87%, M+ 35c|37ci), 213 (98%, M+ 35d2), 178 (76%, M+ - CI), 143 (34%, M+ - 2CI).
EXAMPLE 37. 6-Chloro-2,4-dimethoxyquinoline
Figure imgf000074_0001
CgrLCUN CnH^Cl Oa
Mol. Wt: 232.5 Mol. Wt: 223.7
2,4,6-Trichloroquinoline (EXAMPLE 15) (1.5 g, 64 mmol) was heated under reflux in excess methanolic sodium methoxide (1.0 g Na in 60 ml MeOH) for 48 hours, then cooled and poured into cold water. The product was obtained by filtration as white needles.
Yield 1.3 g, 91%. Melting point 47-49°C
Found M+: 223.0746. C11H10 35CINO2 requires 223.0400. δπ: 7.93 (1 H, d, 2.4, H5), 7.62 (1 H, d, 8.9, H8), 7.44 (1 H, dd, J8.9, 2.4, H7), _
6.14 (1H, s, H3), 3.96 (3H, s, MeO), 3.90 (3H, s, MeO). δc: 164.0 (C2), 163.0 (C4), 145.5 (C8a), 130.5 (C8), 128.9 (C6), 128.4 (C7),
121 .2 (C5), 120.0 (C4a), 91.5 (C3), 55.9 (OMe), 53.5 (OMe). nmax /cm-l: 1622, 1601 , 1576 (s, C=C, C=N), 1208 (s, C-O). m/z: 225 (38%, M+ 37ci), 224 (28%, M+ 3 Q - H), 223 (100%, M+ 35ci), 222
(53%, M+ 35d - H), 193 (20%), 162 (13%), 151 (17%).
EXAMPLE 38. 2,4-Dichloro-6-fluoroquinoline
Figure imgf000075_0001
CRHBFN C9H4CI2FN
Mol. Wt : 111.1 Mol. Wt: 216.0
4-Fluoroaniline (7.0 g, 63 mmol), malonic acid (9.8 g, 94 mmol) and phosphorus oxychloride (60 ml) were heated under reflux for 6 hours, then poured into crushed ice and made alkaline with aqueous NaOH. Filtration gave the crude product as a brown solid, which was continuously extracted (hexane, 4 h) to yield the title compound as a pale yellow powder. Yield 5.2 g, 38%. Melting point 90- 92°C (Found C: 49.98, H: 1.57, N: 6.23%. C9H CI2FN requires C: 50.04, H: 1.87, N: 6.48%.) Found M+: 214.9703. C9H435CI2FN requires 214.9705. δH: 8.04 (1 H, dd, J 9.3, 5.1(JH-F), H8), 7.80 (1 H, dd, J 9.1 (JH.F), 2.8, H5), 7.56
(1H, ddd, J 9.3, 8.0 (JH-F 2.8, H7), 7.53 (1 H, s, H3). δc: 161.3 (d, Jc-F 251 , C6), 149.3 (C2), 145.1 (C4), 143.6 (d, JC-F 5.5, C8a),
131.7 (d, Jc-F 9-2, C8), 126.3 (d, C.F 10.4, C4a), 122.7 (C3), 121.7 (d, JC-F
25.7, C7), 108.3 (d, C-p 24.9, C5). nmaχ /cm-1: 1620, 1580 (s, C=C, C=N). m/z: 217 (79%, M+ 5c|3 ci), 215 (100%, M+ 35ci2), 180 (54%, M+ - CI), 145
(30%, M+ - 2CI).
EXAMPLE 39. 2.4-Dimethoxy-6-fluoroquinoline
NaOMe, MeOH
Figure imgf000076_0002
Figure imgf000076_0001
CβH4CI FN CnHfoF Oz Mol. Wt: 216.0 Mol. Wt: 207.2
2,4-Dichloro-6-fluoroquinoline (EXAMPLE 38) (3.5 g, 16.2 mmol) was heated under reflux in excess sodium methoxide (2.0 g Na in 100 ml MeOH) for 24 hours.
After aqueous work up the product was obtained as off-white needles, Rf (4:1 hexane:EtOAc) 0.50. Yield 2.5 g, 75%. Melting point 74-77°C.
Found M+: 207.0692. Cn Hι0 NO2 requires 207.0696. δπ: 7.74 (1 H, dd, 9.1 , 5.2 ( H-F). H8), 7.65 (1 H, dd, J 9.5(JH.F), 3.0, H5), 7.34
(1 H, ddd, J 9.1 , 8.3(JH-F), 3.0, H7), 6.22 (1 H, s, H3), 4.03 (3H, s, OMe), 3.97
(3H, s, OMe). δc: 163.4 (C2/C4), 158.8 (d, Jc-F 242.2, C6), 143.8 (C8a), 128.8 (d, JC-F 8.5,
C8), 119.7 (d, Jc-F 9.0, C4a), 119.1 (d, JC-F 24.8, C7), 106.2 (d, JC-F 23.7, C5),
91.3 (C3), 55.8 (OMe), 53.4 (OMe). nmaχ/cnr1: 1616, 1581 (s, C=N and C=C), 1207 (s, C-O). m/z 207(100%, M+), 206 (88%, M+- H), 176 (40%, M+- OMe), 120(37%), 94 (17%, C6H3F+). EXAMPLE 40. 2,4-Dichloro-5,7-dimethylquinoline
Figure imgf000077_0001
CeHnN CnHgClzN Mol Wt 121 2 Mol Wt 226 1
3,5-Dimethylaniline (5.0 g, 41 mmol), malonic acid (6.4 g, 0.62 mmol) and phosphorus oxychloride (40 ml) were heated under reflux for 5 hours. The mixture was poured into crushed ice and made alkaline with 5M NaOH, left to stand overnight, and then filtered to give the crude product as a brown solid. Soxhlet extraction with hexane gave the title compound as yellow needles. Yield 5.9 g, 64%. Melting point 79-81 °C
Found M+: 225.0114. C H9 35CI2N requires 225.0112. δπ: 7.62 (1 H, s, H8), 7.33 (1 H, s, H6), 7.17 (1H, s, H3), 2.93 (3H, s, 5-Me),
2.46 (3H, s, 7-Me). δc: 150 8 (C2), 149.4 (C4), 144.6, 141.6, 135.5 (C5, C7, C8a), 133.8, 127.6, 123.1 (C3. C6, C8), 122.9 (C4a), 25.4 (Me), 2 .8 (Me). nmax/cm-1: 1622, 1562 (s, C=C, C=N). m/z 229 (11%, M+ 37d2), 227 (60%, M+ c|35ci), 225 (100%, M+ 35d2), 212 (28%, M+ 3 CI35CI - Me), 210 (33%, M+ 35d2 - Me), 190 (9%, M+ - CI).
EXAMPLE 41. 2,4,5,7 -Tetramethoxyquinoline
Figure imgf000077_0002
CnH9CI2N02 Ci3H15N04 Mol Wt 258 1 Mol Wt 249 3
2,4-Dιchloro-5,7-dιmethoxyquinoline (EXAMPLE 16) (0.16 g, 0.62 mmol) was heated under reflux in methanolic sodium methoxide (0 50 g Na in 25 ml MeOH) for 48 hours. After cooling, the mixture was poured into water and neutralised
(0.5M HCI), then left to stand for 1 hour before filtering to give the product as white needles. Yield 0.12 g, 78%. Melting point 129-131 °C.
Found M+: 249.0097. C13H15NO4 requires 249.1001. δH: 6.81 (1H, d, 2.2rH8 , 6^8 (1 H, d, J2.2, H6), 6.09 (1 H, s, H3), 4.02 (3H, s, OMe), 3.94 (3H, s, OMe), 3.90 (6H, s, 2 x OMe). δc: 166.3, 164.7, 161.6, 158.5, (C2, C4, C5, C7), 151.7, 105.8 (C4a), 100.1 ,
97.0, 89.3 (C6, C8, C3), 56.5, 56.3, 55.8, 53.6 (4 x OMe). nmaχ/cnr1: 1610, 1594 (s, C=N, C=C), 1210, 1063 (s, C-O-C). m/z: 249 (100%, M+), 248 (85%, M+ - H), 220 (14%), 143 (16%).
EXAMPLE 42. 2,4-Dimethoxy-5,7-dimethylquinoline
Figure imgf000078_0001
CnHgCfeN C13H15N02
Mol. Wt: 226.1 Mol. Wt : 217.3
2,4-Dichloro-5,7-dimethylquinoline (EXAMPLE 40) (2.0 g, 8.8 mmol) was heated under reflux in methanolic sodium methoxide (2.0 g Na in 75 ml MeOH) for
48 hours. The mixture was poured into cold water, left to stand for 1 hour, and then filtered to give the title compound as white needles. Yield 1.6 g, 84%.
Melting point 75-77°C
Found M+: 217.1091. C13H15N02 requires 217.1103. δπ: 7.42 (1 H, s, H8), 6.89 (1 H, s, H6), 6.11 (1 H, s, H3), 4.02 (3H, s, 2-OMe),
3.89 (3H, s, 4-OMe), 2.73 (3H, s, Me), 2.40 (3H, s, Me). δc: 166.6 (C2), 163.3 (C4), 149.0, 139.3, 135.1 (C5, C7, C8a), 128.5, 125.0,
116.3 (C4a), 90.1 (C3), 55.3 (OMe), 53.2 (OMe), 24.2 (Me), 21.3 (Me). nmaχ/cm-1: 1615, 1584 (s, C=C, C=N), 1208, 1038 (s, C-O-C). m/z: 217 (94%, M+), 216 (100%, M+ - H), 202 (49%, M+ - Me), 187 (87%,
M -2Me), 172 (50%, M+ - 3Me), 115 (53%). EXAMPLE 43. 2,4-Dichloro-5-methyl-8-nitroquinoline
Figure imgf000079_0001
C7HβN202 C1DH6CI2N202 Mol. Wt: 152.2 Mol. Wt: 257.1
5-Methyl-2~nitroaniline (3.0 g, 20 mmol), malonic acid (3.1 g, 30 mmol) and phosphorus oxychloride (25 ml) were heated under reflux for 7 hours, and then poured into crushed ice and made alkaline (5M NaOH) before filtering to give a crude brown solid. Soxhlet extraction (hexane, 6 h) of the crude solid gave the pure product as yellow needles. Yield 1.6 g, 31 %. Melting point 126-128°O
(Found C: 48.70, H: 2.76, N: 10.27%. C10H6CI2N2O2 requires C: 46.72, H: 2.35,
N: 10.90%.)
Found M+: 255.9804. C10H635CI2N2O2 requires 255.9806. δH: 7.81 (1 H, d, J 8.0, H7), 7.60 (1 H, s, H3), 7.45 (1 H, d, J 8.0, H6), 3.08 (3H, s, 5-Me). δc 152.0, 147.4, 145.3, 141 .6, 141.1 (C2, C4, C8, C8a, C5), 130.0, 126.2
(C6, C7), 125.5 (C4a), 124.6 (C3), 26.1 (5-Me). nmaχ /cm-1: 1609, 1567 (m, C=C, C=N), 1528 (s, N=0), 874 (m, C-N). m/z: 260 (12%, M+ 37CI2), 258 (55%, M+ 3 c|35ci), 256 (100%, M+ 35C12), 228 (21 %), 226 (29%, M+ - NO).
EXAMPLE 44. 2,4-Dimethoxy-5-methyl-8-nitroquinoline
Figure imgf000080_0001
CιoHeCI2N202 C12H12N2- Mol. Wt 257.1 Mol. Wt: 246.2
2,4-Dichloro-5-methyl-8-n.troquinoline (EXAMPLE 43) (1.0 g, 3.9 mmol) was heated under reflux in excess methanolic sodium methoxide (1.0 g Na in 50 ml
MeOH) for 48 hours. The mixture was then cooled, poured into water and filtered to give the product as a brown powder. Yield 0.4 g, 41%. Melting point >250°C
Found M+: 248.0815. C12H12N20 requires 248.0797. δH: 7.73 (1H, d, J 7.9, H7), 7.09 (1 H, d, J7.9, H6), 6.27 (1 H, s, H3), 4.01 (3H, s, OMe), 3.96 (3H, s, OMe), 2.82 (3H, s, 5-Me). nmax cm-1: 1606 (s, C=C or C=N), 1523 (s, N=0), 1208 (s, C-O). m/z: 248(31%, M+), 247(20%, M÷-H), 218(18%), 204 (16%), 143(49%), 100
(100%).
EXAMPLE 45. 8-Atτ.ino-2,4-dich.oro-5-methylquinoline
Figure imgf000080_0002
2,4-Dichloro-5-methyl-8-nitroquinoline (EXAMPLE 43) (0.30 g, 1.2 mmol) and sodium dithionite (1 g, 5.8 mmol) were heated under reflux in 50% aqueous ethanol (50 ml) for 4 hours. The mixture was made alkaline with 1 M NaOH, and then extracted with ether (3 x 30 ml). The combined organic extracts were dried over magnesium sulfate, and then the solvent evaporated under reduced pressure to give the product as a yellow powder. Yield 0.22 g, 83%. Melting point
1 6-1 8°O
Found M+: 226.0244. C10H8 5CI2N2 requires 226.0065. δH: 7.41 (1 H, s, H3), 7.14 (1 H, dd, J7.9, 0.5, H6), 6.86 (1 H, d, J.7.9.-H7), 4.&4
(2H, br s, NH2), 2.85 (3H, d, J 0.5, 5-Me). δc: 146.4, 144.7, 142.2, 139.9 (C2, C4, C8, C8a), 131.8, 125.0 (C5), 123.8,
122.9 (C4a), 11 1.8 (C3), 24.4 (5-Me). nmax /cnrr1: 3422, 3322 (w, N-H), 1610, 1554 (s, C=C, C=N). m/z: 230 (11%, M+ 37d2), 228 (67%, M+ 3 c|35ci), 226 (100%, M+ 35d2), 225
(49%, M+ - H).
EXAMPLE 46. 2,4-Dimethoxy-5-methylquinoline
Figure imgf000081_0001
2,4-Dichloro-5-methylquinoline (EXAMPLE 17) (0.12 g, 0.57 mmol) was heated under reflux in methanolic sodium methoxide (0.50 g Na in 40 ml MeOH) for 40 hours. After cooling the mixture was poured into ice-cold water, and left to stand for 1 hour before filtering under reduced pressure to give the product as off-white needles. Yield 85 mg, 73%. Melting point 58-60°C
Found M+: 203.0953. Cι2H-|3N02 requires 203.0946. δH: 7.62 (1 H, d, J 8.3, H5), 7.42 (1 H, dd, J 8.3, 7.2, H7), 7.07 (1 H, d, J 7.2, H6),
6.19 (1 H, s, H3), 4.04 (3H, s, OMe), 3.93 (3H, s, OMe), 2.79 (3H, s, 5-Me). δc: 166.6, 163.1 (C2, C4), 148.8, 135.5 (C8a, C5), 129.2, 126.4, 125.5 (C6, C7,
C8), 1 18.6 (C4a), 90.8 (C3), 55.3 (OMe), 53.2 (OMe), 24.3 (5-Me). nmax /cm-1: 161 1 , 1588 (s, C=C, C=N), 1207 (s, C-O). m/z: 203 (100%, M+), 202 (49%, M+ - H), 173 (15%). EXAMPLE 47. 2,4-Dichloro-7-methyl-8-nitroquinoline
Figure imgf000082_0001
C7Hal.202 C,0H6CI2N2O2 Mol. Wt: 152.2 Mol. Wt. 257.1
3-Methyl-2-nitroaniline (EXAMPLE 2) (4.0 g, 26 mmol) and malonic acid (4.1 g, 39 mmol) were heated in phosphorus oxychloride (40 ml) for 6 hours. Standard workup and Soxhlet extraction (hexane, 4h) yielded the title compound as yellow needles. Yield 0.90 g 13%. Melting point 108-110°C. Found M+: 255.9797. C10H6 35CI2N2O2 requires 255.9806. δπ: 8.20 (1 H, d, J 8.6, H5), 7.57 (1 H, s, H3), 7.55 (1 H, d, J 8.6, H6), 2.55
(3H, s, Me). δc: 152.3, 144.3, 139.6, 132.9 (C2, C4, C8, C8a), 130.2 (CH), 126.3, 125.6
(CH), 124.0, 123.3 (CH), 17.6 (Me) nmax/cm-1: 1623, 1574 (s, C=C, C=N), 1537 (s, N=0). m/z: 258 (48%, M+ 37CI35CI), 256 (73%, M+ 35d2), 174 (100%), 139 (56%).
EXAMPLE 48. 4-Methoxy-8-methyl-3-(3-methylbut-2-enyl)-1 H-quinolin- 2-one
Figure imgf000082_0002
C,7H21N02 C,6H19N02 Mol. Wt: 271.4 Mol Wt ■ 257.3 2,4-Dimethoxy-8-methyl-3-(3-methyl-2-buteπyl)quinoline (EXAMPLE 23) (0.40 g, 1.5 mmol) and 4-dimethylaminopyridine (0.18 g, 1 .5 mmol) were dissolved in dry dichloromethane (20 ml) and cooled to -78°C. lodotrimethylsilane (0.30 g, 1 .5 mmol) was added dropwise, and the mixture allowed to attain room temperature overa~period- of 1 hour—and then stirred for a further 40 hours at room temperature. The mixture was then poured into water, washed with 0.1 M hydrochloric acid (20 ml) and extracted with dichloromethane (3 x 20 ml). The combined organic extracts were dried over MgS0 and the solvent removed in vacuo to give a brown residue. Column chromatography (1 :1 hexane:EtOAc) furnished the pure quinoline (Rf 0.31 ) as a pale yellow solid. Yield 0.2g, 55%.
Melting point 135-138°C.
Found M+: 257.1426. C16HιgN02 requires 257.1416. δH: 10.20 (1 H, br s, NH), 7.63 (1 H, d, J 8.0, H5), 7.29 (1 H, d, J 7.3, H7), 7.1 1 (1 H, dd, J 8.0, 7.3, H6), 5.29 (1 H, t, J 6.9, Me2C=CH), 3.92 (3H, s, OMe), 3.40 (2H, d, J 6.9,
Figure imgf000083_0001
2.52 (3H, s, 8-Me), 1.81 (3H, s, C=CCH3), 1.69
(3H, s, C=CCH3). δc: 164.8, 162.4 (C2. C4), 135.8, 132.5 (C8, C8a), 131.2 (CH), 123.3, 122.2 (C4a and =CMe2), 121.9 (CH), 121.5 (CH), 121.0 (CH), 117.1 (C3), 61.8 (OMe), 25.7 (Me), 23.5 (CH2), 18.0 (Me), 17.1 (Me). nmax/cm-1 : 3400 (w, NH), 1636 (s, C=O). m/z 257 (66%, M+), 242 (92%, M+ - Me), 214 (100%, M+ - CMe2), 188 (54%, M+ - Me2C=CHCH2).
EXAMPLE 49. 2,4-Diisopentyloxy-8-methylquinoline
Figure imgf000083_0002
C10H7CI2N C20H2SNO2 Mol. Wt: 212.1 Mol. Wt: 315.5 2,4-Dichloro-8-methylquinoline (EXAMPLE 9) (0.50 g, 2.4 mmol) was heated at 90°C in excess sodium isopentyloxide/isopentyl alcohol (1 .0 g Na in 50 ml isopentyl alcohol) for 48 hours. The mixture was then cooled, neutralised with 2M HCI, and extracted with ether (3 x 30 ml). The combined organic layers were dried -(MgS0 ) and he- solvent evaporated to yield the pure product as a colourless oil.
Yield 0.31 g, 41 %.
Found M+: 315.2199. C20H29NO2 requires 315.2198. δH: 7.91 (1 H, d, J 7.5, H5), 7.43 (1 H, d, J 7.0, H7), 7.19 (1 H, dd, J 7.5, 7.0, H6), 6.19 (1 H, s, H3), 4.52 (2H, t, J 6.8, OCt±?), 4.11 (2H, t, J 6.5, OC b), 2.66 (3H, s, 8-Me), 1.95-1.70 (6H, m, 2 x CHMe2 and 2 x OC^CH^), 1 .00-0.98 (12H, m, 2 x CH(CH3)2). δc: 163.9, 162.9 (02, C4), 146.3 (C8a), 135.2 (C8), 130.4, 122.9, 120.0 (C5, C6, C7), 1 19.4 (C4a), 91.3 (C3), 67 2(OCH2), 64.5 (OCH2), 38.4 (0CH2CH2), 38.0 (OCH2CH2), 25.7 (8-Me), 23.2, 23.0, 18.5. nmax / cm"1 : 1612, 1601 (s, C=C, C=N). m/z: 315 (32%, M+), 245 (49%), 175 (100%, C10H9NO2 +).
EXAMPLE 50. 2,4-Dimethoxy-3-propylquinoline
Figure imgf000084_0001
CuHnNO, C,„H17N02 Mol Wt 189 2 Mol Wt 231 3
A solution of 2,4-dimethoxyquinoline (EXAMPLE 4A) (0.30 g, 1 .6 mmol) in THF (15 ml) was cooled to 0°C under argon, n-butyllithium (0.80 ml of 2.5M solution in hexane) was added, and the mixture stirred for 1 hour at 0°O 1-lodopropane (0.34 g, 2 mmol) was added dropwise, the mixture was stirred at 0°C for 30 minutes and then was allowed to warm to room temperature overnight. The reaction mixture was poured into water and extracted with ether (3 x 20 ml). The combined organic layers were dried (MgS04) and the solvent removed in vacuo to give a yellow oil, which was purified by column chromatography (9:1 hexane:EtOAc) to give the title compound as a colourless oil, Rf 0.67 (9:1 hexane.EtOAc). Yield 65 mg, 17% (approximately 150 mg of starting material also recovered). "Found M+: 231.1267. C14Hι7N02 requires 231 .1259. δπ: 7.90 (1 H, dd, 8.2, 1.4, H5), 7.82 (1H, br. d, J 8.2, H8), 7.55 (1 H, ddd, J 8.2, 6.9, 1.4, H7), 7.35 (1H, ddd, J 8.2, 6.9, 1.0, H6), 2.70 (2H, t, J 7.7, CH2CH2CH3), 1.63 (2H, m, CH2CH2CH3), 1.00 (3H, t, J 7.4, CH2CH2CH3) δc: 162.7, 161.7 (C2. C4), 146.1 (C8a), 128.8, 127.3, 123.6, 122.0 (C5, C6, C7, C8), 121.1 , 118.0 (C4a and C3), 62.3 (OMe), 53.7 (OMe), 26.2 (CTH2), 22.7
(C2Η2), 14.4 (C3Η3). nmax /cm"1: 3064, 2956, 2871 (m, C-H), 1620, 1573 (s, C=C, C=N), 1086, 1012 (s, C-O-C) m/z: 231 (53%, M+), 216 (38%, M+ - Me), 202 (61%, M+ - CH3CH ).
EXAMPLE 51. 2,4-Dimethoxy-3-(1'-hydroxy-n-hexyl)quinoline
Figure imgf000085_0001
CnHn 02 C17H23N03
Mol. Wt: 189.2 Mol Wt: 289.4
2,4-Dimethoxyquinoline (EXAMPLE 4A) (0.30 g, 1.6 mmol) in THF (20 ml) was cooled to 0°C, and n-butyllithium (0.80 ml of a 2.5M solution in hexanes) was added with stirring. Stirring was continued at 0°C for 45 minutes. Hexanal (0.24 g, 2.4 mmol) was added and the mixture stirred at 0°C for 15 minutes, then allowed to warm to room temperature for 45 minutes. The flask contents were poured into water, and the mixture extracted with diethyl ether (3 x 30 ml). The combined organic extracts were dried over MgS0 and the solvent removed in vacuo to give a dark yellow oil. Column chromatography (2:1 hexane:EtOAc) furnished the pure product as a pale yellow oil. Yield 0.21 g, 45%.
Found M+: 289.1670. C17H23N03 requires 289.1678. δH: 7.93 (1 H, dd, J 8.1 , 1.3, H5), 7.83 (1 H, dd, J 8.4, 1 .0, H8), 7.60 (1 H, ddd, J
8.4, 7.0, 1.3, H7), 7.40 (1H, ddd, 8.1 , 7.0, -1.0,- H6-),- 5.1-1 -(1 Hrm-,-C-HQH), 4.13
(3H, s, OMe), 4.00 (3H, s, OMe), 3.38 (1 H, d, J 11.5, OH), 2.01 (1 H, m, ArCH(OH)CH§Hb), 1.77 (1 H, m, ArCH(OH)CHaH_b), 1.39-1.25 (6H, m), 0.90
(3H, m, ArCH(OH)(CH2)4CH3). nmax/cm-1: 3995 (m br, OH), 1644, 1602, 1574 (s, C=C, C=N). m/z: 289 (12%, M+), 218 (100%, M+ - CH3(CH2)4).
EXAMPLE 52. 8-Bromo-2,4-dichloroquinoline
Figure imgf000086_0001
C6HβBrN C9H4BrCI2N Mol Wt 172 0 Mol. Wt: 276 9
2-Bromoaniline (2.0 g, 12 mmol), malonic acid (1.9 g, 18 mmol) and phosphorus oxychloride (30 ml) were heated under reflux for 6 hours. After alkaline aqueous workup and filtration, the crude solid product was continuously extracted with hexane for 6 hours to give the pure quinoline as a pale yellow powder. Yield 1.0g, 31%.
Melting point 10 -103°C
Found M+: 276.8884 (81Br), 274.8898 (/δβr). C9H4Br35ci2N requires 276.8885 and 274.8905. δH: 8.17 (1 H, dd, 8.3, 1.3, H5), 8.11 (1 H, dd, J7.6, 1.3, H7), 7.57 (1 H, s. H3), 7.50 (1 H, dd, J 8.3, 7.6, H6). δc: 150.9, 145.5, 144.7, (C2, C4, C8a), 135.3, 128.2, 126.5 (C4a), 124.1 , 123.0 (one quaternary C missing). nmax /cnr1: 1573 (s, C=N). m/z: 279 (41%, M+ 79BΓ3 CI2 and M+ 8lBr37C|35ci), 277 (100%, M+ 8lβr35ci2 and M+, 79Br37C|35d), 275 (60%, M+ , 79Br35d2), 242 (26%, M+ (277) - 35ci), 161 (17%, M+ - Br, CI).
EXAMPLE 53. 8-Bromo-2,4-dimethoxyquinoline
Figure imgf000087_0001
C9H4BrCI2N C1ιH10BrNO2 Mol Wt 276 9 Mol Wt 268 1
8-Bromo-2,4-dichloroquinoline (EXAMPLE 52) (0.80 g, 2.9 mmol) was heated under reflux in excess methanolic sodium methoxide (1 0 g Na in 50 ml MeOH).
After aqueous workup and filtration the product was isolated as white needles.
Yield 0.50 g, 64%. Melting point 120-123°C (Found C: 49.07, H: 3.55, N: 5.10%.
CιιHιoBrNO2 requires C: 49.28, H: 3.76, N: 5.10%.)
Found M+: 266.9872. C1 1H10 79BrNO2 requires 266.9894. δH: 8.03 (1 H, dd, J 8.2, 1.4, H5), 7.93 (1 H, dd, J 7.5, 1.4, H7), 7.18 (1 H, dd,
J 8.2, 7.5, H6), 6.27 (1 H, s, H3), 4.13 (3H, s, OMe), 4.00 (3H, s, OMe). δc 164.1 , 144.2, 133.7 (CH), 123.6 (CH), 122.3, 121.6 (CH), 120.5, 91.2
(C3), 56.1 (OMe), 53.8 (OMe) (one quaternary C missing). nmax / cm"1: 1620, 1600, 1565 (s, C=C and C=N). m/z: 269 (100%, M+ 81Br), 268 (92%, M+ 81Br - H), 267 (96%, M+ 9BΓ), 266
(81%, M+ 79βr - H), 243 (42%), 189 (40%), 188 (45%, M+ - Br).
EXAMPLE 54. 2.4-Dichloro-8-iodoquinoline
Figure imgf000088_0001
C6HBIN CβH4CI2ll . Mol. Wt: 219.0 Mol. Wt: 323.9
2-lodoaniline (7.0 g, 32 mmol) and malonic acid (5.0 g, 48 mmol) were heated under reflux in phosphorus oxychloride (40 ml) for 5 hours. After standard workup and Soxhlet extraction of the crude with hexane, the pure product was obtained as bright yellow needles, yield 1.3 g, 12.5%. Rf (9:1 hexane:EtOAc) 0.65. Melting point 80-82°C Found M+: 322.8764. CgH435ci2IN requires 322.8767. δH: 8.37 (1 H, dd, J 7.5, 0.9, H7), 8.16 (1 H, dd, J 8.4, 0.9, H5), 7.54 (1 H, s, H3),
7.34 (1 H, dd, J 8.4, 7.5, H6). δc: 149.8 (C2), 146.2 (C8a), 143.5 (C4), 141.1 (C7), 127.8, 124.5 (C4a),
123.9, 121.8 (C3), 100.8 (C8). nmax / cm"1: 1595, 1575 (s, C=C, C=N), 1271 (s). m/z: 327 (13%, M+ 37ci2), 325 (74%, M+ 3 CI 35ci), 323 (100%, M+ 35d2), 196
(25%, M+ (323) - 1), 161 (29%, M+ - 1, CI).
EXAMPLE 55. 2,4-Dimethoxy-8-iodoquinoline
Figure imgf000088_0002
C9H4CI2IN Cι,H10INO2 Mol. Wt: 323.9 Mol Wt: 315.1 2,4-Dichloro-8-iodoquinoline (EXAMPLE 54) (1.0 g, 3 mmol) was heated under reflux in methanolic sodium methoxide (1 .0 g Na in 50 ml MeOH) for 40 hours. After aqueous workup and filtration the title compound was obtained as pale yellow needles. Yield 0.81 g, 86%. Melting. poJD„t:„105-107°C. (Found C: 41.47, H: 3.19, N: 3.91%. CnHioJ O? requires C: 41.93, H: 3.20, N: 4.45%.) Found M+: 314.9756. C11H 0INO2 requires 314.9758. δH: 8.18 (1 H, dd, J 7.4, 1.4, H7), 8.04 (1 H, dd, J 8.1 , 1.4, H5), 7.05 (1 H, dd, J 8.1 , 7.4, H6), 6.24 (1H, s, H3), 4.13 (3H, s, OMe), 3.99 (3H, s, OMe). δc 164.2, 164.1 (C2 and C4), 146.1 (C8a), 140.3 (C7), 124.5, 122.5 (C5 and C6), 119.5 (C4a), 100.4 (C8), 91.0 (C3), 56.1 (OMe), 54.0 (OMe). nmaχ / cm-1: 1619, 1562 (s, C=C, C=N), 1213 (s, C-O). m/z: 315 (100%, M+), 314 (26%, M+ - H), 285 (12%).
EXAMPLE 56. 6-Bromo-2,4-dichloroquinolϊne
Figure imgf000089_0001
C6H6Br C9H,BrCI2N Mol. Wt: 172.0 Mol. Wt: 276.9
4-Bromoaniline (7.0 g, 41 mmol), malonic acid (6.3 g, 61 mmol) and phosphorus oxychloride (50 ml) were heated under reflux for 6 hours. After standard workup and Soxhlet extraction with hexane the product was obtained as yellow needles.
Yield 3.2 g, 28%. Melting point 132-134°C
Found M+: 274.8897. CgH 79Br 5CI2N requires 274.8905. δH: 8.31 (1 H, d, J 1 .3, H5), 7.88-7.82 (2H, m, H7 and H8), 7.50 (1 H, s, H3) δc: 150.7 (C2), 147.1 (C4), 143.6 (C8a), 135.5, 131.0, 126.9 (all Ar-H), 126.6,
123.2, 126.4. nmax/cnr1: 1570, 1547 (s, C=N, C=C). m/z: 281 (5%, M+ 8lBr37ci2), 279 (49%, M+ 9βr ci2 and M+ 81 Br37c| 5ci), 277 (100%, M+ 81βr35CI2 and M+ 9Br37c|35d), 275 (62%, M+ 79Br35d2), 242 (21%, M+ - CI), 161 (20%).
EXAMPLE 57A. 5-Bromo-2,4-dichloroquinoline and EXAMPLE 57B. 7-bromo-2,4-dichloroquinoline
Figure imgf000090_0001
C9H6Brt. CβH4BrCI2N Mol. Wt: 172.0 Mol. Wt: 276.9
3-Bromoaniline (7.0 g, 41 mmol) and malonic acid (6.4 g, 62 mmol) were heated under reflux in phosphorus oxychloride (40 ml) for 6 hours. Standard workup gave the crude product as a brown powder. Soxhlet extraction with hexane yielded a mixture of the two isomeric products; Rf 0.58 and 0.42 (95:5 hexane:EtOAc). Column chromatography furnished the two products as white needles.
Data for 5-bromo-2,4-dichloroquinoline (EXAMPLE 57 A)
Yield 0.70g , 6%. Melting point 130-132°C Rf 0.42 (95:5 hexane: EtOAc).
Found M+: 274.8908. C9H479Br35ci2N requires 274.8905. δπ: 7.99 (1 H, dd, J 8.4, 1.2, H8), 7.93 (1 H, dd, J 7.5, 1.2, H6), 7.55 (1 H, s, H3), 7.53 (1H, dd, 8.4, 7.5, H7). δc: 150.2 (C2), 149.9 (C4), 144.3 (C8a), 135.6, 131.1 , 130.0, 125.3, 123.4,
117.7. nmax/cm-1: 1564, 1545 (s, C=C, C=N). m/z: 281 (6%, M+ 81Br37ci2), 279 (55%, M+ 79Br 7ci2 and M+81Br37C|35d), 277 (100%, M+ 8 Br35ci2 and M+ 9Br3 ci35ci), 275 (75%, M+ 9BΓ35CI2), 242 (22%,
M+ - CI), 240 (16%, M+ 9βr35CI2 - CI), 196 (20%, M+ - Br), 161 (31%, M+ - Br,
CI). Data for 7-bromo-2,4-dichloroquinoline (EXAMPLE 57B)
Yield 1.2 g, 11%. Melting point 102-104°C Rf 0.58 (95:5 hexane: EtOAc).
(Found C: 39.07, H: 1.12, N: 4.81%. C9H4BrCI2N requires C: 39.03, H: 1.46, N:
5.06%)
Found M+: 274.8891. C9H479Br35d2N requires 274.8905. δπ: 8.19 (1H,d, 1.8, H8), 8.03 (1H, d, J 8.9, H5), 7.72 (1H, dd, J8.9, 1.8, H6),
7.50 (1H, s, H3). δc: 151.1, 148.6 (C2.C4), 144.5(C8a), 131.5(CH), 131.3(CH), 126.2, 125.5
(CH), 124.0, 122.4 (CH). nmaχ/cnr1: 1599, 1570, 1547 (s, C=C, C=N). m/z: 281 (4%,M+81Br37d2), 279(45%, M+79Br37Cl2 and M+ 81 Br37C|35ci), 277
(100%, M+81Br35CI2and M+ 79BΓ3 C|35C|), 275 (75%, M+ 9Br5d2), 242 (23%,
M+-CI), 240(21%, M+ 9Br 5d2 - CI), 212(13%), 161 (20%, M+ - Br, CI).
EXAMPLE 58. 6-Bromo-2,4-dimethoxyquinoline
Figure imgf000091_0001
6-Bromo-2,4-dichloroquinoline (EXAMPLE 56) (1.5 g, 5.4 mmol) was heated under reflux in excess methanolic sodium methoxide (1.5 g Na in 75 ml MeOH) for
48 hours, then cooled and poured into cold water. After standing for 2 hours the mixture was filtered to give the product, fine pale yellow needles. Yield 1.35 g,
93%. Melting point: 54-56°C.
Found M+: 266.9883. CnH10 79BrNO2 requires 266.9895. δπ: 8.17 (1H, d, J 1.3, H5), 7.66-7.61 (2H, m, H7, H8), 6.20 (1H, s, H3), 4.03
(3H, s, 2-OMe), 3.96 (3H, s, 4-OMe). δc: 164.5 (C2), 163.3 (C4), 146.1 (C8a), 133.5, 129.1, 124.8 (C5, C7,
C8), 120.92, 117.0 (C4a, C6), 91.8 (C3), 56.2 (OMe), 53.9 (OMe). nmax/cm-1: 1621 , 1596. 1573 (s, C=C, C=N). 1209, 1044 (s, C-O-C). m/z: 269 (100%, M+, 81 Br), 268 (95%, M+ - H), 267 (100%, M+, 79Br), 266
(87%, M+ - H), 239 (24%), 238 (20%), 213 (17%), 143 (22%).
EXAMPLE 59. 5-Bromo-2,4-dimethoxyquinoline
Figure imgf000092_0001
C9H4BrCI2N C11H10Br O2 Mol. Wt: 276.9 Mol. Wt: 268.1
5-Bromo-2,4-dichloroquinoline (EXAMPLE 57A) (0.25 g, 0.9 mmol) was heated under reflux in excess methanolic sodium methoxide (1.0 g Na in 50 ml MeOH) for
45 hours. After cooling, the mixture was poured into cold water and left to stand overnight in a refrigerator. Filtration gave the title compound as fine white needles.
Yield 0.20 g, 82%. Melting point 86-88°C
Found M+: 266.9905. C1 H10 79BrNO2 requires 266.9895. δπ: 7.73 (1 H, dd, J 8.1 , 0.9, H8), 7.60 (1 H, dd, J 7.6, 0.9, H6), 7.33 (1 H, dd, J
8.1 , 7.6, H7), 6.26 (1 H, s, H3), 4.03 (3H, s, OMe), 3.95 (3H, s, OMe). δc: 164.6, 163.8 (C2. C4), 149.9 (C8a), 131 .1 , 130.1 , 127.7, (C-6,7,8), 1 18.4,
116.6 (C5, C4a), 92.3 (C3), 55.8 (OMe), 53.8 (OMe). nmax/cnr1: 1608, 1573 (s, C=C, C=N), 1212 (s, C-O-C). m/z: 268 (100%, M+ 81βr - H), 267 ( 15%, M+ 79BΓ), 266 (98%, M+ 79BΓ - H),
182 (12%), 1 14 (26%).
EXAMPLE 60. 7-Bromo-2,4-dimethoxyquinoline
Figure imgf000092_0002
CgHiBrCy. CHH^BΓNOJ Mol. Wt: 276.9 Mαl. Wt.: 26B.1 7-Bromo-2,4-dichloroquinoline (EXAMPLE 57B) (0.30 g, 1 .1 mmol) was heated under reflux in methanolic sodium methoxide (1 .0 g Na in 50 ml MeOH) for
48 hours. After cooling, the mixture was poured into cold water, left to stand for 2 hours, and then filtered to give the title compound as white needles. Yield 0.22 g,
76%. Melting point 76-78°C
Found M+: 266.9871. C1 1 H10 79BrNO2 requires 266.9895. δH: 7.96 (1 H, d, 1 .9, H8), 7.88 (1 H, d, J8.7, H5), 7.40 (1 H, dd, J 8.7, 1.9, H6),
6.20 (1 H, s, H3), 4.03 (3H, s, OMe), 3.97 (1 H, s, OMe). δc: 164.5, 163.8 (C2. C4), 148.0 (C8a), 129.4, 126.6, 124.1 , 123.3, 1 17.7,
91 .0 (C3), 55.8 (OMe), 53.6 (OMe). nmaχ/cπr1 : 1618, 1596, 1574 (s, C=C, C=N), 208 (s, C-O-C). m/z: 269 (100%, M+ 81 Br), 268 (88%, M+ 81 Br - H), 267 (96%, M+ 79βr), 266
(87%, M+ 79βr - H), 239 (36%, M+ 81 Br - CH20), 237 (33%, M+ 79βr - CH20).
EXAMPLE 61. 2,4-Dimethoxy-6-phenyiquinoline
Figure imgf000093_0001
C^H.oBrNOa C17H,5N02 Mol. Wt: 268.1 Mol. Wt: 265.3
6-Bromo-2,4-dimethoxyquinoline (EXAMPLE 60) (0.40 g, 1.5 mmol), benzeneboronic acid (0.20 g, 1.6 mmol), tetrakis(triphenylphosphine) palladium(O)
(52 mg, 3 mol%), sodium carbonate (0.32 g in 1 ml H20), ethanol (0.5 ml) and toluene (8 ml) were heated at 80°C under argon for 48 hours. After cooling, ether (5 ml) and water (10 ml) were added, and the flask contents transferred to a separating funnel. The mixture was extracted with diethyl ether (3 x 30 ml), the combined organic extracts dried (MgS04) and the solvent removed in vacuo to give a brown residue. Column chromatography (9:1 hexane : EtOAc) furnished the pure compound as a white powder. Yield 0.35 g, 88%. Melting point 121-123°C. Found M+: 265.1110. C 7Hι5N02 requires 265.1 103. δπ: 8.27 (1 H, d, J 1.5, H5), 7.89-7.82 (2H, m, H8, H7), 7.70 (2H, dd, J 7.3, 1.4,
H2' and H6'), 7.46 (2H, t, J 7.3, H3' and H5'), 7.35 (1 H, dd, J 7.3, 1.4, H4'), 6.24
( H, s, H3), 4.07 (3H, s, OMe), 4.00 (3H, s, OMe) δc: 164.1 , 164.0 (C2, C4), 146.5, 140.9, 136.1 (CT, C6, C8a), 129.3, 128.9,
127.3, 127.2, 127.1 , 119.9, 119.4, 91.0 (C3), 55.8 (OMe), 53.5 (OMe). nmaχ/crτr1: 1626, 1600, 1580 (m, C=C, C=N), 1207 (s, C-O). m/z: 265 (100%, M+), 264 (62%, M+ - H), 236 (19%), 235 (25%).
EXAMPLE 62. 2,4-Dimethoxy-7-phenyl quinoline
Figure imgf000094_0001
CnH^Brl-Oj C17H,5N02 Mol. Wt: 268.1 Mol. Wt: 265.3
7-Bromo-2,4-dimethoxyquinoline (EXAMPLE 60) (0.10 g, 0.33 mmol), benzeneboronic acid (0.06 g, 0.5 mmol), tetrakis(triphenylphosphine) palladium (0) (13 mg, 0.011 mmol), aqueous sodium carbonate (80 mg, 0.74 mmol in 0.5 ml H20), ethanol (0.5 ml) and toluene (5 ml) were heated at 80°C under argon for 48 hours. After cooling, the reaction mixture was washed with water (20 ml) and extracted with ether (3 x 30 ml). The combined organic extracts were dried (MgS04), and the solvent removed under reduced pressure to give the crude product (a brown oil) which was purified by column chromatography (9:1 hexane:EtOAc), furnishing the title compound (Rf 0.40) as white prisms. Yield 80 mg, 84%. Melting point 118-120°C. (Found C: 76.96, H: 5.69, N: 5.14%. C17H15N02 requires C: 76.96, H: 5.70, N: 5.28%.) Found M+: 265.1096. C17H15N02 requires 265.1103. δH: 8.09 (1 H, d, J 8.5, H5), 8.00 (1 H, d, J 1.9, H8), 7.73 (2H, dd, J 7.1 , 2.0, H2', H6"), 7.59 (1 H, dd, J8.5, 1.9, H6), 7.46 (2H, t, J 7.1 , H3\ H5'), 7.39-7.34 (1 H, m, H4'), 6.21 (1H, s, H3), 4.07 (3H, s, OMe), 3.98 (3H, s, OMe). δc: 164.3, 163.9 (C2. C4), 147.4, 142.7, 140.7 (C8a, C1\ C7), 128.9, 127.7,
127.5, 124.8, 122.8, 122.4 (C2'+ 6', C3' + 5', C4\ C5, C6, C8), 118.3 (C4a), 90.7
(C3), 55.8 (OMe), 53.5 (OMe). nmax/cnr1: 1617, 1610, 1578 (s, C=C, C=N), 1206 (s, C-O). m/z: 265 (79%, M+), 264 (41 %, M±- H), 217-(-22%)r2 3 (21%),-212-(2-2%)-201
(32%).
EXAMPLE 63. 2,4-Dimethoxy-5-phenylquinoline
Figure imgf000095_0001
C1 lH10Brt-O2 C17H1SN02 Mol. W : 268.1 Mol. Wt: 265.3
5-Bromo-2,4-dimethoxyquinoline (EXAMPLE 59) (0.15 g, 0.56 mmol), benzeneboronic acid (76 mg, 0.62 mmol), tetrakis(triphenylphosphine) palladium (0) (19 mg, 0.017 mmol, 3 mol%), aqueous sodium carbonate (0.12 g in 0.5 ml H20), ethanol (0.5 ml) and toluene (8 ml) were heated at 80°C for 48 hours. After cooling, the reaction mixture was washed with water (20 ml) and extracted with diethyl ether (3 x 30 ml). The combined organic extracts were dried, and the solvent removed under reduced pressure to give a brown oil. Column chromatography (9:1 hexane:EtOAc) furnished the pure quinoline (Rf 0.33) as white plates. Yield 0.12 g, 81 %. Melting point 97-99°C (Found C: 76.78, H: 5.54,
N: 5.17%. C17H15N02 requires C: 76.96, H: 5.70, N: 5.28%.)
Found M+: 265.1 106. Cι7Hι5NO2 requires 265.1 103.
6H: 7.80 (1 H, dd, J8.3, 1.2, H8), 7.55 (1H, dd, J 8.3, 7.2, H7), 7.35-7.27 (5H, m, 5xArH), 7.13 (1 H, dd, J 7.2, 1.2, H6), 6.14 (1 H, s, H3), 4.06 (3H, s, 2-OMe), 3.48 (3H, s, 4-OMe). δc: 165.6, 163.1 (C2, C4), 148.7, 144.7, 173.7 (C8a, C1 ', C5), 129.2, 127.9, 127.4, 127.3, 127.2, 126.5 (CH), 117.5 (C4a), 91 .7 (C3), 55.4 (OMe), 53.8 (OMe). nmaχ cm-1: 1612, 1581 (s, C=C, C=N), 1209 (s, C-O-C). m/z: 265 (100%, M+), 232 (33%), 164 (17%).
EXAMPLE 64. 2,4-D.methoxy-6 (2'.4'.6'-trimethylphenyl)quinoline
Figure imgf000096_0001
CnH10BrNO2 C20H21NO2
Mol. Wt: 268.1 Mol. Wt. 3074
6-Bromo-2,4-dimethoxyquinoline (EXAMPLE 58) (0.40 g, 1.5 mmol), 2,4,6- trimethylbenzene-boronic acid (0.28 g, 1.7 mmol), tetrakis(triphenylphosphine) palladium (0) (52 mg, 3 mol%), sodium carbonate (0.32 g, 3 mmol in 1 ml H 0), ethanol (0.5 ml) and toluene (9 ml) were heated at 80°C under argon for 48 hours.
After cooling ether (5 ml) and water (10 ml) were added, and the flask contents transferred to a separating funnel. The mixture was extracted with diethyl ether (3 x 30 ml), the combined organic extracts dried (MgS04) and the solvent removed in vacuo to give a brown solid. Column chromatography (9:1 hexane:EtOAc) yielded the pure arylquinoline (Rf 0.30) as a white powder. Yield 0.34 g, 74%. Melting point 199-201 °C.
Found M+: 308.1652. C20H22NO2 requires 308.1651. δπ: 7.83 (2H, m, H5, H8), 7.39 (1 H, d, J 8.6, 1 .9, H7), 6.95 (2H, s, H3\ H5"), 6.24 (1 H, s, H3), 4.08 (3H, s, OMe), 3.96 (3H, s, OMe), 2.34 (3H, s, 6'-Me),
2.01 (6H, s, 2'-Me, 6'-Me). δc: 164.4, 164.2 (C2, C4), 146.2 (C8a), 139.2, 137.0, 136.7 (C6, C1 \ C4'),
136.6 (C2\ C6'), 132.2, 128.5, 127.3, 122.5 (C5, C7, C8, C3'+5'), 119.7 (C4a),
91.2 (C3), 56.1 (OMe), 53.9 (OMe), 21.5 (Me), 21.3 (Me). nmax/cnr1 : 1624, 1598, 1574 (s, C=C, C=N), 1204 (s, C-O). m/z 308 (88%, M+), 307 (55%, M+ - H), 279 (100%, M+ - CH3 + CH2), 190
(36%). EXAMPLE 65. 2,4-Dimethoxy-6-(4'-methoxyphenyl)-quiπoline
Figure imgf000097_0001
6-Bromo-2,4-dimethoxyquinoline (EXAMPLE 58) (0.40 g, 1.5 mmol), (4-methoxybenzene)-boronic acid (0.25 g, 1.6 mmol), tetrakis(triphenylphosphine) palladium (0) (52 mg, 0.045 mmol, 3 mol%), aqueous sodium carbonate (0.32 g, 3 mmol in 1 ml H20), ethanol (1 ml) and toluene (8 ml) were heated at 80°C under argon for 48 hours. After cooling, water (20 ml) was added, and the mixture extracted with diethyl ether (3 x 20 ml). The combined organic layers were dried (MgS04) and the solvent removed under reduced pressure to give a brown oil. Column chromatography (4:1 hexane:EtOAc) gave the title compound (Rf 0.42) as white flakes. Yield 0.30 g, 68%. Melting point 107-109°C. (Found C: 72.96, H: 5.72, N: 4.64%. C18H17N02 requires C: 73.28, H: 5.80, N: 4.74%.)
Found M+: 295.1203. C18H17N02 requires 295.1208. δH: 8.21 (1 H, s, H5), 7.82 (2H, s, H7 and H8), 7.63 (2H, d, 8.5, H2' and H6'), 6.99 (2H, d, J 8.5, H3' and H5'), 6.22 (1 H, s, H3), 4.06 (3H, s, OMe), 3.99 (3H, s, OMe), 3.85 (3H, s, OMe). δc: 164.4, 164.2 (C2, C4), 159.5 (C4'), 146.5 (C8a), 136.2, 133.9 (C6\ C1'),
129.5 (CH), 128.7 (CH), 127.6 (CH), 119.8(C4a), 119.5(CH), 114.7 (CH), 91.4 (C3), 56.2 (OMe), 55.8 (OMe), 53.9 (OMe). nmaχ/cm-1: 1626, 1604, 1570 (s, C=C C=N), 1210 (s, C-O). m/z: 295(100%, M+), 278(22%), 250 (12%), 133 (10%). EXAMPLE 66. 2,4-Dimethoxy-β-(4'-fluorophenyl)-quinoline
Figure imgf000098_0001
C11H10Bι O2 C,7HMFN02
Mol. Wt: 268.1 Mol. Wt.: 2B3.3
6-Bromo-2,4-dimethoxyquinoline (EXAMPLE 65) (0.40 g, 1.5 mmol),
4-fluorobenzeneboronic acid (0.25 g, 1.8 mmol),tetrakis(triphenylphosphine) palladium (0) (52 mg, 0.045 mmol, 3 mol%), aqueous sodium carbonate (0.32 g, 3 mmol in 1 ml H20), ethanol (1 ml) and toluene (10 ml) were heated at 80°C under argon for 48 hours. After cooling, water (20 ml) was added, and the mixture extracted with diethyl ether (3 x 30 ml). The combined organic layers were dried
(MgS04) and the solvent removed in vacuo to give the crude product, which was purified by column chromatography (4:1 hexane:EtOAc) to give the title compound (Rf 0.40) as a white powder. Yield 0.37 g, 87%. Melting point 115-117DC (Found C: 72.04, H: 4.93, N: 4.63%. Cι7H14FN02 requires C: 72.07, H: 4.98, N: 4.94%.)
Found M+: 283.1002. C17Hι4FN02 requires 283.1009. δπ: 8.20 (1 H, d, J 1.9, H5), 7.84-7.78 (2H, m, H7, H8), 7.69-7.62 (2H, m, H2\ H6'), 7.16-7.10 (2H, m, H3\ H5'), 6.24 (1 H, s, H3), 4.07 (3H, s, OMe), 4.00 (3H, s, OMe). δc: 164.4, 164.3 (C2, C4), 162.8 (d, 1JC.F 246, C4'), 146.8 (C8a), 135.6, 132.5,
129.5, 129.1 (d, 2JC_F 20, C3\ C5'), 127.8, 120.1 , 1 19.8 (C4a), 1 16.2 (d, 3JC-F 8, C2\ C6'), 91.5 (C3), 56.2 (OMe), 53.9 (OMe). nmax/cnr1: 1626, 1603, 1569 (s, C=C, C=N), 1210 (s, C-O). m/z: 283 (100%, M+), 183 (32%). EXAMPLE 67. 2,4-Dimethoxy-8-phenylquinoline
Method A - Tetrakis triphenylphosphine palladium (0) as catalyst.
Figure imgf000099_0001
C11H10BrNO2 Mol. Wt.: 268.1
8-Bromo-2,4-dimethoxyquinoline (EXAMPLE 53) (0.40 g, 1 .5 mmol) was dissolved in toluene (10 ml) under argon. Tetrakis(triphenylphosphine)- palladium (0) (52 mg, 3 mol%) and aqueous sodium carbonate (2.0 ml of a 2M solution) were added, and the mixture stirred for 5 minutes. Then benzeneboronic acid (0.20 g, 1 .7 mmol) in ethanol (1 ml) was added, and the mixture was then heated under reflux for 48 hours. After cooling, the mixture was poured into a separating funnel, and the reaction flask washed with water (20 ml) and ether (20 ml), the washings being added to the separating funnel. The aqueous layer was extracted with ether (3 x 20 mi), and the combined organic layers were dried over magnesium sulfate before removal of the solvent under reduced pressure. The crude product was purified by column chromatography (9:1 hexane:EtOAc) to yield the title compound (Rf 0.43) as white plates. Yield 0.16 g, 40%. Melting point 76-78°C. (Found C: 76.34, N: 5.66, N: 5.02%. C17H15N02 requires C: 76.96, H: 5.70, N: 5.28%.) Found M+: 265.1105. Cι7Hι5N0 requires 265.1 103. δH: 8.16 (1 H, dd, 8.2, 1 .5, H5), 7.90 (2H, dd, J 8.3, 1 .5, H2\ H6'), 7.77 (1 H, dd, J 7.2, 1 .5, H7), 7.56-7.52 (2H, m, Ar-H), 7.49-7.43 (2H, m, Ar-H), 6.29 (1 H, s, H3), 4.01 (3H, s, OMe), 3.99 (3H, s, OMe). δc: 164.5, 163.4 (C2. C4), 144.7, 140.4, 138.5 (C1\ C8, C8a), 131.3, 131 .1 , 127.9, 127.2, 123.5, 121.8 (C5, C6, C7, C2'-6'), 120.1 (C4a), 90.7 (C3), 56.2
(OMe), 53.8 (OMe). nmax cm"1: 1619, 1583 (s, C=C, C=N), 206 (s, C-O). m/z 265 (64%, M+), 264 (100%, M+ - H), 250 (7%, M+ - CH3), 188 (8%, M+ -
Ph).
Method B - 1 ,4-bis(diphenylphosphino)butane palladium (II) chloride as catalyst.
Figure imgf000100_0001
C1-|H10BrNO2 C17H15N02 Mol. Wt: 268.1 Mol. Wt: 265.3
1 ,4-Bis(diphenylphosphinyl)butane (24 mg, 5.5 x 10"5 mol) was added, with stirring, to bis(benzonitrile) palladium (II) chloride (21 mg, 5.5 10"5 mol) in toluene (3 ml), and the mixture stirred for 20 minutes under argon to generate the required catalyst, 1 ,4-bis(diphenylphosphino)butane palladium (II) chloride, as an orange solid. Then 8-bromo-2,4-dimethoxyquinoline (EXAMPLE 67) (0.30 g, 1.1 mmol), benzeneboronic acid (0.15 g, 1.2 mmol), aqueous sodium carbonate (0.25 g dissolved in 1.0 ml H20), ethanol (0.5 ml) and a further 5 ml of toluene were added, and the mixture heated at 90°C for 48 hours. The mixture was washed with water, extracted with diethyl ether (3 x 30 ml), the combined organic extracts dried, and the solvent removed in vacuo to give a brown oil. Column chromatography (9:1 hexane:EtOAc) yielded the arylquinoline as a white powder.
Yield 0.12 g, 40%. Spectral data as for compound prepared by method A.
Method C - bis(tricyclohexylphosphine)palladium( II) chloride as catalyst
Figure imgf000101_0001
C11H,0BrNO2 C17H,5N02 Mol. Wt: 268.1 Mol. Wt: 265.3
8-Bromo-2,4-dimethoxyquinoline (EXAMPLE 67) (0.20 g, 0.75 mmol), benzeneboronic acid (0.10 g, 0.82 mmol), aqueous sodium carbonate (0.16 g, 1.5 mmol, in 0.5 ml H20), bis(tricyclohexylphosphine)palladium (II) chloride (28 mg, 5 mol%), ethanol (0.5 ml) and toluene (5 ml) were stirred at 90°C under argon for 48 hours. After cooling, water (15 ml) was added and the mixture transferred to as separating funnel . The reaction flask was washed with ether and the washings also transferred to the funnel. The aqueous layer was extracted with ether (2 x 20 ml), the combined organic extracts dried (MgS04), and the solvent removed in vacuo to give an orange residue. Column chromatography (9:1 hexane:EtOAc) furnished the title compound as white needles. Yield 0.11 g, 56%. Spectral data as for method A.
Method D - from the iodoquinoline.
Figure imgf000101_0002
2,4-Dimethoxy-8-iodoquinoline (EXAMPLE 55) (0.40 g, 1.3 mmol), benzeneboronic acid (0.18 g, 1.5 mmol), tetrakis(triphenylphosphine)palladium (0) (45 mg, 3 mol%), aqueous sodium carbonate (0.32 g, 3.0 mmol, in 1 ml H2O), ethanol (0.5 ml) and toluene (7 ml) were heated under reflux in an argon atmosphere for 48 hours. Workup as in Method C. Yield after column chromatography (9:1 hexane:EtOAc) 0.14 g, 41%.
Spectral data in agreement with the compound prepared by method A.
EXAMPLE 68. 2,4-Dimethoxy-8-(4'-methoxyphenyi)quinoline
Figure imgf000102_0001
C11H,0BrNO2 C1aH17l.03 Mol. Wt: 268.1 Mol. Wt: 295.3
8-Bromo-2,4-dimethoxyquinoline (EXAMPLE 53) (0.40 g, 1.5 mmol), (4-methoxybenzene)-boronic acid (0.25 g, 1.6 mmol), tetrakis(triphenylphosphine) palladium (0) (52 mg, 3 mol%), aqueous sodium carbonate (2.0 ml of a 2M solution), ethanol (1 ml) and toluene (10 ml) were heated at 90°C under argon for 48 hours. After cooling, water (20 ml) was added, and the mixture extracted with diethyl ether (3 x 20 ml). The combined organic layers were dried (MgS04) and the solvent removed under reduced pressure to give an orange oil, which was purified by column chromatography (9:1 hexane:EtOAc) to give white plates, Rf 0.29. Yield 0.14 g, 32%. Melting point 85-88°C (Found C: 73.43, H: 5.84, N: 4.68%. C18H17N03 requires C: 73.20, H: 5.80, N: 4.68%.) Found M+: 295.1200. C18H17N03 requires 295.1208. δH: 7.95 (1 H, dd, J 8.2, 1.5, H5), 7.67 (2H, d, J 8.8, H2' and H6'), 7.57 (1 H, dd, J
7.2, 1 .5, H7), 7.29 (1 H, dd, J 8.2, 7.2, H6), 6.91 (2H, d, 8.8, H3' and H5'), 6.15 (1 H, s, H3), 3.90 (3H, s, OMe), 3.84 (3H, s, OMe), 3.79 (3H, s, OMe). δc: 164.5, 163.3, 159.0 (C2, C4, C4'), 144.7, 138.0, 132.8 (C8a, C8, C1'), 132.2 (CH), 130.9 (CH), 123.5 (CH), 121.3 (CH), 120.1 (C4a), 1 13.4 (CH), 90.6 (C3), 56.2 (OMe), 55.7 (OMe), 53.8 (OMe). nmax / cm-1 : 1618, 1582 (s, C=C, C=N). m/z: 295 (100%, M+), 294 (93%, M+ - H), 214 (82%), 199 (46%).
EXAMPLE 69. 2,4-Dimethoxy-8-(2'-naphthyl)quinoline
Figure imgf000103_0001
C^H^Br Oj C21H17N02 Mol. Wt: 268.1 Mol. Wt: 315.4
8-Bromo-2,4-dimethoxyquinoline (EXAMPLE 53) (0.40 g, 1.5mmol), 2-naphthylboronic acid (0.30 g, 1.7 mmol), Pd(PPh3)4 (52 mg, 3 mol%), aqueous sodium carbonate (2.0 ml of a 2M solution), ethanol (1 ml) and toluene (10 ml) were heated at 85°C under argon for 48 hours. The cooled reaction mixture was washed with water (20 ml), and extracted with diethyl ether (3 x 30 ml), the combined organic extracts dried (MgS04) and the solvent removed in vacuo to give a brown oil. Column chromatography (9:1 hexane: EtOAc) furnished the pure naphthylquinoline as white plates (Rf 0.40), yield 0.3 g, 63%. Melting point
127-129°C (Found C: 79.62, H: 5.52, N: 4.28%. C21H17N02 requires C: 79.98, H: 5.43, N: 4.44%.)
Found M+: 315.1255. C21H-|7N02 requires 315.1259. δH: 8.19 (1H, d, J 1.4, H1'), 8.10 (1H, dd, J 8.2, 1.5, H5), 7.99 (1 H, dd, J 8.6, 1.7, Np-H), 7.89-7.87 (3H, m, Ar-H), 7.78 (1 H, dd J 7.2, 1 .5, H7), 7.49-7.40 (3H, m, Ar-H), 6.24 (1 H, s, H3), 3.99 (3H, s, OMe), 3.87 (3H, s, OMe). δc: 164.2, 163.1 (C2, C4), 144.5 (C8a), 138.0, 137.8, 133.5, 132.5, 131.2 (CH), 129.6 (CH), 129.1 (CH), 128.2 (CH), 127.6 (CH), 126.4 (CH), 125.8 (2 x CH), 123.2 (CH), 121.6 (CH), 119.8, 90.4 (C3), 55.8 (OMe), 53.5 (OMe). nmax /cm-1; 1618, 1591 , 1577 (s, C=C, C=N), 1209 (s, C-O). m/z: 315 (100%, M+), 314 (99%, M+ - H), 300 (11%, M+ - Me), 189 (39%, CιιH-|iNO2 +).
EXAMPLE 70. 8-(4'-Fluoropheny[)-2,4-dimethoxyquinoline
Figure imgf000104_0001
8-Bromo-2,4-dimethoxyquinoline (EXAMPLE 53) (0.40 g, 1.5 mmol), 4-fluorobenzeneboronic acid (0.25 g, 1.8 mmol), tetrakis(triphenylphosphine) palladium (0) (52 mg, 3 mol%), aqueous sodium carbonate (2.0 ml of a 2M solution), ethanol
(1 ml) and toluene (10 ml) were heated at 90°C under argon for 48 hours. The product was obtained after aqueous workup and ether extraction as a pale brown oil. After leaving to stand overnight, the oil crystallised to give pale orange prisms. Recrystallisation from hexane gave colourless prisms. Yield 0.15 g, 35%. Melting point: 108-110°C
Found M+: 283.1013. C17H14FN02 requires 283.1009. δH: 8.09 (1 H, dd J 8.2, 1.5, H5), 7.79-7.75 (2H, m, H2', H6"), 7.65 (1 H, dd J 7.3, 1 .5, H7), 7.40 (1 H, dd 8.2, 7.3, H6), 7.18-7.13 (2H, m, H3\ H5'), 6.26 (1 H, s, H3), 4.02 (3H, s, OMe), 3.92 (3H, s, OMe). δ 164.1 , 163.0 (C2, C4), 162.1 (d, 1JC-F 246, C4'), 144.2 (C8a), 137.0, 135.8,
132.2 (d, 3 C-F 8, C2', C6'), 130.7, 123.0, 121.5 (C5, C6, C7), 119.7, 1 14.3 (d, 2JC.F 21 , C3\ C5'), 90.3, 55.8 (OMe), 53.3 (OMe). nmax /cm"1 : 1620, 1582 (s, C=C, C=N), 1206 (s, C-O). m/z 283 (79%, M+), 282 (100%, M+ - H), 253 (13%), 188 (8%, M+ - C6H4F). EXAMPLE 71. 2,4-Dimethoxy-8-(2',4',6'-trimethylphenvQquinoline
Figure imgf000105_0001
8-Bromo-2,4-dimethoxyquinoline (EXAMPLE 53) (0.40 g, 1.5 mmol), 2,4,6- trimethylbenzene-boronic acid (0.28 g, 1 .7 mmol), tetrakis(triphenylphosphine) palladium (0) (52 mg, 3 mol%), aqueous sodium carbonate (2.0 ml of a 2M solution), ethanol (1 ml) and toluene (10 ml) were heated at 90°C under argon for 48 hours. After workup by the usual method a brown oil was obtained. Column chromatography (9:1 hexane: EtOAc) yielded the title compound as white plates, yield 80 mg, 17%, Rf 0.55. (0.2 g ofthe reduced 2,4-dimethoxyquinoline was also obtained). Melting point 1 12-1 14°C (Found C: 77.47, H: 6.77, N: 4.45%. C20H2ιNO2 requires C: 78.15, H: 6.89, N: 4.56%.) Found M+: 307.1571 . C20H21NO2 requires 307.1572. δH: 8.06 (1 H, dd, J 7.7, 2.0, H5), 7.41 -7.34 (2H, m, H6 and H7), 6.94 (2H, s, 3Η and 5'H), 6.19 (1 H, s, H3), 3.98 (3H, s, OMe), 3.66 (3H, s, OMe), 2.35 (6H, s, 2'Me and 6'Me), 1 .90 (3H, s, 4'Me). δc: 164.2, 162.9 (C2, C4), 145.3 (C8a), 138.3, 137.5, 136.6, 136.0 (4 x quaternary C), 131 .3, 127.6, 123.1 , 121.0 (4 x Ar-H), 1 19.6, (C4a) 90.5 (C3), 55.9 (OMe), 53.2 (OMe), 21.3 (4'Me), 20.8 (2'Me, 6'Me). nmaχ/ cm-1; 1618, 1586, 1583 (s, C=C, C=N). m/z 307, (59%, M+), 292 (100%, M+ - Me), 277(14%). EXAMPLE 72. 8-Brorno-4-rnethoxy 1.W-quinolin-2-one
Figure imgf000106_0001
8-Bromo-2,4-dimethoxyquinoline (Example 53) (0.60 g, 2.2 mmol) was heated in
3% hydrobromic acid in 1 :1 THF:water (32 ml) under reflux for 4 hours. The cooled solution was neutralised with sodium carbonate, and the THF removed in vacuo to precipitate the organic products. The precipitate was filtered off and dried under suction, and then subjected to a continuous (Soxhlet) extraction with hexane for 6 hours. Unreacted starting material (0.15 g) was recovered from the hexane. The quinolin-2-one product, white flakes, remained undissolved in the extraction thimble. Yield 0.38 g, 67%. Melting point >250°C Found M+: 252.9734. C10H8 79BrNO2 requires 252.9738. δπ: 8.76 (1 H, br s, NH), 7.86 (1 H, dd, J 8.1 , 1.0, H5), 7.70 (1 H, dd, J 7.8, 1 .0, H7), 7.07 (1 H, dd, J 8.1 , 7.8, H6), 5.95 (1 H, s, H3), 3.97 (3H, s, OMe). δc: 164.2, 163.5, 135.4 (C8a), 134.3, 122.8, 122.7 (C5, C6, C7), 1 17.1 , 108.9, 96.9 (C3), 56.4 (OMe). nmax/cnr1: 3383 (m, N-H), 1681 (s, C=0), 1592 (m, C=C). m/z 255 (97%, M+ 81 Br), 253 (100%, M+ 79βr), 212 (23%, M+ 8lβr - CONH), 210 (25%, M+ 79βr - CONH), 1 16 (18%).
BIOLOGICAL TESTING
(I) ANTHELMINTIC ACTIVITY
The anthelmintic properties of a number of compounds of the invention were tested against a benzimidazole sensitive Haemonchus contortus isolate. This assay is an in vitro larval development assay that is applicable to all parasitic nematodes with free-living life cycle stages.
(i) Activity against Haemonchus contortus
In the Haemonchus contortus assay, the eggs of parasitic nematodes are applied to the wells of a microtitre plate containing the test compound. After the eggs hatch, L1 larvae develop through to the L3 stage. Development of the larvae can be inhibited at a number of stages by nematocides. The morphology and stages of inhibition are highly characteristic for common modes of action and offer additional pharmacological criteria for the uniqueness of the activity observed. These observations are extremely informative where the assay is used as a primary screen for anthelmintic activity (Gill, J.H et al, Int. J. Parasit. (1991 ), 21_, 771 -776 and Gill, J.H. et al, Int. J. Parasit. (1995), 25, 463-470).
Protocol
Samples of compounds were weighed and dissolved by addition of dimethylsulfoxide (DMSO) to give a final stock concentration of 10,000 μg/ml. If a compound was not soluble at this concentration, the suspension was gently warmed to achieve dissolution. Compounds failing to dissolve were then diluted to 5,000 μg/ml and warmed. Poorly soluble compounds were handled by repeated dilution and warming until the dissolution was complete as possible.
Twelve serial z dilutions in DMSO solution were prepared from each stock solution, each of which was then diluted 1/5 with water. Aliquots (10 μl) of each dilution were transferred to the bioassay plates and diluted a further 20-fold with agar (2%, 190 μl) to give a final concentration range of 0.045 to 100 μg/ml (2,048-fold range), or a corresponding range for compounds where the stock concentration was lower than 10,000 μg/ml. Any precipitation was found to redissolve upon addition of hot agar.
Test Organism
The McMaster isolate of H. contortus is a reference susceptible strain routinely maintained by passage in sheep; this isolate has had little, if any, exposure to any anthelmintic. Nematodes eggs were isolated from the faeces of infested animals according to standard literature procedures.
Procedure
The effect of the test compounds on larval development was determined in the assay described by Lacey et al (1990), "A larval development assay for the simultaneous detection of broad spectrum anthelmintic resistance" in "Resistance of Parasites to Antiparasitic Drugs", Round Table Conference held at the VII International Congress of Parasitology, Paris, August, 1990 (Edited by Boray, J.C, Martin, P.J and Roush, R.P.), pp177-184, MSD AGVET, Rahway, NJ, USA). Briefly, 80 to 100 nematode eggs were added to the surface of the agar matrix containing the test compound, supplemented with a nutrient medium and incubated at 26°C until larvae in the control (no drug) wells developed to the L3 stage. A qualitative assessment of the larvae in each well was made on Day 5 of the assay (see Column "NeT" in Table 1 ). The wells for each dilution of every compound (from highest to lowest concentration) were inspected to determine the well number corresponding to the lowest concentration at which development was inhibited in 99% of the nematode larvae present. As the well numbers correspond to a two-fold serial dilution of each compound, a titre (dilution factor) is generated as 2n"\ where n is the well number. By dividing the highest concentration by the titre, an LD99 value was obtained, representing the concentration required to inhibit development in 99% of the nematode larvae present. The results of the assay for a selection of compounds are shown in Table 1. The nematocidal activity of the compounds in Table 1 are given as LD99 values in μg/ml, and represents the concentration required to inhibit development of 99% of Haemonchus contortus larvae.
Figure imgf000109_0001
Table 1. Anthelmintic activity data The data in Table 1 indicate that representative compounds of the invention, 37, 58, 51 , 65. 67 and 68, possess high nematocidal activity.
(ii) Activity against Schistosoma mansoni cercariae
The anthelmintic properties of a number of compounds of the invention were tested against recently released cercarial larvae of the human schistosome trematode, Schistosoma mansoni. The assay monitored cercarial behaviour changes and death as determined by a cessation of larval movement.
PROTOCOL
Samples of compounds were weighed and dissolved in ethanol to provide 50 mM stock solutions. These were serially diluted in ethanol (1 :1 by volume) to provide a range of stock concentrations from 50 mM downwards.
In tests, these were added at a 1 :99 dilution, to provide a range of in-well concentrations in the series 500 μM, 250 μM, 125 μM etc., to cercariae in 1 ml of water in 12 well tissue culture plates (Linbro). This dilution protocol produces a maximum in-well concentration of ethanol of 1% by volume, which does not significantly affect cercarial behaviour or longevity.
Cercariae of S. mansoni were obtained through the maintenance of the parasite life cycle in NMRI strain laboratory mice and Biomphalaria glabrata snails. Infected snails were induced to shed cercariae by exposure of water at 28°C and bright light. Approximately 30 cercariae were placed in each test well within 2 hours of their release from the snail hosts. For each compound and concentration, assays were set up in duplicate and repeated 3 times with different populations of cercariae. For each assay, the cercariae were observed with low power microscopy to assess cercarial activity 30 minutes after exposure to the test compound. At this time, the number of immobile cercariae in each well was counted and then all cercariae fixed and stained with Lugol's iodine to assess the percentage of cercariae that were immobile and presumed dead. Results from the dilution series were employed to estimate the LD50 (30 minutes) for each compound. The results from this assay are shown in Table 2.
Figure imgf000111_0001
Table 2. Activity against S. mansoni cercariae
(iii) Activity against Caenorhabditis elegans
The anti-nematode properties of a number of compounds of the invention were tested against the free-living nematode Caenorhabditis elegans. The assay monitored behavioural changes and death as determined by complete cessation of movement by the worms.
PROTOCOL Samples of compounds were weighed and dissolved in ethanol to provide 50 mM stock solutions. These were serially diluted in ethanol (1 :1 by volume) to provide a range of stock concentrations from 50 mM downwards. In tests, 20 μl of these stock solutions were added to 1.98 ml of C. elegans suspension in lidded glass vials to give a final dilution of 1 :99. This gives a range of in-well concentrations in the series 500 μM, 250 μM, 125 μM, etc. This dilution protocol produces a maximum in-well concentration of ethanol of 1% by volume which does not significantly affect nematode behaviour or longevity.
C. elegans were maintained in culture of agar plates seeded with Escherischia coli bacteria. The nematodes were harvested 7 days after inoculation, into 0.05 M phosphate buffer - pH 7, and counted. The volume of the suspension was adjusted to give about 500 nematodes/ml. Aliquots of 1.98 ml were dispensed into glass vials and 20 μl of drug stock solution added. After 60 minutes, five samples of 100 μl were removed, and in each of these, the total number of nematodes and the number that were inactive were counted. From these five replicated values the mean percentage of immobile, presumed dead, nematodes associated with each concentration could be estimated. Results from dilution series were used to estimate the LDS0 (60 minutes) for each compound. The results from this assay are shown in Table 3.
Figure imgf000112_0001
Table 3. Activity against C. elegans (III) ECTOPARASITIC ACTIVITY
A number of compounds of the invention were tested against certain species of ectoparasites in accordance with the following bioassay protocols.
(i) Activity against Lucilia cuprina
(a). Topical application to adult male Lucilia cuprina
Adult male blowflies aged between 3 and 7 days of the species L. cuprina were lightly anaesthetised to permit handling, and 1 microlitre of the test solution, at a range of dilutions, was applied to the dorsal thorax. Four replicates of 15 blowflies were treated at each test dilution. A control group, treated with the solvent alone, was included for comparative purposes.
The treated blowflies and the controls were maintained in recovery containers under appropriate rearing conditions for 48 hours. Percentage mortality, as determined by no response of the adult blowfly if touched, was recorded at 24 and 48 hours after treatment (Table 4).
(b). Mortality test for larval Lucilia cuprina
First stage larvae, less than 24 hours of age, were placed on a surface that had been impregnated with the serial dilutions of the test compound. Four replicates of 50 larvae were exposed at each dilution. A control group, treated with the solvent alone, was included for comparative purposes.
The exposed larval blowflies were held in appropriate rearing conditions for 24 hours. Percentage mortality was recorded at 24 hours by counting dead and live larvae (Table 4). (c). Insect growth regulator (IGR) test for larval Lucilia cuprina
First stage larvae, less than 24 hours of age, were placed on prepared media that had been impregnated with serial dilutions of the test compound. Four replicates of 100 larvae were exposed at each dilution. A control group, treated with the solvent alone, was included for comparative purposes.
The exposed larval blowflies were held in appropriate rearing conditions and were checked periodically. Just prior to pupation, the test lids on the holding containers were removed and the holding containers placed on a layer of sand to facilitate migration and pupation of the larvae. Percentage mortality and percentage IGR activity were recorded weekly (Table 4).
Figure imgf000114_0001
NT = not tested
Table 4. Results of bioassays against Lucilia cuprina (ii) Activity against the cattle tick Boophilus microplus
(a), njection test for engorged female Boophilus microplus
Engorged female ticks of Boophilus microplus were injected, through the cuticle between the mouthparts and first leg, with 1 microlitre of the test compound in a range of dilutions. Four replicates of 15 ticks were treated at each dilution. A control group, treated with the solvent alone, was included for comparative purposes.
The treated ticks were maintained at 25 ± 1°C for 14 days. Mortality and oviposition were recorded at 7 and 14 days. The results were recorded for either percentage mortality or percentage inhibition of oviposition (Table 5).
Figure imgf000115_0001
Table 5. Activity against Boophilus microplus
The data in Tables 4 and 5 indicate that all compounds have a low level of activity against adult Lucilia cuprina. Two compounds, i.e. 67 and 68, demonstrated a good level of activity against this larval stage of the life cycle of Lucilia cuprina. None ofthe compounds tested demonstrated any insect growth regulator activity at the concentrations tested against larval Lucilia cuprina. All test compounds, with the exception of compound 67, demonstrated moderate to good activity against the cattle tick, Boophilus microplus, with particularly good activity being demonstrated by compound 61. It should be noted that compound 68 demonstrated activity against both larval Lucilia cuprina and adult Boophilus microplus, thus demonstrating activity against both an insect and acarine ectoparasite.

Claims

1. The use of a compound of Formula (I), (IA) or (IB):
Figure imgf000117_0001
in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of infections caused by parasitic helminths or arthropod ectoparasites, wherein:
R1 represents H, G, to C6 alkyl or benzyl;
R2, R3, R4, R5, R6 R7 and R8 are each independently selected from the group consisting of: (i) hydrogen;
(ii) C, to C20 alkyl, which may be branched, or unbranched and unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of: C6 to C10 aryl, CN, F, CI, Br, I,
OH, SH, N02, OR9, SR9, COR9, COOR10 and NR10R11; (iii) C2 to C20 alkenyl, which may be unsubstituted or substituted by 1 -3 substituents independently selected from the group consisting of Cs to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9,
COOR10 and NR10R11; (iv) C2to C10 alkynyl, which may be unsubstituted or substituted by 1 -3 substituents independently selected from the group consisting of C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10 and NR10R11; (v) Cβ to C15 aryl, which may be unsubstituted or substituted by 1 -5 substituents independently selected from the group consisting of C1 to Cβ_alky),.Cβ_Jo. C15.,aryl, OR9,..SR9, CN, F, CI, Br, I, OH, SH,
N02, COR9, COOR10, OCF3, CF3 and NR10R11; (vi) C3 to C8 cycloalkyl, which may be unsubstituted or substituted by 1 -5 substituents independently selected from the group consisting of
C, to C6 alkyl, Ce to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, H02, COR9, COOR10, OCF3, CF3 and NR10R11;
(vii) a heterocyclic group which may be aromatic or non-aromatic having from 5 to 10 ring atoms wherein 1 , 2 or 3 of the ring atoms are selected from nitrogen, oxygen or sulfur atoms and the remainder are carbon atoms; (viii) OR12;
(ix) a halo group selected from F, CI, Br or I; (x) NR10R"; (xi) COOR10; (xii) N02; (xiii) SR12;
(xiv) CONR10R11; (xv) COR9; (xvi) CN; (xvii) OH; or (xviii) SH,
wherein:
R9 represents C, to Cβ alkyl or Cβ to C15 aryl;
R10 and R11 are the same or different and each is independently selected from the group consisting of hydrogen, C, to C6 alkyl and C6 to C15 aryl; and R12 represents C, to C6 alkyl, which may be branched or unbranched and unsubstituted or substituted by 1 -3 substituents independently selected from the group consisting of C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10 and NR10R11;
or an N-oxide derivative thereof, wherein the quinoline ring nitrogen forms an N-oxide group, or a pharmaceutically acceptable salt, solvate or quaternary ammonium salt thereof, with the proviso that (a) at least one of R2 and R4 is other than hydrogen and (b) for the compounds of Formula (IA) wherein R3 represents dimethylallyl and R4 represents ethoxy, at least one of R5, R6, R7 and R8 is other than hydrogen.
2. The use according to Claim 1 wherein R2 represents
(i) C, to Ce alkyl, which may be branched, or unbranched and unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of C6 to C10 aryl, CN, F, CI, Br, I,
OH, SH, N02, OR9, SR9, COR9, COOR10 and NR10R11;
(ii) C6 to C10 aryl, which may be unsubstituted or substituted by 1-5 substituents independently selected from the group consisting of C, to C6 alkyl, C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH,
NOz, COR9, COOR10, OCF3> CF3 and NR10R11; (iii) C3 to C8 cycloalkyl, which may be unsubstituted or substituted by 1-5 substituents independently selected from the group consisting of C. to C6 alkyl, C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10, OCF3, CF3 and NR10R11;
(iv) OR12;
(v) a halo group selected from F, CI, Br or I; (vi) NR10R11; (vii) COOR10; (viii) SR12;
(ix) CONR10R11; (x) COR9; or (xi) CN wherein R9, R10, R11 and R12 are as defined as in Claim 1 .
3. The use according to Claim 2 wherein R2 represents 5. (i) unsubstituted C, to C6 alkyl, which may be branched or unbranched;
(ii) C6 to C10 aryl, which may be unsubstituted or substituted by 1 -5 substituents independently selected from the group consisting of C1 to C6 alkyl, Ce to C10 aryl, OCF3, CF3, OR9 or SR9; (iii) OR12; o (iv) a halo group selected from F, CI, Br or I;
(v) COOR10; or (vi) COR9 wherein R9, R10 and R12 are as defined as in Claim 1 .
5 A. The use according to Claim 3 wherein R2 represents
(i) OR12, wherein R 2 is as defined as in Claim 1 ; or (ii) a halo group selected from F, CI, Br or I.
5. The use according to Claim 4 wherein R2 represents 0 (i) OR12 wherein R12 represents unsubstituted C1 to C6 alkyl, which may be branched, or unbranched; or (ii) a halo group selected from F, CI, Br or I.
6. The use according to Claim 5 wherein R2 represents methoxy or halo. 5
7. The use according to any preceding claim wherein R3 represents (i) hydrogen;
(ii) G, to C20 alkyl, which may be branched, or unbranched and unsubstituted or substituted by 1-3 substituents independently 0 selected from the group consisting of C6 to C10 aryl, CN, F, CI, Br, I,
OH, SH, N02, OR9, SR9, COR9, COOR10 and NR10R11; (iii) C2 to C20 alkenyl, which may be unsubstituted or substituted by 1 -3 substituents independently selected from the group consisting of
C. to C6 alkyl, C6 to C10 aryl, OR8 or SR9, CN, F, CI, Br, I, OH, SH,
N02, COR9, COOR10 and NR10R11; (iv) Cs to C15 aryl, which may be unsubstituted or substituted by 1-5 substituents independently selected from the group consisting of
C, to C6 alkyl, C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH,
N02, COR9, COOR10, OCF3, CF3 and NR10R11;
(v) C3 to C8 cycloalkyl, which may be unsubstituted or substituted by 1 -5 substituents independently selected from the group consisting of
C- to Ca alkyl, Cβ to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH,
N02, COR9, COOR10, OCF3, CF3 and NR10R11;
(vi) OR12 wherein R12 represents C, to C6 alkyl, which may be branched or unbranched and unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of OR9, SR9, CN,
F, CI, Br, I, OH, SH, NOz and NR10R11 wherein R10 and R11 are the same or different and each is independently selected from the group consisting of hydrogen, C1 to C6 alkyl and C6 to C1S aryl; or (vii) a halo group selected from F, CI, Br or I, wherein unless stated otherwise, R9, R10, R11 and R12are as defined as in
Claim 1.
8. The use according to any preceding claim wherein R3 represents (i) hydrogen; (ii) unsubstituted C1 to C6 alkyl, which may be branched or unbranched
(iii) unsubstituted C6 to C15 aryl; (iv) OR12 wherein R12 represents C1 to C6 alkyl; or (v) a halo group selected from F, CI, Br, I.
9. The use according to any preceding claim wherein R3 represents hydrogen or halo.
10. The use according to any preceding claim wherein R3 represents hydrogen.
11. The use according to any preceding claim wherein R4 represents
(i) C, to C20 alkyl, which may be branched, or unbranched and unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of C6 to C10 aryl, OR9, SR9, CN,
F, CI, Br, I, OH, SH, NO2, COR9, COOR10 and NR10R11;
(ii) C6 to C15 aryl, which may be unsubstituted or substituted by 1-5 substituents independently selected from the group consisting of C1 to Ce alkyl, C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH,
N02, COR9, COOR10, OCF3, CF3 and NR10R11; (iii) C3 to C8 cycloalkyl, which may be unsubstituted or substituted by 1 - 5 substituents independently selected from the group consisting of C, to C6 alkyl, C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10, OCF3, CF3 and NR10R11;
(iv) OR12 wherein R12 represents C^ to C20 alkyl, which may be branched, or unbranched and unsubstituted or substituted by 1 -3 substituents independently selected from the group consisting of OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10 and NR10R11; (v) a halo group selected from F, CI, Br or I;
(vi) NR10R11; (vii) COOR10; (viii) SR12; (ix) CONR10R11; (x) COR9; or
(xi) CN, wherein R9, R10, R 1 and R12 are as defined as in Claim 1 .
12. The use according to Claim 1 1 wherein R4 represents (i) unsubstituted C1 to C6 alkyl, which may be branched or unbranched;
(ii) unsubstituted C6 to C10 aryl; (iii) OR12; (iv) a halo group selected from F, CI, Br or I;
(v) COOR10; or
(vi) COR9, wherein R9, R10 and R12 are as defined as in Claim 1 .
13. The use according to Claim 12 wherein R4 represents (i) OR12 wherein R12 is as defined as in Claim 1 ; or (ii) a halo group selected from F, CI, Br or I.
14. The use according to Claim 13 wherein R4 represents
(i) OR12 wherein R12 represents unsubstituted C, to C6 alkyl, which may be branched, or unbranched; or (ii) a halo group selected from F, CI, Br or I.
15. The use according to Claim 14 wherein R4 represents methoxy or halo.
16. The use according to any preceding claim wherein R5, R6, R7 and R8 are each independently selected from the group consisting of: (i) hydrogen; (ii) C- to C20 alkyl, which may be branched, or unbranched and unsubstituted or substituted by 1 -3 substituents independently selected from the group consisting of Ca to C10 aryl, OR9, SR9, CN,
F, CI, Br, I, OH, SH, N02, COR9, COOR10, and NR10R11;
(iii) C6 to C15 aryl, which may be unsubstituted or substituted by 1-5 substituents independently selected from the group consisting of
C. to C6 alkyl, C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH,
N02, COR9, COOR10 , OCF3, CF3 and NR10R11;
(iv) C3 to C8 cycloalkyl, which may be unsubstituted or substituted by 1 -5 substituents independently selected from the group consisting of C. to Cs alkyl, C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH,
N02, COR9, COOR10, OCF3, CF3 and NR10R11; (v) a heterocyclic group having from 5 to 10 ring atoms wherein 1 , 2 or 3 of the ring atoms are selected from nitrogen, oxygen or sulfur atoms and the remainder are carbon atoms;
(vi) OR12; (vii) a halo group selected from F, CI, Br or I;
(viii) COR9;
(ix) CN; and
(x) OH, wherein R9, R10, R 1 and R12 are as defined as for Claim 1.
17. The use according to Claim 16 wherein R5, R5, R7 and R8 are each independently selected from the group consisting of:
(i) hydrogen
(ii) unsubstituted C, to Cβ alkyl, which may be branched or unbranched; (iii) C6 to C10 aryl, which may be unsubstituted or substituted by 1 -5 substituents independently selected from the group consisting of
C. to C6 alkyl, C6 to C10 aryl, OR9, SR9; (iv) the group OR12; and (v) a halo group selected from F, CI, Br and I.
18. The use according to Claim 17 wherein R5, Re, R7 and R8 are each independently selected from the group consisting of:
(i) hydrogen
(ii) C6 to C10 aryl, which may be unsubstituted or substituted by 1-5 substituents independently selected from the group consisting of
C, to C6 alkyl, C6 to C10 aryl, OR9, SR8, OCF3 and CF3; and (iii) a halo group selected from F, CI, Br or I.
19. The use according to Claim 18 wherein R5, R6, R7 and R8 are each independently selected from hydrogen, C6 to C10 aryl, which may be unsubstituted or substituted by 1-3 alkoxy groups OR9, wherein R9 is as defined as in Claim 1.
20. The use according to any preceding claim wherein R2 and R4 both represents methoxy.
21. The use according to any preceding claim wherein R5 represents
(i) hydrogen
(ii) C, to Cβ alkyl which may be branched or unbranched and unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of C6 to C10 aryl, OR9, SR9or a halo group selected from F, CI, Br and I;
(iii) C6 to C10 aryl which may be unsubstituted or substituted with 1-5 substituents independently selected from the group consisting of C. to Cs alkyl, Cs to C10 aryl, OR9, SR9, F, CI, Br, I, OCF3 and CF3; or
(iv) a halo group selected from F, CI, Br and I.
22. The use according to any preceding claim wherein R5 represents hydrogen, unsubstituted C, to C6 alkyl, or a halo group selected from F, CI, Br and I.
23. The use according to any preceding claim wherein R5 represents hydrogen.
24. The use according to any preceding claim wherein Rs represents (i) hydrogen,
(ii) C, to C6 alkyl which may be branched or unbranched and unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of ORe, SR9and a halo group selected from F, CI, Br and I; (iii) C6 to C10 aryl which may be unsubstituted or substituted with 1-5 substituents independently selected from the group consisting of C, to C6 alkyl, C6 to C10 aryl, OR9, SR9, F, CI Br, I, OCF3 and CF3; or (iv) a halo group selected from F, CI, Br and I.
25. The use according to any preceding claim wherein R7 represents hydrogen, unsubstituted C1 to C6 alkyl, or a halo group selected from F, CI Br and I.
26. The use according to any preceding claim wherein R7 represents hydrogen.
27. The use according to Claim 1 wherein one of R5, R6, R7 and R8 is other than hydrogen, and the remaining three represent hydrogen.
28. The use according to any preceding claim wherein R9 represents unsubstituted C, to C6 alkyl.
29. The use according to any preceding claim wherein R10 and R11 are the same or different and each is independently selected from the group consisting of H and unsubstituted C1 to Ce alkyl.
30. The use according to any preceding claim wherein R'2 represents unsubstituted C, to C6 alkyl.
3.1. The use according to any preceding claim wherein R1 represents H.
32. The use according to Claim 1 wherein the compound of Formula (I) has the structure:
Figure imgf000127_0001
33. The use according to Claim 1 wherein the compound of Formula (I) is selected from the group consisting of:
Figure imgf000127_0002
34. The use according to any preceding claim wherein the helminth is a nematode.
35. The use according to Claim 34 wherein the nematode is selected from the group consisting of: Ostertagia lyrata, O. ostertagi, O. circυmcincta,
Cooperia oncophora, C. pect/nata, C. punctata, C. surnabada, C. curticea, Haemonchus contortus, H. placet, Trichostrongylus axei, T. colubriformis, T. vetrinus, Bunostomum phlebotomum, B. trigonocephalum, Oesophagostomum radiatum, O. dentatum, O. venulosum, O. columbianum, Strongyloides papillosus, S. westeri, S. stercoralis,
Nematodirus helvetianus, N. spathiger, N. filicolis, Trichuris spp., Strongylus vulgaris, S. edentatus, S. equinus, Triodontophorus spp., Oxyuris equi, Parascaήs equorum, Habronema muscae, Oncocerca spp., Dirofilaria immitis, Toxocara canis, Toxascaris leonina, Ancylostoma caninum, A. braziliense, A. duodenale, Thelazia spp., Uncinana stenocephala, Chaberia ovina, Ascaris lumbricoides, Dictyocaulus vivaparus, D. arnfieldi, D.Jilaria, Brugia malayi, B. timori, Dioctophyma renale, Enterobius vermicularis, Loa loa, Mansonella ozzardi, M. perstans, M. streptocerca, Necator americanus, Onchocerca volvulus, Stronglyloides stercoralis, Trichinella spiralis, T. triciura and Wuchereria bancrofti.
36. The use according to Claim 35 wherein the nematode is a plant-damaging nematode selected from the genera Meloidogyne, Heterodera, Ditylenchus, Aphelenchoides, Radopholus, Globodera, Pratylenchus, Longidorus and Xiphenema.
37. The use according to any of Claims 1 to 33 wherein the helminth is a cestode.
38. The use according to Claim 37 wherein the cestode is selected from the group consisting of Diphyllobothrium latum, D. caninum, Echinococcus granulosus, E. multilocularis, Hymenolepsis diminuta, Taenia multiceps, T. saginatus, T. serialis, T. solium and Vampirolepis nana.
39. The use according to any of Claims 1 to 33 wherein the helminth is a trematode.
40. The use according to Claim 39 wherein the trematode is selected from the group consisting of Clonorchis sinensis, Dicrocoelium dendriticum, an echinostome, Fasciolopsis buski, Fasciola hepatica, a heterophyid, Nanophyetus salmincola, Opisthorchis felineus, O. viver ni, Paragonimus kellicotti, P. westermani, Schistosoma haematobium, S. japonicum, S. mansoni, S. intercalatum and S. mekongi.
41. A compound of Formula (II), (IIA) or (IIB):
Figure imgf000129_0001
Figure imgf000129_0002
wherein:
R1a represents H, C. to C6 alkyl or benzyl
R2a represents OR12 or SR12;
R4a represents OR12 or SR12;
R3a, R5a, R6a, R7a and R8a is selected from the group consisting of:
(i) hydrogen;
(ii) C, to C6 alkyl, which may be branched or unbranched and unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10 and NR10R11;
(iii) C2 to C20 alkenyl, which may be unsubstituted or substituted by 1 -3 substituents independently selected from the group consisting of C, to C6 alkyl, C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10 and NR10R11;
(iv) C2 to C10 alkynyl, which may be unsubstituted or substituted by 1 -3 substituents independently selected from the group consisting of C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10 and NR 0R11;
(v) C6 to C1S aryl, which may be unsubstituted or substituted by 1-5 substituents independently selected from the group consisting of C, to C6 alkyl, C6 to C10aryl, OR8, SR9, CN, F, CI, Br, I, OH, SH, N02, COOR10, COR9, OCF3, CF3and NR10R11; (vi) C3 to C8 cycloalkyl, which may be unsubstituted or substituted by 1-5 substituents independently selected from the group consisting of C. to Ce alkyl, Ce to C10 aryl, OR9, SR9, CN, F, CI, Br, OH, SH, N02, COOR10, COR9, OCF3, CF3 and NR10R11; (vii) a heterocyclic group, which may be aromatic or non-aromatic, having from 5 to 10 ring atoms wherein 1 , 2 or 3 of the ring atoms are selected from nitrogen, oxygen or sulfur atoms and the remainder are carbon atoms; (viii) OR12; or (ix) a halo group selected from F, CI, Br or I;
with the proviso that at least one of R5a, R6a, R7a and R8a is selected from the group consisting of:
(i) C2 to C10 alkenyl, which may be unsubstituted or substituted by 1 -3 substituents independently selected from the group consisting of
C. to Cβ alkyl, C6 to C10 aryl, OR9 or SR9, CN, F, CI, Br, I, OH, SH,
N02, COR9, COOR10 and NR10R11; (ii) C2to C10 alkynyl, which may be unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10 and NR10R11; (iii) C6 to C15 aryl, which may be unsubstituted or substituted by 1 -5 substituents independently selected from the group consisting of
C, to C6 alkyl, C6 to C10aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10 and NR10R11;
(iv) OR12; or (v) a halo group selected from F, CI, Br or I,
wherein R9 represents C, to C6 alkyl or C6 to C15aryl;
R10 and R11 are the same or different and each is independently selected from the group consisting of hydrogen, C, to C6 alkyl and C6 to C1g aryl; and R12 represents C, to C6 alkyl, which may be branched or unbranched and unsubstituted or substituted by 1 -3 substituents independently selected from the group consisting of OR8, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10 and NR10R11;
or an N-oxide derivative thereof, wherein the quinoline ring nitrogen forms an N-oxide group, or a pharmaceutically acceptable salt, or solvate, or addition salt or a quaternary ammonium salt thereof.
42. A compound according to Claim 41 wherein R3a, R5a, R6a, R7a and R8a are independently selected from the group consisting of:
(i) hydrogen;
(ii) G, to C6 alkyl, which may be branched or unbranched and unsubstituted or substituted by 1 -3 substituents independently selected from the group consisting of C6 to C10 aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10 and NR10R11;
(iii) C2to C6 alkynyl, which may be unsubstituted or substituted by 1-3 substituents independently selected from the group consisting of Cβ to C10 aryl, OR9 or SR9, CN, F, CI, Br, I, OH, SH, N02, COR9,
COOR10 and NR10R11;
(iv) CB to C10 aryl, which may be unsubstituted or substituted by 1-5 substituents independently selected from the group consisting of C, to C6 alkyl, C6 to C10aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10, OCF3J CF3 and NR10R11;
(v) OR12 wherein R 2; and
(vi) a halo group selected from F, CI, Br and I,
wherein R9, R10, R11 and R12are as defined as in Claim 41 .
43. A compound according to Claim 41 or Claim 42 wherein R3a represents H.
44. A compound according to any of Claims 41 to 43 wherein R5a, RSa, R7a and R8a are selected from the group consisting of:
(i) hydrogen;
(ii) unsubstituted C, to Ce alkyl which may be branched or unbranched; (iii) unsubstituted C, to Cs alkynyl, which may be branched or unbranched;
(iv) unsubstituted Cβto C10 aryl;
(v) OR12; or
(vi) a halo group selected from F, CI, Br or I.
45. A compound according to any of Claims 41 to 44 wherein one of R5a, R6a, R7a and R8a is other than hydrogen and the remaining three represent hydrogen.
46. A compound according to any of Claims 41 to 45 wherein one of R5a, Rδa,
R7a and R8a represents a group selected from:
(i) Cβ to C10 aryl, which may be unsubstituted or substituted by 1-5 substituents independently selected from the group consisting of C, to C6 alkyl, C6 to C10aryl, OR9, SR9, CN, F, CI, Br, I, OH, SH, N02, COR9, COOR10, OCF3, CF3 and NR10R11;
(ii) OR12; or
(iii) a halo group selected from F, CI or Br, and the remaining three represent hydrogen, wherein R9, R10, R11 and R12 are as defined in Claim 41 .
47. A compound according to any of Claims 41 to 46 wherein one of R5a, R6a,
R7a and R8a represents C6 to C10 aryl, which may be unsubstituted or substituted by 1-5 substituents independently selected from the group consisting of CΛ to C6 alkyl, C6 to C10aryl, OR9, SR9, F, CI, Br, I, OCF3 and CF3; and the remaining three represent hydrogen.
48. A compound according to any of Claims 41 to 47 wherein at least one of Reaand R8a represents a group selected from: F, CI, Br, I and OR12 wherein R12 as defined as in Claim 41.
49. A compound according to any of Claims 41 to 48 wherein least one of R6a and R8a is selected from phenyl which may be unsubstituted or substituted by 1-5 substituents independently selected from the group consisting of CT to Ce alkyl, C6 to C10 aryl, F, CI, Br, I, OCF3, CF3, OR9 and SR9 wherein R9 represents , to CB alkyl.
50. A compound according to any of Claim 49 wherein at least one of R6a and R8a is selected from phenyl which may be substituted by 1-3 methoxy groups.
51. A compound according to any of Claims 41 to 50 wherein R6a represents hydrogen.
52. A compound according to any of Claims 41 to 51 wherein R7a represents hydrogen.
53. A compound according to any of Claims 41 to 52 wherein R9 represents unsubstituted C, to C6 alkyl.
54. A compound according to any of Claims 41 to 53 wherein R 0 and R11 are the same or different and each is independently selected from the group consisting of H and C1 to Cs alkyl.
55. A compound according to any of Claims 41 to 54 wherein R1a represents H.
56. A compound according to Claim 41 selected from the group consisting of:
Figure imgf000134_0001
57. A compound according to Claim 41 selected from the group consisting of:
Figure imgf000134_0002
58. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to any of Claims 41 to 57 in a pharmaceutical carrier.
59. A process for the production of a compound of Formula (π):
Figure imgf000134_0003
or an intermediate thereof, wherein R2a and R4a represent OR12 or SR12 and R 2 represents C, to C6 alkyl, and R3a, R5a, R6a, R7a and R8a are as defined in any of Claims 41 to 56, and are other than C2 to C10 alkenyl, C2 to C10 alkynyl, or C6 to C15 aryl, comprising the steps of: (a) subjecting a compound of Formula (in)
Figure imgf000135_0001
wherein R5b, R6b, R7b and R8 respectively represent the groups R5a, R6a, R7a and R8a or precursors thereof, to reaction with malonic acid in the presence of phosphorus oxychloride to produce a compound of Formula (IV):
Figure imgf000135_0002
(b) subjecting the compound of Formula (IV) to reaction with NaXR12, wherein X represents oxygen or sulphur to form a compound of Formula (V):
Figure imgf000135_0003
and optionally,
(c) introducing a group R3a or a precursor thereof, where R3a is other than hydrogen, into the 3-position of the quinoline ring, by subjecting the compound of Formula (V) to a deprotonation reaction at the quinoline 3-position using a strong base, and quenching the anion with an electrophile to form the group R3a or a precursor thereof.
60. A process for producing a compound of Formula (II) or an intermediate thereof, wherein at least one of. R5!„-..R6a, Rla and R8a represents a substituent selected from substituted or unsubstituted C2 to C10 alkenyl, substituted or unsubstituted C2 to C10 alkynyl, substituted or unsubstituted C6 to C15 aryl or a substituted or unsubstituted C5to C10 heteroaryl group as defined in any of Claims 41 to 56, comprising reacting a compound of Formula (II) wherein one of R5a, R6a, R7a and R8a represents Br, I or triflate, with a boronic acid derivative of Formula (VI):
(OH)2B-ψ (VI)
wherein ψ represents a substituted or unsubstituted C2 to C10 alkenyl, substituted or unsubstituted C2 to C10 alkynyl, substituted or unsubstituted C6 to C15 aryl or a C5 to C10 heteroaryl group as defined as in any of Claims 40-55, the reaction being carried out in the presence of a base and a palladium or nickel catalyst under Suzuki coupling conditions.
61. A process according Claim 60 wherein the catalyst is selected from the group consisting of Pd(PPh3)4, Ni(dppf)CI2 Pd(dba)2, Pd(OAc)2, Pd(OAc)2/(o-tol)3P, Pd(OAc)2/dppf, (PhCN2PdCI2/Ph3As, (CH3CN)2PdCI2, Pd-C, (Ph3P)2NiCI2, Pd(dppb)CI2, bis(tricyclohexyl-phosphine)palladium(ll) chloride, (Ph3P)2PdCI2 and trans-di-μ-acetatobis[2-(di-o-tolylphosphino)- benzyl]dipalladium(ll).
62. A process according to Claim 61 wherein the catalyst is selected from Pd(PPh3)4 and Pd(PPh3)2CI2.
63. A process according to any of Claims 60 to 62 wherein the base is selected from Na2C03, NaHC03, K2C03, Cs2C03, K3P04, Et3N, Ag20, Ba(OH)2 and CsF.
s 64. AjDrpcess according to Claim 63 wherein the base is Na2C03.
65. A process according to any of Claims 60 to 64 wherein the reaction is carried out in a solvent comprising a hydrocarbon.
o 66. A process according to Claim 65 wherein the solvent comprises a hydrocarbon selected from toluene and benzene.
67. Use according to Claim 1 , of a compound of Formula (I), (IA) or (IB) as defined in any of Claims 1 to 33, in the manufacture of a pharmaceutical 5 composition for the treatment or prophylaxis of infections caused by arthropod ectoparasites.
68. Use according to Claim 67 wherein the arthropod ectoparasites are selected from the group consisting of flies, lice, keds, fleas, ticks, mites and certain copepod of fish. 0
69. Use according to Claim 68 wherein the arthropod ectoparasites are ticks selected from the group consisting of Boophilus spp, Rhipicephalus spp, Ixodes spp, Hyalomma spp, Amblyomma spp, Dermacentor spp and Argas spp. 5
70. Use according to Claim 68 wherein the arthropod ectoparasites are mites selected from the group consisting of Psoroptes spp, Chorioptes spp, Sarcoptes spp and Demodex spp.
0 71. Use according to Claim 68 wherein the arthropod ectoparasites are flies selected from the group consisting of Musca spp, Stomoxys spp, Oestrus spp, Culicoides spp, Tabanus spp, Phlebotomus spp, Simulium spp, Lucilia spp, Calliphora spp, Dermatobia spp and Hypoderma spp.
72. Use according to Claim 68 wherein the arthropod ectoparasites are lice selected from the group consisting of Linognathus spp, Bovicola spp,
Haematopinus spp and Solenopotes spp.
73. Use according to Claim 68 wherein the arthropod ectoparasites are keds.
74. Use according to Claim 73 wherein the ked is Melophagus ovinus.
75. Use according to Claim 68 wherein the arthropod ectoparasites are fleas.
76. Use according to Claim 75 wherein the flea is Ctenocephalides spp.
77. Use according to Claim 68 wherein the arthropod ectoparasite is an ectoparasite of fish.
78. Use according to Claim 77 wherein the ectoparasite is a copepod parasite selected from the group consisting of Lepeophtheirus salmonis and Caligus elongatus.
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