EP0222839A1 - Antimalariaverbindungen - Google Patents
AntimalariaverbindungenInfo
- Publication number
- EP0222839A1 EP0222839A1 EP86903140A EP86903140A EP0222839A1 EP 0222839 A1 EP0222839 A1 EP 0222839A1 EP 86903140 A EP86903140 A EP 86903140A EP 86903140 A EP86903140 A EP 86903140A EP 0222839 A1 EP0222839 A1 EP 0222839A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- mono
- ylamino
- compound
- general formula
- phenol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
Definitions
- the present invention relates generally to having compounds having anti alarial activity, to processes for the preparation thereof, to pharmaceutical compositions containing these compounds and to methods of treatment using the compounds or compositions.
- the present invention relates to a class of mono- and di-Mannich bases, derived from 4-(7'- substituted -1' , 5'- naphthyridin-4*-yla ino) phenols and 4-(7'- substituted- quinolin -4'-ylamino) phenols which have been found to exhibit antimalarial activity against a number of species of Plasmodia, particularly the principal human malarial parasite Plasmodium falciparum.
- X represents a halogen or halogen-substituted alkyl group
- Y represents CH or N; and R 1 and R2, which may be the same or different, represent hydrogen, aminoalkyl, mono- or di-alkylaminoalkyl, mono- or di-(substituted alkyl)aminoalkyl, mono- or di-(cycloalkyl)aminoalkyl, mono- or di-(aryl)aminoalkyl, mono- or di-(substituted aryl)aminoalkyl, or alkyl substituted by a nitrogen-containing heterocyclic or mono- or di-alkyl- substituted heterocyclic group; provided that R1 and R2 are not both hydrogen; and that R 2 is not diethylaminomethyl when X is chloro, Y is CH and R is hydrogen; or when X is bromo, Y is N and R is hydrogen.
- Preferred subgroups of compounds within the general formula I are compounds in which X represents halogen and Y represents N, and compounds in which X represents halogen substituted alkyl and Y represents CH.
- X represents a bromo, chloro or fluoro group, or a trifluoromethyl group.
- R 1 and/or R2 represgnt aminomethyl, mono- or di-alkylaminomethyl, mono- or di-(substituted alkyl)aminomethyl, mono- or di-(cycloalkyl)aminomethyl, mono- or. di-(aryl)aminomethyl, mono- or di-(substituted aryl)aminomethyl, or methyl substituted by a nitrogen-containing heterocyclic or mono- or di-alkyl substituted heterocyclic group.
- R 1 and/or R2 aarree are represented by R 1 and/or R2 aarree::
- Particularly preferred compounds of this invention are the di-Mannich bases, i.e. compounds in which both R 1 and R2 are other than hydrogen.
- this invention provides a process for the preparation of compounds of the general formula (I) , which comprises reaction of a compound of the general formula (II) :
- the compound of general formula II is refluxed with the appropriate amine or heterocyclic compound in ethanolic formalin. Where a moderate amount of the amine or heterocyclic compound is used, the mono-Mannich base is prepared. Excess amounts of the amine or heterocyclic compound lead to preparation of the di-Mannich bases.
- the compounds of the general formula II in which X is bromo and Y is N may be prepared from 3-bromo-8-chloro-l,5-naphthyridine (Barlin, G.B., and Tan, W.-L., Aust.J.Chem.1985, 3_8, 459 ) b Y heating with aqueous methanolic p-aminophenol hydrochloride.
- the compound of the general formula II in which X is triflugromethyl and Y is CH may be prepared from 4-chloro-7-trifluoromethyl.quinoline (Snyder, H.R. , et.al., J. m.Chem.Soc. , 1947, 6_9, 371) by refluxing with aqueous methanolic p-aminophenol hydrochloride.
- Other compounds of the general formula II may be prepared in an analogous manner.
- the compounds of the general formula I may be prepared by reaction of a compound of general formula III:
- this reaction is performed under reflux in aqueous methanol.
- the compounds of the present invention have exhibited antimalarial activity when screened by in vivo evaluation for activity against P.vinckei vinckei in mice following preliminary examination of each compound for toxicity and for safe dosage levels prior to the antimalarial studies.
- a number of compounds of this invention have been more effective than chloroquine, against the sensitive strain, and approximately as effective as mefloquine and amodiaquine against the resistant strain.
- Certain compounds of this invention have also shown activity in vivo against P.berghei in mice.
- the present invention also provides a pharmaceutical composition for use in treatment of malaria in an animal, including a human, which comprises an effective amount of a compound of the general formula I, together with a pharmaceutically acceptable carrier or diluent therefor.
- a method of treating malaria in an animal including a human, which comprises administering to the animal an effective amount of a compound of the general formula I.
- the tripicrate was prepared in, and recrystallized from, ethanol. It had m.p. 176-178°. (Found: C, 45.0, H, 4.0; N, 15.7.
- the dipicrate was prepared in and recrystallized from ethanol. It had m.p. 216-218°. (Found: C, 44.5; H, 3.5; N, 15.6. C 24 H 2 gBr 5 0 3 .2(CgH 3 N 3 0 7 ) requires C, 44.5; H, 3.5; N, 15.8%) .
- the naphthyridines were tested for acute toxicity in mice by intraperitoneal injection in normal saline or peanut oil. Each test chemical was injected in a single dose of 200 mg/kg of body weight [except for 4-(7'-bromo-1' ,5'-naphthyridin-4'-ylamino)-2,6-bis- (diethylamino and pyrrolidin-1"-yDmethylphenol which, due to toxicity at 200 mg/kg, were run at 100 mg/kg] to three mice. No apparent ill effects were observed and all mice survived to and beyond 4 days in the above tests and in control experiments with normal saline and peanut oil.
- Times given are those after injection of the chemical under test.
- Time h, hours; d, days; w, weeks; Oh denotes pretreatment.
- TN88 PO 200 14 12 1 ⁇ 1 ⁇ 1 3 15 21 ⁇ 1 ⁇ 1 ⁇ 1
- a PO peanut oil
- NS normal saline
- mice Each quinoline used in the antimalarial screening was tested for acute toxicity in three mice by intraperitoneal injection, each with a single dose in normal saline or peanut oil, at a dose of 100 mg/kg of body weight. No apparent ill effects were observed. and all mice survived to and beyond 6 days in the above tests, and in control experiments with normal saline and peanut oil.
- Times given are those after injection of the chemical under test.
- Time h, hours; d, days; w, weeks; Oh denotes pre reatmen .
- NS normal saline.
- N-methyIpiperazine (2.0ml) and ethanol (10.0ml) were treated as above.
- the product was purified by column (alumina; chloroform) and thin-layer chromatography (silica; methanol) to give a yellow oil which crystallized m.p. 163-164°. (Found: C, 62.9;
- mice Each 1,5-naphthyridine and quinoline used for antimalarial screening was tested for acute toxicity in mice by intraperitoneal injection in normal saline or peanut oil.
- Each test chemical was injected in a single dose of 100 mg/kg of body weight [except for 2,6-bis(4"-methylpiperazin-1"-ylmethyl)-4-(7'-tri- fluoromethylquinolin -4'-ylamino)phenol which, due to the death of one mouse at a dose of 100 mg/kg, was run at 50 mg/kg] to three mice.
- test chemical was given at a dosage of 100 mg/kg of body weight except for 2,6-bis(4"-methylpiperazin- 1"-ylmethyl)-4-(7'-trifluoromethylquinolin-4'- ylamino)phenol which was at 50 mg/kg, and blood counts were made at 9, 24, 48 and 72h and thereafter as shown in Table 3.
- Times given are those after injection of the chemical under test.
- Time h, hours; d, days; Oh denotes pretreatment.
- Mono- and di-Mannich bases derived from 4-(7'-bromo or 7'-chloro-1' ,5'-naphthyridin-4*- ylamino) henol and 4-(7'-trifluoromethylquinolin-4'- ylamino)phenol were assayed for antimalarial activity (using an in vitro radioisotopic technique) against three isolates of-Plasmodium falciparum. The results are shown in Tables 4, 4A and 5.
- the 1,5- naph hyridines TN78 and particularly TN79 were significantly less toxic than amodiaquine (or chloroquine) .
- the 7-trifluoromethylquinolines TN108 and TN112 were, on the evidence available, also less toxic than amodiaquine and chloroquine.
- the FCQ27 line of Plasmodium falciparum (origin: Papua New Guinea, first isolated at The Walter and Eliza Hall Institute of Medical Research, Melbourne) (Chen et al.. Southeast Asian Journal of Tropical Medicine and Public Health, 1980, 1_1, 435), was obtained from Dr.G.Butcher (Royal Newcastle Hospital, Newcastle, Australia) .
- the Kl line (origin: Kanchanaburi, Thailand) (Thaithong and Beale, Transactions of the R ⁇ yal Society of Tropical Medicine and Hygiene, 1981, 75 ⁇ , 271) was obtained from Dr. .Saul (Queensland Institute of Medical Research) .
- FCQ2 line (origin Madang, Papua New Guinea, first isolated at The Walter and Eliza Hall Institute of Medical Research, Melbourne) (Chen et al., supra) was obtained from Dr. .Saul (Queensland Institute of Medical Research) . All isolates were maintained routinely by the in vitro culture technique of Trager and Jensen (Science, 1976, 193, 673). Stock cultures contained a 5% suspension of washed human erythrocytes, type O in RPMI 1640 medium (Flow), supplemented with 25mM HEPES-KOH pH 7.2, 32mM NaHC0 3 and 10% human serum type O. Gentamicin (40 ⁇ g/ml) was added to all media. Cultures were maintained in modular incubator chambers (Flow) at 37.5°C in a gas mixture of 5% C0 2 , 5% 0 2 and 90% N.,.
- Chloroquine phosphate was purchased from Sterling Pharmaceuticals (Sydney, Australia) and amodiaquine hydrochloride from Parke Davis and Co., (Sydney). Mefloquine hydrochloride was a gift from the Walter Reed Army Institute of Research. The series of 4-(7'-bromo- and 7*-chloro-1' ,5*-naphthyridine-4'- ylamino)phenols and trifluoromethylquinolin-4*-ylamino phenols were prepared in the laboratories of the John Curtin School of Medical Research, Australia. Stock solutions of chloroquine and amodiaquine were prepared in ddw and subsequently diluted in RPMI medium.
- the isotope was supplied as a lyophylate (5000 mCi/ml) in ampoules containing 5.0 mCi (Amersham, U.K.).
- a solution containing 20 ⁇ Ci of H-hypoxan hine per ml of 1640 medium was prepared.
- Microculture plates (Falcon, 96 well, flat bottom) were prepared as described by Desjardins et al (supra) with some modifications. A volume of 50 ⁇ l of complete RPMI solution was first added to all wells. Then, leaving Row A as the control row a further 50 ⁇ l of chloroquine in RPMI was added to the first three wells of Row B and serial twofold dilutions made across the plate and continued in Row C The same procedure was repeated for the test compounds in subsequent rows. A working volume of 50 ⁇ l was preferred to 25 ⁇ l in order to reduce replicate error.
- Y 2 - log Y,)] was employed.
- Y 5Q was the dpm value midway between parasitized and non-parasitized control cultures and
- X- , Y.. , X_ and Y 2 are the concentration and dpm values for the data points above and below the dpm midpoints. Differences between mean IC 0 values were compared using Student's t-test, with P ⁇ 0.05 considered significant.
- mice were injected with a single i.p. dose of the test chemical in peanut oil (0.4ml) (except for amodiaquine hydrochloride and chloroquine diphosphate which were in 0.4ml normal saline), and were observed at 0.5h, 3h and daily thereafter to 7 days.
- Results are expressed as the mean ( ⁇ SE) of three tests calculated after logarithmic transformation of data unless specified otherwise.
- Results are expressed as the mean ( ⁇ SE) of three tests calculated after logarithmic transformation of data unless otherwise specified.
- Results are expressed as the mean ( ⁇ SE) of 5 tests calculated after logarithmic transformation of the data unless specified otherwise.
- the acute intraperitoneal LD 5Q of chloroquine in mouse is 73mg/kg.
- the Antwerp/Kasapa (ANKA) strain of Plasmodium bergei was isolated on 7 March, 1965 at the Prince Leopold Institute, Antwerp, Belgium from infected mosquitoes caught in the forest galleries of Kasapa, Zaire by Bafort [Vincke,I.H. and Bafort,J. (1968). Resultats de martenasmodium berghei. Ann.Soc.Belg.Med.Trop. , 48, 439-454]. This strain was obtained from the School of Public Health and Tropical Medicine, Sydney, Australia. Protocol
- test mice were each given a dose of 10 million parasites of the ANKA strain of P.berghei in sodium citrate on Day 1. The parasitaemia of the mice was then allowed to reach £ 20% on Day 5. Then a dose 0.8mg/kg of TN77, TN112, and chloroquine were each given orally to three separate replicate mice for four consecutive days and the parasitaemia followed for up to 21 days.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU613/85 | 1985-05-17 | ||
AUPH061385 | 1985-05-17 | ||
AU819/85 | 1985-05-30 | ||
AUPH081985 | 1985-05-30 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0222839A1 true EP0222839A1 (de) | 1987-05-27 |
EP0222839A4 EP0222839A4 (de) | 1988-11-09 |
Family
ID=25642949
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP19860903140 Withdrawn EP0222839A4 (de) | 1985-05-17 | 1986-05-16 | Antimalariaverbindungen. |
Country Status (2)
Country | Link |
---|---|
EP (1) | EP0222839A4 (de) |
WO (1) | WO1986006718A1 (de) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10253091B2 (en) | 2009-03-19 | 2019-04-09 | Chugai Seiyaku Kabushiki Kaisha | Antibody constant region variant |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5240916A (en) * | 1989-07-27 | 1993-08-31 | Dowelanco | Naphthyridine derivatives |
GB9127252D0 (en) * | 1991-12-23 | 1992-02-19 | Boots Co Plc | Therapeutic agents |
CN1052232C (zh) * | 1993-04-06 | 2000-05-10 | 中国人民解放军军事医学科学院微生物流行病研究所 | 取代的噁嗪衍生物 |
GB9312891D0 (en) * | 1993-06-22 | 1993-08-04 | Boots Co Plc | Therapeutic agents |
GB9510757D0 (en) * | 1994-09-19 | 1995-07-19 | Wellcome Found | Therapeuticaly active compounds |
AR004010A1 (es) | 1995-10-11 | 1998-09-30 | Glaxo Group Ltd | Compuestos heterociclicos |
EP0885198B1 (de) | 1996-03-05 | 2001-12-19 | AstraZeneca AB | 4-anilinochinazolin derivate |
ATE300521T1 (de) * | 1996-09-25 | 2005-08-15 | Astrazeneca Ab | Chinolin-derivate die den effekt von wachstumsfaktoren wie vegf vezögern |
RS49779B (sr) | 1998-01-12 | 2008-06-05 | Glaxo Group Limited, | Biciklična heteroaromatična jedinjenja kao inhibitori protein tirozin kinaze |
US6372757B1 (en) | 1998-05-08 | 2002-04-16 | Smithkline Beecham P.L.C. | Phenylurea and phenylthio urea derivatives |
GB9914763D0 (en) * | 1998-09-08 | 1999-08-25 | Ufc Limited | Antimalarial compounds |
US6933299B1 (en) | 1999-07-09 | 2005-08-23 | Smithkline Beecham Corporation | Anilinoquinazolines as protein tyrosine kinase inhibitors |
ATE377597T1 (de) | 1999-07-09 | 2007-11-15 | Glaxo Group Ltd | Anilinochinazoline als protein-tyrosin- kinasehemmer |
GB0012874D0 (en) * | 2000-05-27 | 2000-07-19 | Ufc Limited | 4-Aminoquinolines |
JP2004533418A (ja) * | 2001-03-14 | 2004-11-04 | ザ・ユニヴァーシティ・オヴ・リヴァプール | 抗マラリア化合物 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB612115A (en) * | 1945-10-23 | 1948-11-09 | Parke Davis & Co | Process for the manufacture of quinoline compounds |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR1437359A (fr) * | 1961-04-07 | 1966-05-06 | Parke Davis & Co | Nouveaux composés du quinoléylamino-o-crésol-1-oxyde et leurs procédés d'obtention |
CH536841A (de) * | 1968-01-05 | 1973-05-15 | Dr Friedheim Ernst A H | Verfahren zur Herstellung eines therapeutisch wirksamen Mittels, insbesondere eines Antimalariamittels, mit einem Chinolinringsystem |
US3948920A (en) * | 1971-10-19 | 1976-04-06 | Aktiebolaget Astra | New anti-malarial agents |
ATE4422T1 (de) * | 1979-10-18 | 1983-08-15 | Warner-Lambert Company | Substituierte 5-((7-chlor-4-chinolinyl)amino)-3(aminomethyl)-(1,1'-biphenyl)-2-ol-verbindungen verfahren zu ihrer herstellung; und die verbindungen enthaltende pharmazeutische zusammensetzungen. |
FR2498187A1 (fr) * | 1981-01-16 | 1982-07-23 | Rhone Poulenc Sante | Procede de preparation d'amino-4 chloro-7 quinoleines |
US4466965A (en) * | 1982-07-26 | 1984-08-21 | American Hospital Supply Corporation | Phthalazine compounds, compositions and use |
-
1986
- 1986-05-16 EP EP19860903140 patent/EP0222839A4/de not_active Withdrawn
- 1986-05-16 WO PCT/AU1986/000142 patent/WO1986006718A1/en not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB612115A (en) * | 1945-10-23 | 1948-11-09 | Parke Davis & Co | Process for the manufacture of quinoline compounds |
Non-Patent Citations (1)
Title |
---|
See also references of WO8606718A1 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10253091B2 (en) | 2009-03-19 | 2019-04-09 | Chugai Seiyaku Kabushiki Kaisha | Antibody constant region variant |
Also Published As
Publication number | Publication date |
---|---|
EP0222839A4 (de) | 1988-11-09 |
WO1986006718A1 (en) | 1986-11-20 |
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Legal Events
Date | Code | Title | Description |
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PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
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17P | Request for examination filed |
Effective date: 19870113 |
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AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE FR GB IT LI LU NL SE |
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A4 | Supplementary search report drawn up and despatched |
Effective date: 19881109 |
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STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
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18D | Application deemed to be withdrawn |
Effective date: 19891201 |
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RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: TAN, WENG-LAI Inventor name: BARLIN, GORDON, BRUCE |