CN1097422A - 3-N-alkyl-3,4-dihydro-amino-7,8,9,10 (7,10)-four (two) the hydrogen naphtho-s of the assorted virtue of 2H-4-replacement-(2,1-e)-(1,3) oxazine derivative - Google Patents

3-N-alkyl-3,4-dihydro-amino-7,8,9,10 (7,10)-four (two) the hydrogen naphtho-s of the assorted virtue of 2H-4-replacement-(2,1-e)-(1,3) oxazine derivative Download PDF

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CN1097422A
CN1097422A CN93103886A CN93103886A CN1097422A CN 1097422 A CN1097422 A CN 1097422A CN 93103886 A CN93103886 A CN 93103886A CN 93103886 A CN93103886 A CN 93103886A CN 1097422 A CN1097422 A CN 1097422A
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malaria
alkyl
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CN1052232C (en
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李福林
李国福
王云铃
高守海
焦岫卿
李玉兰
丁德本
丁建新
王俭
赵京花
杨俊德
王效义
乌增炎
单承启
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Institute of Microbiology and Epidemiology of AMMS
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Abstract

The present invention relates to formula (I) compound, it is treating and/or preventing the purposes of malaria, contains its pharmaceutical composition and treats and/or prevents the method for malaria, and each group sees specification sheets for details among the formula I.

Description

3-N-alkyl-3,4-dihydro-amino-7,8,9,10 (7,10)-four (two) the hydrogen naphtho-s of the assorted virtue of 2H-4-replacement-(2,1-e)-(1,3) oxazine derivative
The present invention relates to 3-N-alkyl-3, it is amino that 4-dihydro-2H-(4-replaces assorted virtue)-7,8,9,10(7,10)-four (two) hydrogen naphtho-s-(2,1-e) (1,3)-oxazine derivatives, it is treating and/or preventing the purposes of malaria, contains its pharmaceutical composition and treats and/or prevents the method for malaria.
Malaria is normal a kind of transmissible disease of sending out among the human masses, and the 2.0 hundred million plasmodium carrier and 100,000,000 malaria patients that have an appointment every year have an appointment in the whole world at present.The treatment of malaria depends on pharmacological agent, and people have now developed many antimalarial agents, as piperaquine phosphate, and Miaquin, benzfluorenol, Mefloquine hydrochloride, chloroquini phosphas, Artemether, Artemisinin, the hydrochloric acid quinoline is peaceful etc.But along with the frequent use of these medicines, plasmodium has generally produced resistance to these medicines, causes the curative effect of these medicines to reduce greatly.Therefore, a kind of not only to have had no drug resistance but also had the good antimalarial agent that treats and/or prevents the malaria effect be very urgent in exploitation.
Terminology used here " malaria " mainly refers to vivax malaria and pernicious malaria.
The objective of the invention is to find not only to have no drug resistance but also have the good antimalarial agent that treats and/or prevents the malaria effect.
The present inventor finds that unexpectedly logical formula I compound has the good malaria effect that treats and/or prevents, and has no drug resistance through extensively and profoundly research,
Wherein
The heteroaryl of Ar for replacing, preferred following formula group:
Figure 931038863_IMG10
X is a halogen, preferred chlorine and bromine,
R is-CH 2-CH 2-or-CH=CH-,
R 1C for straight or branched 2-5Alkyl,
The present invention is based on above-mentioned discovery is accomplished.
One of theme of the present invention relates to formula I 3N-alkyl-3, and it is amino-7,8,9 that 4-dihydro-2H-4-replaces assorted virtue, 10(7,10)-four (two) hydrogen naphtho-s-(2,1-e)-(1,3)-oxazine derivatives
Wherein
The heteroaryl of Ar for replacing, preferred
Figure 931038863_IMG12
X is a halogen, preferred chlorine, and bromine,
R is-CH 2-CH 2-or-CH=CH-,
R 1C for straight or branched 2-5Alkyl.
According to the present invention, logical formula I compound can prepare by following reaction scheme 1:
Figure 931038863_IMG13
Ar wherein, R, and R 1Define the same.
Step 1: the formula II compound in the step 1 can be by being similar to J.Heterocycl Chem 1982,19(3), and 663-7 and org Synth IV, the method preparation described in 882.
Step 2: formula III compound and Ar-Cl are by 1: the 1-2 weight ratio is reacted in rare alcohol or alcoholic solvent, reaction heated and stirred 3-20 hour.
Step 3: the formula IV compound is alkalized with sig water, get formula (V) compound.
Step 4: with formula (V) compound, formaldehyde and H 2NR 1By 1: 1-4: the 1-2 mol ratio, in ethanol, to react, reaction refluxes and stirred 5-25 hour, obtains the formula I compound.
In above-mentioned reaction scheme, used alcohol is C 1-3Alkyl alcohol, preferred alcohol; Used alkali is selected from ammoniacal liquor, alkaline carbonate, its supercarbonate or its oxyhydroxide;
According to the present invention, in preferred logical formula I compound,
Figure 931038863_IMG14
X is a chlorine or bromine,
R is-CH 2-CH 2-or-CH=CH-,
R 1Be straight or branched C 2-5Alkyl.
According to the present invention, the logical formula I compound of the present invention is one long-acting, quick-acting, efficient, has no drug resistance and the avirulent medicine that treats and/or prevents malaria, and it is all to Bai Shi plasmodium K in vivo or external 173The anti-chloroquine strain of strain and persister RC(thereof) good killing action is all arranged, killing the plasmodium rate is 100%.When the logical formula I compound of the present invention was used as prophylactic, the time that the plasmodium infection is avoided in its prevention was one month.
What another theme of the present invention related to is the pharmaceutical composition that contains generalformula, and this pharmaceutical composition can pass through this area ordinary method, pharmaceutical excipient commonly used in formula I compound and the pharmacy field is mixed prepare.Pharmaceutical composition of the present invention can be made into and be suitable for medicinal various formulations, as tablet, and capsule etc.
Another theme of the present invention is the method that treats and/or prevents malaria, and this method comprises the formula I compound administration of the effective amount for the treatment of and/or preventing in malaria patients or need the mankind of prevention of malaria.Route of administration is the various route of administration that are suitable for, preferred oral.Oral administration dosage can change in wide range, is generally 7-17mg formula I compound/kg body weight, during preferred 8-13mg/ kg body weight oral administration, and preferred first day oral 5-8 sheet, second day oral 3-5 sheet, every contains the 100mg9301 compound.
Following biological test is used for further specifying the good antimalarial effect of formula I compound of the present invention.
1. compare with other antimalarial drug, Bai Shi plasmodium K 173The antimalarial effect of strain and resistant strain thereof:
(1) test materials:
Experimental animal: Kunming outbreeding system small white mouse, body weight 18-22g plant in male Switzerland.
Test plasmodium: Bai Shi plasmodium (plasmodium berghei) K 173Strain,
The anti-chloroquine strain of its resistant strain RC-(RC/K173)
Trial drug: 9301-3-N-tertiary butyl-3,4-dihydro-2H-6-(7-chloro-4-quinoline amino)-7,8,9,10-tetrahydrochysene naphtho--(2,1-e)-(1,3)-oxazine,
The phosphoric acid Miaquin, benzfluorenol, quinine hydrochloride, Artemisinin, Artemether, chloroquini phosphas, piperaquine phosphate.
(2) test method:
Get and infect 4-5 days mouse blood of plasmodium, behind the conventional counting, be diluted to 0.2ml, wherein contain 1 * 10 with physiological saline 7The red corpuscle of individual parasitism.Every intraperitoneal mouse inoculation 0.2ml, inoculation day is D 0, be D next day 1, by that analogy.Each trial drug is established 5-6 dosage respectively by k=0.6, and each dosage adds a small amount of tween 80 and grinds, and becomes suspension or solution with distilled water diluting then.Every mouse administration 0.2ml, except that 9301 usefulness were irritated stomach and two kinds of route of administration of abdominal injection, other trial drug was gastric infusion.Adopt peters " 4 days inhibition test methods ", D behind the inoculation protozoon 0-D 3Successive administration 4 days, every day 1 time.D 4Coat the blood sheet behind every test group mouse equivalent blood sampling mixing, methyl alcohol is fixed, behind the Giemsa stain, and microscopic examination plasmodium parasitic rate.Ratio with administration group and control group parasitic rate is that plasmodium is suppressed rate.Obtain ED with return law of the straight line 50And ED 90, again from the ED of sensitive strain 50Or ED 90ED with drug resistance strain 50Or ED 90Ratio obtain resistance index I 50Or I 90
(3) result:
Test-results is summarized among the table 1-4.
9301 pairs of mouse malarias of table 1 K173 strain protozoon inhibition test result test one (4-d, p.o)
Dosage (mg/kg) The protozoon parasitic rate ( 0/ 00) Protozoon inhibiting rate (%) ED 50 ED 90
3.600 2.160 1.296 0.778 0.467 blanks are tested 2 1.500 0.900 0.540 0.324 0.194 blanks and are tested 3 1.500 0.900 0.540 0.324 0.194 blanks 0 0 0.1 21 50 117 0 6 76 134 146 208 0 3 61 164 186 201 100.00 100.00 99.91 82.05 57.26 100.00 97.12 63.46 35.58 29.81 100.00 98.51 69.65 18.41 7.46 0.48 0.34 0.40 0.74 0.77 0.69
Table 1(is continuous)
Dosage (mg/kg) The protozoon parasitic rate ( 0/ 00) Protozoon inhibiting rate (%) ED 50 ED 90
Test 4 1.500 0.900 0.540 0.324 0.194 blanks 0 0.8 18 150 214 228 100.00 99.65 92.11 34.21 6.14 0.33 0.51
X ED 50＝0.39±0.07 ED 90＝0.68±0.12
Annotate: 4 days PO=oral administrations of 4-d=administration
9301 pairs of mouse malarias of table 2 K173 strain protozoon inhibition test result tests one (4-d, ip opening)
Dosage (mg/kg) The protozoon parasitic rate ( 0/ 00) Protozoon inhibiting rate (%) ED 50 ED 90
1.500 0.900 0.540 0.324 0.194 blank tests 2 1.500 0.900 0.540 0.324 0.194 1.1 5 126 194 160 208 0 0.1 74 110 194 99.47 97.60 39.42 6.73 21.15 100.00 99.95 63.18 45.27 3.48 0.44 0.36 0.85 0.55
Table 2 (continuing)
Dosage (mg/kg) The protozoon parasitic rate ( 0/ 00) Protozoon inhibiting rate (%) ED 50 ED 90
Test 3 1.500 0.900 0.540 0.324 0.194 blanks 0 0.2 17 156 188 228 100.00 99.91 92.54 31.58 17.54 0.32 0.50
X ED 50＝0.37±0.06
ED 90＝0.63±0.19
Annotate: 4-d=administration 4 days
The ip=intraperitoneal injection
Table 3 9301 is relatively tired to the antimalarial of Bai Shi plasmodium K173 strain with other antimalarial drugs
Medicine ED 90(mg/kg) ED 90Ratio
9301 piperaquine phosphate amodiaquine lumefantrine Mefloquine chloroquine diphosphate Artemether qinghaosu quinin hydrochlorides 0.68±0.12 1.53±0.15 2.25±0.07 2.44±0.34 2.94±0.05 3.25±0.13 5.42±0.56 56.59±7.26 71.50±4.76 1.0 2.3 3.3 3.6 4.3 4.8 8.0 83.2 105.1
Annotate: ED 90Ratio is each medicine ED 90With 9301ED 90Ratio, the multiple of each pharmaceutical quantities that is drawn is 9301 antimalarial and tires and be the multiple of each medicine.
Table 4 9301 compares with other antimalarial drugs, and the antimalarial of Bai Shi plasmodium RC strain is tired
Medicine The ED of RC and N 90 I 90
RC N
Mefloquine lumefantrine chloroquine diphosphate piperaquine phosphate amodiaquine qinghaosu quinin hydrochloride Artemether 9301 182.52 182.70 291.60 342.73 18.60 401.20 367.40 18.30 1.20 3.94 2.44 3.25 1.53 2.25 56.59 71.50 5.42 0.68 62.1 74.9 89.7 224.0 8.3 7.1 5.7 3.4 1.8
Can see obviously that by table 1-4 data the logical formula I compound of the present invention is to mouse plasmodium K 173Strain and resistant strain thereof have very strong killing action, and have the antimalarial active that is higher than other known antimalarial agent.
Two, prevention of malaria test:
Adopt small white mouse with body weight 20 ± 2 grams, 80, male and female half and half, be divided into 8 groups, every group 10, wherein, two groups give the present invention 9301 compounds by the oral respectively and abdominal cavity of 40mg/kg dosage, two groups give the present invention 9301 compounds by the oral respectively and abdominal cavity of 100mg/kg dosage, two groups give the quinoline piperazine by the oral respectively and abdominal cavity of 40mg/kg dosage, two groups give the quinoline piperazine by the oral respectively and abdominal cavity of 100mg/kg dosage, administration same day, the 7th day, the 14th day and the 21st day, get 10 mouse peritoneals inoculations 8 * 10 for every group 6The red corpuscle of individual plasmodium parasitism, and behind each inoculated malaria protozoon, got the tail blood smear on the the 5th～7th day respectively and check plasmodium, write down positive mouse number simultaneously, the results are shown in Table 5.
Can see obviously that by table 6 time that the pre-protection against rodents malaria of the present invention's 9301 compounds protozoon infects was 4 weeks, and the quinoline piperazine was 2 weeks.Therefore formula I compound of the present invention has more long lasting prevention of malaria effect.
3. acute toxicity test
Give every group and contain 20 mouse, once oral and intraperitoneal administration the present invention 9301 compounds of totally 9 groups small white mouse difference were observed 7 days, record mice dying rate.The result shows the oral LD of the present invention's 9301 compounds 50Be 1500mg/kg, abdominal injection LD 50Be 900mg.Above-mentioned LD 50Data show that the logical formula I compound safety range of the present invention is wide, nontoxicity.
The present invention further specifies the present invention with following preparation embodiment, but it does not mean that any limitation of the invention.
Embodiment 1
(1) α-5,6,7, the preparation of 8-tetralol
Get 400 milliliter of 7.8% sodium hydroxide solution and place there-necked flask, be heated with stirring to 70 ℃, add naphthyl alcohol 10 grams, continue to be heated to 90 ℃.Keep 90-95 ℃, add alumino nickel, control reaction process with thin-layer chromatography, reaction needs 50 gram alumino nickels approximately.Filter, use hcl acidifying, separate out pale solid.Filter collection solids, oven dry gets α-5,6,7,8-tetralol 7.5 grams.Productive rate 77%, mp67-69 ℃.
(2) 4-amino 5,6,7, the preparation of 8-tetrahydrochysene-1-naphtholate hydrochlorate
Get 50 milliliters in Sodium sulfanilate 13.2 grams, water, place the beaker heating for dissolving.Be cooled to the Sodium sulfanilate crystallization with frozen water and separated out, added Sodium Nitrite 5.1 grams and be dissolved in the solution of 14 ml waters the cooling of external application cryosel, temperature is reduced to about 0 ℃, keep this temperature, stir and splash into 22.5 milliliters of hydrochloric acid, after dripping off, reaction soln becomes oyster white.Keep about 0 ℃, stir 40 minutes standby.
Get α-5,6,7,85 milliliters of 8-tetralol 10 grams, diluted sodium hydroxide solutions place flask, stir and make dissolving.With the cryosel cooling, cool the temperature to 0 ℃, keep this temperature, stir the diazonium salt solution that adds above preparation, in about 0 ℃, stirred 30 minutes, put 30 minutes, then heating, when temperature is increased to 50 ℃, between 50-70 ℃, continue to stir, add V-Brite B 32.2 grams.The khaki color precipitation is separated out in the very fast disappearance of solution colour simultaneously.Continue to stir 30 minutes, stop heating, the cooling reactant, filter collection solid is with rare V-Brite B solution washing solid, solid is made hydrochloride, and oven dry gets 4-amino-5,6,7,8-tetrahydrochysene-1-naphtholate hydrochlorate 9.8 grams, productive rate 72%, mp 273-275 ℃ (decomposition).
(3) 4-(7-chloro-4-quinoline amino) 5,6,7, the preparation of 8-tetrahydrochysene-1-naphthols
Get 4-amino-5,6,7,8-tetrahydrochysene-1-naphtholate hydrochlorate 10 restrains 150 milliliters of Diluted Alcohols, and 4,7-dichloroquinoline 12.5 grams, place there-necked flask, stirring heating, the very fast dissolving of solid, separated out yellow solid in about 30 minutes, and be heated with stirring to 3-10 hour, the solid that the filter collection is separated out, wash solid with Diluted Alcohol, then with solid suspension in weak ammonia, alkalize filter collection solid, washing, oven dry gets 4-(7-chloro-4-quinoline amino)-5,6,7,8-tetrahydrochysene-1-naphthols 13.3 grams, productive rate 81%, mp270-9 ℃ (decomposition).
(4) 3N-tertiary butyl-3,4-dihydro-2H-6-(7 chloro-4-quinoline amino)-7,8,9,10-tetrahydrochysene naphtho--(2,1-e) (1,3)-oxazine
Get 4-(7-chloro-4-quinoline amino)-5,6,7,8-tetrahydrochysene-1-naphthols 12.5 150 milliliters of 95% ethanol of gram, 7.1 milliliters in 36% formaldehyde, tert-butyl amine place there-necked flask, stirring and refluxing for 6 milliliters, react filtration in 10-20 hour, filtrate was cooled off 10-30 hour, and the solid that the filter collection is separated out is used the washing with alcohol solid, oven dry, get 3N-tertiary butyl-3,4-dihydro-2H-6-(7 chloro-4-quinoline amino)-7,8,9,10-tetrahydrochysene naphtho--(2,1-e) (1,3)-oxazine 14.5 grams, productive rate 85%, mp208-216 ℃ (decomposition).
Description of drawings:
Fig. 1-3-N-tertiary butyl-3,4-dihydro-2H-6-(7-chloro-4-quinoline amino)-7,8,9,10-tetrahydrochysene naphtho--(2,1-e)-(1,3)-oxazine 1H-NMR spectrum
Fig. 2-3-N-tertiary butyl-3,4-dihydro-2H-6-(7-chloro-4-quinoline amino)-7,8,9,10-tetrahydrochysene naphtho--(2,1-e)-infrared spectra of (1,3)-oxazine.

Claims (13)

1, logical formula I compound
Figure 931038863_IMG2
Wherein
The heteroaryl of Ar for replacing, preferred following formula group:
Figure 931038863_IMG3
X is a halogen, preferred chlorine or bromine,
R is-CH 2-CH 2-, or-CH=CH-
R 1C for straight or branched 2-5Alkyl.
2, the compound of claim 1, wherein
R is-CH 2-CH 2-,
X is a chlorine
R 1Be straight or branched C 2-5Alkyl,
Ar is
3, the compound of claim 1, wherein
R is-CH 2-CH 2-
X is a bromine
R 1Be straight or branched C 2-5Alkyl,
Ar is
Figure 931038863_IMG5
Figure 931038863_IMG6
4, the compound of claim 1, wherein
R is-CH=CH-
X is a chlorine
R 2Be straight or branched C 2-5Alkyl,
Ar is
Figure 931038863_IMG7
5, the compound of claim 1, wherein
R is-CH=CH-
X is a bromine
R 1Be straight or branched C 2-5Alkyl,
Ar is
Figure 931038863_IMG8
6, the arbitrary logical formula I compound of claim 1-4 is used for the treatment of and/or prevention of malaria.
7, a kind of being used for the treatment of and/or the pharmaceutical composition of prevention of malaria, it is characterized in that: with the formula I compound of the arbitrary requirement of claim 1-4 as activeconstituents.
8, the pharmaceutical composition of claim 5, wherein said composition is made into the various form of administration that are suitable for by means known in the art.
9, the pharmaceutical composition of claim 6, wherein said formulation are tablet.
10, the pharmaceutical composition of claim 6, wherein said formulation are capsule.
11, treat and/or prevent the method for malaria disease, it comprises and will treat and/or prevent the claim 1-4 requirement of significant quantity that the pharmaceutical composition that logical formula I compound or claim 5-8 require delivers medicine to malaria patients or needs the mankind of prevention of malaria.
12, the method for claim 9, wherein route of administration comprises any route of administration that is suitable for.
13, the method for claim 9, wherein route of administration is oral.
CN93103886A 1993-04-06 1993-04-06 3N-alkyl-3,4-dihydro-2H-4-substituted heteroaromatic azyl-7,8,9,10(7,10)-naphthane-(2,1-e)-(1,3) Expired - Fee Related CN1052232C (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103232444A (en) * 2013-04-18 2013-08-07 中国人民解放军军事医学科学院微生物流行病研究所 Naphthoquine derivatives, and preparation and application thereof
CN105085505A (en) * 2014-05-07 2015-11-25 昆明制药集团股份有限公司 Novel preparation process for naphthoquine salt
CN112409254A (en) * 2020-12-08 2021-02-26 重庆康乐制药有限公司 Preparation method of naphthoquine phosphate

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PH19255A (en) * 1983-09-16 1986-02-17 Smithkline Beckman Corp Salts of antimalarial phenanthrene methanol compounds
WO1986006718A1 (en) * 1985-05-17 1986-11-20 The Australian National University Antimalarial compounds

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103232444A (en) * 2013-04-18 2013-08-07 中国人民解放军军事医学科学院微生物流行病研究所 Naphthoquine derivatives, and preparation and application thereof
CN103232444B (en) * 2013-04-18 2015-07-22 中国人民解放军军事医学科学院微生物流行病研究所 Naphthoquine derivatives, and preparation and application thereof
CN105085505A (en) * 2014-05-07 2015-11-25 昆明制药集团股份有限公司 Novel preparation process for naphthoquine salt
CN105085505B (en) * 2014-05-07 2018-03-13 昆药集团股份有限公司 A kind of naphthol quinic salts new preparation process
CN112409254A (en) * 2020-12-08 2021-02-26 重庆康乐制药有限公司 Preparation method of naphthoquine phosphate

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