GB1562965A - 1,3-diaza fluorene - Google Patents
1,3-diaza fluorene Download PDFInfo
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- GB1562965A GB1562965A GB15792/77A GB1579277A GB1562965A GB 1562965 A GB1562965 A GB 1562965A GB 15792/77 A GB15792/77 A GB 15792/77A GB 1579277 A GB1579277 A GB 1579277A GB 1562965 A GB1562965 A GB 1562965A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
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Description
(54) 1,3-DIAZAFLUORENES (71) We, A. CHRISTIAENS SOCIETE ANONYME, a joint stock company organised under the laws of Belgium, of 60 Rue de L'Etuve, B-1000 Brussels,
Belgium, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:
This invention relates to new derivatives of 1,3-diazafluorene and to the use thereof in the pharmaceutical field.
According to one aspect of the invention rhere are provided derivatives of 1,3diazafluorene of general formula:
[in which n is 1, 2 or 3, the C,H group having a straight or branched chain; and
R represents a carboxylic acid group, an amino group of the formula
(in which Rl and R2 each represents a C1----C4 alkyl radical, such as a methyl or ethyl radical, or form together with rhe adjacent nitrogen atom a heterocyclic ring, such as piperazino, methylpiperazino, pyrrolidino or piperidino ring), an amido group of the formula
(in which R, and R2 have the meanings given above), or an aminocarbamoyl group of the formula
(in which m is 1, 2 or 3 and Rl and R2 have the meanings given above)l.
This invention relates also to the acid addition salts, such as hydrochlorides or hydrobromides, of the 1,3-diazafluorene derivatives of formula (I), in which R is an amino, amido or aminocarbamoyl group, or to the alkali metal salts, such as sodium salts, of the 1,3-diazafluorene derivatives of formula (I) in which R is a carboxylic acid group.
The compounds of formula (I) have interesting antimalarial properties.
The invention therefore also provides pharmaceutical compositions containing a 1,3-diazafluorene derivative of the formula I, preferably a pharmaceutically acceptable salt thereof, i.e. either an acid addition salt or a salt of an alkali metal, as the active ingredient, together with one or more pharmaceutically acceptable vehicles or carriers.
It has been surprisingly found that the compounds of the general formula I are active for the treatment of malaria. The antimalarial activity of the compounds of formula I has been tested on mice infested by Plasm odium berghei.
These tests dealt with the schizontocidal activity of the tested compounds after intraperitoneal or oral administration.
The inoculation was performed with blood obtained by heart puncture from infested mice and diluted with a 10% sodium citrate aqueous solution.
The inoculum containing about 50% of parasited red blood cells was injected intraperitoneally to healthy mice weighing about 20 g.
The usual time for the appearance of plasmodia in the blood of such infested animals is about three days.
Starting from the fourth day Giemsa coloured smears were counted daily for parasites.
The compounds to be tested were administered three hours after the infestation of the animals. This treatment was repeated daily during the three days following the first administration, so that the test compounds were administered over a total of four days.
The treated animals were examined together with untreated controls and controls treated with a reference compound.
According to the observed results, the activity of the compounds (absence of parasites after 4, 8 and 14 days) is graded by means of a proportional number of x-marks, in the following table I.
TABLE I
Compound Formula I:
Code number Example CnH2n R Relative activity
TABLE I (Continued)
Compound Formula I:
Code number Example CnH2n R Relative activity
A similar schizontocidal activity has also been observed with some specially selected compounds of the above described series (such as compounds 1304, 1242, 2159, 2212, 2162) against other species of animal Plasmodium (P. vinckei, P. gallinaceum, P. knowlesi) and even against Plasm odium talciparum, a typical human species, when tested in the monkey Aotus trivirgatus Moreover, it has been discovered that beside their schizontocidal properties rhe compounds also possess a gametocytocidal activity making the parasites unable to be transmitted by mosquitoes to other susceprible individuals.
This additional feature may be of the utmost practical importance for the interruption of the life cycle of the malaria causative organisms and consequently for the eradication of the disease.
Coming back to the schizontocidal activity it has also been found that, according to the dosage used and to the duration of the treatment, it was possible either to obtain a quick and permanent cure of the experimental disease or to maintain a low level of infestation which in combination with a reduced pathogenicity of the parasite can lead to a spontaneous and definitive recovery by active immunisation. The obtention of attenuated living strains of Plasmodium may also be of interest for preparing antimalarial-vaccines.
The new compounds of formula I in which R represents a carboxylic acid group and which are represented by the following formula:
in which n has the meaning given above, may be prepared by hydrolysis of an ester of the following formula
in which Alk represents a C14 alkyl group, such as ethyl, and n has the meaning given above.
The esters of formula III, which are themselves new compounds and are encompassed within the scope of the present invention, may be prepared by reacting an alkyl a-bromoalkanoate of the formula
Br-CnH2n-COO-Alk (IV) in which n and Alk have the meanings given above, with 6,8-dibromo-1,3-diaza fiuorene-9-one oxime of the following formula:
the oxime of formula V being itself obtained by reaction of 6,8-dibromo-l$-diaza- fiuorene-9-one of formula
with hydroxylamine hydrochloride (NH2OH. HC1).
The new compounds of formula II may also be prepared by reaction of 6,8dibromo-1,3-diazofluorene of formula VI with an acid of the formula
This type of reaction has been described by Newman and Lutz, J. Am. Soc., 2469 (1956).
The compounds of formula I, in which R represents an amino group and which are represented by the following formula
in which n, R1 and R2 have the meanings given above, may be prepared by reaction of 6,8-dibromo-1,3-diazofiuorenone of formula VI with an hydrochloride of an amine of the formula
in which n, R1 and R2 have the meanings given above.
The compounds of formula I in which R represents an amido or aminocarbamoyl group, and which are represented by the following formula
in which x is 0 or 1 and in which n, m, R, and R2 have the meanings given above are prepared by reacting an acid chloride of the formula
in which n has the meanings given above with a compound of the formula
in which m, x, R1 and R2 have the meanings given above.
The acid chlorides of formula XI are new compounds which may be obtained by reaction of the corresponding acid of formula II with thionyl chloride (SOCI2).
The compound of formula VI used as starting compound in the processes given above is also a new compound which may be obtained by oxidizing 6,8-dibromo-9 chloro-9-cyano-1,3-diazafluorene of formula XIII with nitric acid according to the following equation:
Br CI CN Br U NNNN Br (XIII) Br (VI) The compound of formula XIII which is also a new compound may be obtained by chlorination of 3H - 6,8 - dibromo - 9 - cyano - indeno [2,1 - d]pyrimidine of formula XIV according to the following equation:
The compound of formula XIV which is also a new compound may be obtained by bromination of 3H - 9 - cyano - indeno[2,1 - d]pyrimidine of formula XV in acetic acid according to the following equation:
The compound of formula XV is a known compound disclosed in Belgian Patent no 602,129. It is obtained by reflexing l-cyano-2-amino-indene of formula XVI
according to the following equation in fonnamide: NH l I xextinH2 NH (XVI) (XV) The compound of formula XVI is also a known compound, obtained as disclosed by Ch. W. Moore and J. C. Thorpe in J.C.S. 93, 65 (1908).
The invention is illustrated by the following examples.
Example 1.
Preparation of O - [1' - (carboxy) - ethyl - 6,8 - dibromo - 1,3 - diazafluorene - 9
one oxide (compound of formula II: CnH2n= > CHCHs; formula I: R=
----COOH; CnH2"= > CHCH,) First Process 1) Preparation of 6,8 - dibromo - 1,3 - diazafluorene - 9 - one oxime (compound
of formula V)
40 g of 6,8 - dibromo - 1,3 - diazafluorene - 9 - one (compound of formula VI) are dissolved in 6.5 1 of methanol. To the solution thus obtained, a solution of 20 g of hydroxylamine hydrochloride in the minimum amount of water is added. The mixture of said solutions is then refluxed for 4 hours during which time the desired osime of formula V precipitates. After distilllation of 5 litres of methanol, the reaction mixture is cooled, the desired oxime is filtered off, thoroughly rinsed with acetone and dried. Yield: 65%.
Said product is recrystallized from dimethylformamide to give a white powder.
Melting point 275-280 C.
Analysis:
Found: C 37.32%; H 1.43%; N 11.80%; Br 44.85%
Calculated: C 37.21%; H 1.41%; N 11.83%; Br 45.02% 2) Preparation of O - [1' - (ethoxycarbonyl)ethylj 6,8 - dibromo - 1,3 - diaza
fluorene - 9 - one oxime (compound of formula III: Alk=ethyl, CnH2n=
CH-CH3)
45 g of 6,8 - dibromo - 1,3 - diazafluorene - 9 - one oxime are dispersed in 600 ml of isopropanol and 600 ml of anhydrous acetone in the presence of 30 g of potassium carbonate and 20 ml of ethyl ebromopropionate (formula IV: CnH2E= CH----CH3). This mixture is refluxed until the oxime is dissolved. The solution thus obtained is filtered hot to remove salts, and the solvent is distilled off until crystallization starts. One obtains a yellowish-brown product which is filtered off, crystallized from 1.5 litre of acetone to give the desired ester of formula IV as tiny nacreous yellow needles, melting point: 16O-1620C. Yield: 75%.
Analysis:
Found: C 42.31%; H 2.65%; N 9.45%; Br 35.09%
Calculated: C 42.31%; H 2.66%; N 9.25%; Br 35.19% 3) Preparation of O - [1' - (carboxy)ethylj - 6,8 - dibromo - 1,3 - diazafluorene- 9 - one oxime (compound of formula II=CaH2"= > CHCH3) 10 g of O - [1 - (ethoxycarbonyl)ethyl] - 6,8 - dibromo - 1,3 - diazafluorene9 - one oxime are poured into 100 ml of 70% H2SO4, 50 ml of water are added gradually which raises the inner temperature of the reaction vessel to 500C. The solution starting from orange becomes yellow. The temperature of the reaction mixture rises to 70"C and is maintained for i hour. During reaction, the ester becomes completely dissolved and the acid is obtained shortly after, poured into 1 litre water and filtered off. The yellow insoluble matter is dissolved in diluted aqueous ammonia and precipitated back by means of 2N hydrochloric acid.
One obtains in that way a yellow precipitate which is rinsed and dried and thereafter recrystallized from ethyl acetate to give the desired acid of formula II as pale yellow microcrystals, melting point 230"C. Yield: quantitative.
Analysis:
Found: C 39.44%; H 2.11%; N 9.90%; Br 37.50%
Calculated: C 39.37%; H 2.12%; N 9.83%; Br 37.42%
Second process
The desired compound of formula II is also prepared by heating under reflux 3.4 g of 6,8 - dibromo - 1,3 - diazafluorenone (compound of formula VI), 1.6 g of a-(isopropylidene-amino-oxy) -propionic acid (a compound of the formula VII) and 0.5 g of para-toluene sulfonic acid, in 100 ml of 70% acetic acid, during 24 hours.
After cooling, the obtained precipitate is 'filtered and washed with water. The residue is extracted with water, made alkaline with ammonia and again filtered. After acidification, filtration and drying, the obtained acid melting at about 2300C is obtained.
The 6,8 - dibromo - 1,3 - diazafluorenone of formula VI used in the above (and following) preparations has been obtained in the following way:
1) Preparation of 3H - 6,8 - dibromo - 9 - cyano - indeno [2,1 - d] - pyrimidine
(compound of formula XIV)
20 g (0.103 mole) of 3H - 9 - cyano - indeno [2,1 - d] - pyridine (compound of formula XV) are dispersed in 600 ml of pure acetic acid. The dispersion is refluxed and 20 ml of bromine are added thereto as quickly as possible. Heating is continued for another 15 minutes, the mixture is cooled slightly and poured entirely into 2 litres of water. A yellowish-white precipitate is obtained, filtered off and rinsed with water.
Said precipitate is dissolved in one litre of tepid benzene, the solution is filtered and decanted, the benzene solution is evaporated to half its initial volume. The same
amount of ethanol is added to it. This solution is refluxed until a yellow nacreous product ceases to precipitate. It is the desired product of formula XIV.
After recrysrallization from dimethylformamide, said product melts at 4100 C.
Yield 85%.
Analysis:
Found: C 41.68%; H 1.52%; N 11.88%; Br 44.96%
Calculated: C 41.05%; H 1.43%; N 11.97%; Br 45.53%
2) Preparation of 6,8 - dibromo - 9 - chloro - 9 - cyano - 1,3 - diazafluorene
(compound of formula XIII)
3.5 g -(0.01 mole) of 3H - 6,8 - dibromo - 9 - cyano - indeno [2,1 - d]pyrimidine
are dispersed in 100 ml of anhydrous chloroform. The dispersion is refluxed and an
excess of dry chlorine is added for about 1 hour. Aft* that time, the yellow product
has undergone dissolution and the solution thus obtained is entirely decolourizod. The
excess of chlorine and also the hydrochloric acid formed are removed by means of a
stream of nitrogen. The mixture is filtered, the solvent of the filtrate is evaporated
and the residue is recrystallized from benzene to give white needles of the desired
product of formula XIII, melting point: 199-2000C. Yield: 93%.
Analysis:
Found: C 37.97%; H 1.14%; N 10.59%; Cl 9.10%; Br 41.01%
Calculated: C 37.38%; H 1.04%; N 10.90%; Cl 9.19%; Br 41.46% 3) Preparation of 6,8 - dibromo - 1,3 - diazafluorene - 9 - one (compound of formula
VI)
12 g (0.0306 mole) of 6,8 - dibromo - 9 - chloro - 9 - cyano - 1,3 - diazafluorene are dispersed in 150 ml of pure acetic acid in the presence of 3 g of mercury, 60 ml of fuming nitric acid are added dropwise at a rate such that the inner temperature of the reaction vessel does not exceed 40"C. Said temperature is thereafter maintained for 1 hour at 40"C an;i;then for three hours at 55"C. During said operation, a yellow product precipitates. Upon cooling in refrigerator and dilution of the mother liquors, 10 g of a yellow product with mercury are obtained. Said product is taken up with 150 ml of formamide and is heated to 110 C at which temperature the mercury is liberated. Upon cooling, the desired product of formula VI crystallises.
Said product coloured greenish is filtered off and recrystallized from acetone to give fine yellow needles like cotton-wool, melting point 218-2200C. Yield: 60%.
Analysis:
Found: C 38.82%; H 1.45%; N 8.23%; Br 46.97%
Calculated: C 38.86%; H 1.18%; N 8.23%; Br 47.00%
Examples 2 to 6.
By the first process indicated in example 1 and using the suitable ethyl bromosubstituted carboxylic esters of formula III, mentioned in table III below, one obtains the acids of formula II listed in the following table II.
The sodium salts of the acids are obtained from the corresponding acid by usual acid base reactions.
TABLE II
Formula II
Compound CnH2n = Recrystallization Melting point
Example code number (formula I: R = COOH solvent C Analysis C H N Br
d-N mo mm rs u) s o ccr, m mcrr 111 mm Nm N cz mu jhi nii co oo ~ N t < N m v) m m f ~ n N n 2 2150 -CH2- ethanol/water > 3000 calc. 35.89 1.38 9.65 36.74 viv; mm o < m salt) found. 35.91 ori 9.83 36.52 CH3 oa oe or 3 2149 o S o o CH3 C2Hs " 2212 o rio CH3 os t b o O CH3 a ,Ea CH3 o c a, -CH- sodium salt of 1279 o o X ce e i V- l-V V- I V- l-V V- I o os ~ t c e N t m xo TABLE II
Ethyl esters of formula III (Alk = C2H5)
Used in Compound Recrystallization Melting point
Example code number CnH2n = solvent C Analysis C H N Br
co oo Cil OCV 00 \dd i cm cm mcr, crv, vro? vlccl Invl O o;o; odod oa; NNU nij cic; To c9 n N N cS boo -CH2- ethanol/acetone 198-200 calc. 40.84 2.51 9.52 36.23 0000 mcr) rov, found. cc;r;^ ^ ^ ^ te te tt 3 1270 = ethanoVacetone 195-196 calc. 43.52 3.22 8.95 34.06 found. 43.34 3.39 8.98 34.20 CH C2He O n 4 2211 -CH- ethanol 150-152 calc. 43.52 3.22 8.95 34.06 ~ { ~ o o o o o o X 'o o o o c c Pec o Ho o vW vU vv crv o ~ R n N < t Example 7.
Preparation of the hydrochloride of 9 - ( - diethylamino - ethoxy - imino) - 6,8dibromo - 1,3 - diazafluorene (formula VIII: CnH2n=CH2CH2; formula I:
CnH2n=-CH2-CH2:
3.4 g (0.01 mole) of 6,8 - dibromo - 1,3 - diazafluorenone (formula VI) and 2.25 g (0.025 mole) of the dihydrochloride of - diethylamino - ethoxy - amine (formula IX: CnH2n=-CH2CH2R2=R2=-C2H5) are refluxed during 1 hour in 200 ml of methanol.
The solvent is then removed under vacuum and lukewarm water is added to the residue. The aqueous solution is made alkaline and the obtained precipitate is treated with chloroform. After drying, the solution is filtered and concentrated to dryness.
The residue is treated with isopropanol and the yellow precipitate is separated by filtration. The obtained compound melts at 114115 C.
The hydrochloride is prepared at a pH of 5. After recrystallization from a mixture of ethanol and methanol, the obtained hydrochloride melts at 24P2450C.
Analysis:
Calculated %: C=41.61; H=3.90; N=11.41; Br=32.57; Cl=7.22
Found %: C=41.57; H=4.00; N=11.71; Br=32.57; Cl=7.38
EXAMPLES 8 and 9.
The compounds listed in the following table IV are prepared in the manner described in example 7, using the suitable amine of formula IX instead of p-dietayl- aminoethoxy-amine.
TABLE IV
Analysis
Acid Melting
Formula I addition point
Example R CnH2n salt C C H N Br Cl
t \d Fb, ta crr F o 5s 0 3 3 V1 O 6 oO t t m st O o o ~ m o o oo Y H, ric; HBr oc oE CH3 Found. 35.40 ot o 10.35 44.80 m vx o e j vivT ricr; mm a a 5 = CH2-CH2 HCl 3 e O U O ULr, 43.35 L; V 1:; 900 V) l l m 0s n t :C V 1N 1N E V 00 0E EXAMPLE 10.
Preparation of the hydrochloride of O - {1' - [2 - (dimethylaminoethyl) carbamoyl]ethyl} - 6,8 - dibromo - 1,3 - diazafluorene - 9 - one oxime (compound of formula
X CnH2n=CHCH2 m=2, x=1, R1=R2=CH3; formula I: CnH2n=CHCH3;
10 g of O - [1' - (carboxy)ethyl] - 6,8 - dibromo - 1,3 - diazafluorene - 9 - one oxime (formula II, CnH2n=CH-CH3) are dispersed in 50 ml of SOCl2. The dispersion is refluxed until dissolution of the dispersed matter. The reaction lasts 6 hours.
After that time, the thionyl chloride is distilled under reduced pressure. The residue is taken up with 50 ml of benzene and the latter is distilled under vacuum so as w eliminate any traces of thionyl chloride. There remains a yellow residue and this is taken up with 100 ml of chloroform. This gives a suspension which contains the o - [1' - (carbonyl - chloride) ethyl] 6,8 - dibromo - 1,3 - diazafluorene - 9 - one oxime (formula XI). Said suspension is cooled to 0 C in a bath of ice and 10 ml of p-dimethylaminoethylamine are added slowly, the temperature being kept below 10"C.
The insoluble matter becomes completely dissolved. The residue mixture is allowed to come back to room temperature and then the chloroform is distilled under reduced vacuum. The residue is taken up with diluted hydrochloric acid, heated a little and a yellow insoluble matter is removed by filtration. The filtrate is rendered alkaline by means of aqueous ammonia which liberates the base of the desired 0 - (1' dimethyl - aminoethyl) carbonyl] ethyl) 6,8 - dibromo - 1,3 - diazafluorene - 9 - one oxime. Said product is extracted by means of a solvent non miscible with water, such as chloroform. After drying of the organic solution, the solvent is distilled under vacuum. The reddish brown residue is recrystallized from benzene or methanol giving the desired purified product as yellow flakes, melting point 175-1780C. Yield: 80%.
The base thus purified, i.e. 8.5 g, is dispersed in 100 ml of water. 1N hydrochloric acid is added gradually until the dispersed matter is completely dissolved.
The final pH is 5.
The water is distilled off under vacuum, leaving a semi-solid residue which is dried by forming an azeotrope in 200 ml of benzene. The solvent is then distilled under vacuum leaving a yellow residue which is dissolved in 200 ml of methanol.
The solution is evaporated until crystallization starts. In this way one obtains the desired hydrochloride of the compound of formula I as yellow microcrystals, melting point 242-2440 C.
Analysis:
Found: C 40.43%; H 3.78%; N 13.31%; Br 29.65%; Cl 6.65%
Calculated: C 40.50%; H 3.77%; N 13.12%; Br 29.94%; Cl 6.64%
EXAMPLES 11 to 19.
The compounds of the following table V are prepared as described in example 10 using a suitable acid chloride of the formula XI instead f the d - [1 - (rarbonyl chloride) - ethyl] - 6,8 - dibromo - 1,3 - diazafluorene - 9 - one oxime and a suitable compound of the formula XII instead of the p-dimethylaminoethylamine.
FORMULA X
Example CnH2n [NH-(CH2)m]x
TABLE V
Acid Melting Analysis (%) addition point salt C C H N Br Cl
\d\d \d\d \d\d v;vi ooa ma oo *-ry, -rC 3m rcr oo Fa cji cc;ri N'i cii j o \o O x o > oo So So ~ oo t ot F \ 0 00 " s9 o CH3 x m o m t 3 N HCl 229-231 calc. 41.66 4.04 12.78 29.18 6.47 Ch O 4 e sD \0 m 00 CH- CH3 yCH3 12 -CH- x 1; .a Y 39.10 3.56 13.40 30.40 6.76 CH3 c a es o o o m o oo a CH3 14 ! x-l;m=2 C2Hs HCl 220-222 calc. 42.76 4.30 12.46 28.45 6.31 -CH- N U found. 42.86 4.41 12.41 28.39 6.29 CH3 15 -CH- x = 1; m = 2 HCl 198-200 calc. 40.45 4.07 11.79 26.91 5.97 \ found. 40.48 4.06 11.98 26.86 5.73 II 11 11 11 11 E E E E E II 11 11 ll 11 x x pe x > < FORMULA X .
Example CnH2n . [NH-(CH2)m]x .
TABLE V
Acid Melting Analysis (%) addition point salt C C H N Br Cl
o ~ b cn m > H vo \D9 \ou, \ou, co- oc r-crr \ov, rc, gcO IDy, . * * . . . . . of ch x oo oo F t cv, ocoo tO 006 t4 00 cij icj ricj di o\o to \ou, \oa, oo \or r;c; i cic; bt: nos te n tt CH2 95 oo o \5 o t F " N-(H3 16 -CH- x = tt found. 42.00 r .e /C2Hs o -CH2- x o 1; c o 2 o HCl 242-243 calc. 41.66 4.04 12.78 29.18 6.47 l t cl t CH2 x = 0 HOl 217-220 calc. 39.32 3.66 12.74 29.07 es N N-(H3 WI (H,O) found. 40.07 3.76 12.70 28.83 6.27 7C2H5 V CH2- n=1;m=3 N " N g a Ut Y7 ' ' D} wn =. X n I X U
Examples 20 to 30.
Examples of typical pharmaceutical compositions
according to the invention.
The active compounds of formula I used in the pharmaceutical compositions given hereafter were selected more specifically among the compounds of examples 1, 5, 6, 8, 10 or 14.
Example 20--Capsules and tablets.
Compound of example 10 300 mg
Starch 95 mg
Magnesium stearate 5 mg
for 1 capsule or tablet
Example 21--Capsules and tablets.
Compound of formula I 300 mg
Starch 70 mg Lactose 25 mg
Talc 40 mg
Magnesium stearate 5 mg
for 1 capsule or tablet
Example 22----Capsules and tablets
Compound of formula I 300 mg
Starch 160 mg
Polyvinylpyrrolidone 25 mg Talc 7 mg
Magnesium stearate 3 mg
for 1 capsule or tablet
Example 23Coated tablets.
Tablet: see examples 20,21 or 22
Coating
Gumlac 2.0 mg
Gum-Sandarac 0.4 mg
Castor oil 0.5 mg
Talc 70.0 mg
Arabic gum 16.0 mg Methylparaoxybenzoate 0.01 mg
Starch 5.0 mg
Sucrose 12.0 mg
for 1 coated tablet
Example 24--Sugar coated pills
Core: see example 23.
Sugar coating
Sucrose 200 to 300 mg
Titanium oxide 2.5 mg
Polish wax 0.3 mg
for 1 pill
Example 23-Enterosoluble tablets.
Tablet: see examples 1, 2 or 3
Enteric coating
Arabic gum 15 mg
Talc 50 mg
Cellulose acetophalate 30 mg Ethylphthalate 8 mg
Methylparaoxybenzoate 0.01 mg
Magnesium stearate 1 mg
Sucrose 10 mg
for 1 enterosoluble tablet
Example 26-Enterosoluble pills.
Core: see example 25
Sugar coating:
Sucrose 200-300 mg
Titanium oxide 2 mg
Polish wax 0.3 mg
for 1 enterosoluble pill
Example 27-Capsules Compound of formula I 50 mg
Lactose 130 mg
Starch 70 mg
for 1 capsule
Example 28-Powder.
Compound of formula I 100 mg
Powdered flavourings 25 mg
Standardised acacia gums 500 mg
Sucrose qs ad 3g
for 1 sachet
Example 29Injectable solution.
Soluble compound of formula I 750 mg
(such as the compounds of examples 1 and 5)
Water for injections qs ad 10 ml
for 1 ampulla
Example 30-Suppositories.
Claims (23)
- Compound of example 1, 5 or 6 200 mg Witepsoll(registered Trade Mark) H 12 (of Dynamit Nobel) qs ad 3g WHAT WE CLAIM IS:1. Derivatives of 1,3-diazafluorene of general formula:[in which n is 1, 2 or 3, the CnH group having a straight or branched chain; and R represents a carboxylic acid group, an amino group of the formula(in which R1 and R2 each represents a C1-C4 alkyl radical, or form together with the adjacent nitrogen atom a heterocyclic ring), an amido group of the formula(in which R1 and R2 have the meanings given above), or an aminocarbamoyl group of the formula(in which m is 1, 2 or 3 and R1 and R2 have the meanings given above)] and the alkali metal and acid addition salts thereof.
- 2. Derivatives of 1,3-diazafluorene according to claim 1 in which R1 and R2 each represents a methyl or ethyl group, or form together with the adjacent nitrogen atom a piperazino, methylpiperazino, pyrrolidino or piperidino ring.
- 3. Derivatives of 1,3-diazafluorene according to claim 1, in which R represents a carboxylic acid group and which are represented by the formula:in which QiH has the meanings given in claim 1, and the alkali metal salts thereof.
- 4. Derivatives of 1,3-diazafluorene according to claim 1, in which R represents an amino group and which are represented by the formula:in which 6H,, R1 and R2 have the meanings given in claim 1, and the acid addition salts thereof.
- 5. Derivatives of 1,3-diazafluorene according to claim 1, in which R represents an amido group and which are represented by the formulain which 6H,, R1 and R2 have the meanings given in claim 1, and the acid addition salts thereof.
- 6. Derivatives of 1,3-diazafluorene according to claim 1, in which R represents an aminocarbamoyl group and which are represented by the formula:in which CH,, m, R1 and R2 have the meanings given in claim 1, and the acid addition salts thereof.
- 7. 0 - [1' - (Carboxy) - ethyl] - 6,8 - dibromo - 1,3 - diazafluorene - 9 - oneoxime and the sodium salt thereof.
- 8. 0 - [1' - (Carboxy) - propyl] - 6,8 - dibromo - 1,3 - diazafluorene - 9 - oneoxime and the sodium salt thereof.
- 9. 9 - (p - flimethylamino - ethoxy - amino) - 6,8 - dibromo - 1,3 - diazafluorene, and the pharmaceutically acceptable acid addition salts thereof.
- 10. 0 - (1' [2 - (Dimethylaminoethyl)carbamoyl] ethyl) - 6,8 - dibromo - 1,3diazafluorene - 9 - one oxime, and the pharmaceutically acceptable acid addition salts thereof.
- 11. 0 - (1' - [2 - (D'iethylaminoethyl)carbamoyl]ethyl) - 6,8 - dibromo - 1,3diazafluorene - 9 - one oxime, and the pharmaceutically acceptable acid addition salts thereof.
- 12. Pharmaceutical compositions containing as active ingredient at least one compound according to any one of the preceding claims, together with a pharmaceutical carrier or excipient
- 13. Derivatives of 1,3-diazafluorene of general formulain which n is 1, 2 or 3, the C,H2 group having a straight or branched chain, and Alk represents a C14 alkyl group.
- 14. A derivative of 1,3-diazafluorene of the formula
- 15. A derivative of 1,3-diazafluorene of the formula
- 16. A derivative of 1,3-diazafluorene of the formula
- 17. A process for the preparation of compounds as defined in claim 3 which comprises hydrolysing a compound of formula III as defined in claim 13.
- 18. A process for the preparation of compounds as defined in claim 3 which comprises reacting a compound of formula VI as defined in claim 14 with a compound of formula(wherein n is as defined in claim 1).
- 19. A process for the preparation of compounds as defined in claim 4 which comprises reacting a compound of formula VI as defined in claim 14 with a compound of formula(wherein R1, R2 and n are as defined in claim 1).
- 20. A process for the preparation of compounds of formula I as defined in claim 1 (in which R represents an amido or aminocarbamoyl group) which comprises reacting an acid chloride of formula(wherein n is as defined in claim 1) with a compound of formula(wherein m, R1 and R2 are as defined in claim 1, and x is 0 or 1).
- 21. A process for the preparation of compounds as defined in claim 1 substantially as herein described.
- 22. A process for the preparation of compounds as defined in claim 1 substantially as herein described in any of Examples 1 to 19.
- 23. Compounds as claimed in claim 1 whenever prepared by a process as claimed in any of claims 17 to 22.
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB15792/77A GB1562965A (en) | 1977-04-15 | 1977-04-15 | 1,3-diaza fluorene |
| BE186576A BE865704A (en) | 1977-04-15 | 1978-04-05 | NEW DERIVATIVES OF 1,3-DIAZAFLUORENE, THEIR PREPARATION AND THEIR USE |
| DE19782816011 DE2816011A1 (en) | 1977-04-15 | 1978-04-13 | 1,3-DIAZAFLUORENE DERIVATIVES AND MEDICINAL PRODUCTS CONTAINING THEM |
| NL7803982A NL7803982A (en) | 1977-04-15 | 1978-04-14 | NEW 1.3-DIAZAFLUOREEN DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS. |
| FR7811143A FR2387222A1 (en) | 1977-04-15 | 1978-04-14 | NEW DERIVATIVES OF 1,3-DIAZAFLUORENE, THEIR PREPARATION AND THEIR USE AS AN ANTIMALARIC MEDICINAL PRODUCT |
| AU35108/78A AU515767B2 (en) | 1977-04-15 | 1978-04-14 | Derivatives of 1, 3-diazafluorene |
| JP4472278A JPS53149986A (en) | 1977-04-15 | 1978-04-15 | Diazafluorenes and method for its production and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB15792/77A GB1562965A (en) | 1977-04-15 | 1977-04-15 | 1,3-diaza fluorene |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1562965A true GB1562965A (en) | 1980-03-19 |
Family
ID=10065547
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB15792/77A Expired GB1562965A (en) | 1977-04-15 | 1977-04-15 | 1,3-diaza fluorene |
Country Status (7)
| Country | Link |
|---|---|
| JP (1) | JPS53149986A (en) |
| AU (1) | AU515767B2 (en) |
| BE (1) | BE865704A (en) |
| DE (1) | DE2816011A1 (en) |
| FR (1) | FR2387222A1 (en) |
| GB (1) | GB1562965A (en) |
| NL (1) | NL7803982A (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB929734A (en) * | 1960-04-01 | 1963-06-26 | Manuf Prod Pharma | Substituted indeno-pyrimidines |
-
1977
- 1977-04-15 GB GB15792/77A patent/GB1562965A/en not_active Expired
-
1978
- 1978-04-05 BE BE186576A patent/BE865704A/en unknown
- 1978-04-13 DE DE19782816011 patent/DE2816011A1/en not_active Withdrawn
- 1978-04-14 AU AU35108/78A patent/AU515767B2/en not_active Expired
- 1978-04-14 FR FR7811143A patent/FR2387222A1/en not_active Withdrawn
- 1978-04-14 NL NL7803982A patent/NL7803982A/en not_active Application Discontinuation
- 1978-04-15 JP JP4472278A patent/JPS53149986A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| NL7803982A (en) | 1978-10-17 |
| FR2387222A1 (en) | 1978-11-10 |
| BE865704A (en) | 1978-10-05 |
| DE2816011A1 (en) | 1978-10-19 |
| JPS53149986A (en) | 1978-12-27 |
| AU3510878A (en) | 1979-10-18 |
| AU515767B2 (en) | 1981-04-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed | ||
| PCNP | Patent ceased through non-payment of renewal fee |