IE41495B1 - Dihydroapovincaminic acid amide - Google Patents
Dihydroapovincaminic acid amideInfo
- Publication number
- IE41495B1 IE41495B1 IE157175A IE157175A IE41495B1 IE 41495 B1 IE41495 B1 IE 41495B1 IE 157175 A IE157175 A IE 157175A IE 157175 A IE157175 A IE 157175A IE 41495 B1 IE41495 B1 IE 41495B1
- Authority
- IE
- Ireland
- Prior art keywords
- methyl
- acid
- compound
- salt
- dihydro
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D461/00—Heterocyclic compounds containing indolo [3,2,1-d,e] pyrido [3,2,1,j] [1,5]-naphthyridine ring systems, e.g. vincamine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
1472238 N - Methyl - 16,17 - dihydroapovincamide SYNTHELABO 17 July 1975 [16 June 1975] 30069/75 Addition to 1461300 Heading C2C [Also in Division A5] The novel compound N-methyl-16,17-dihydroapovincamide or a pharmaceutically acceptable acid addition salt thereof may be prepared by reacting 16,17-dihydroapovincaminic acid or a functional derivative thereof with methylamine and optionally forming a pharmaceutically acceptable acid addition salt thereof.
Description
This invention relates to a certain dihydroapovincaminic acid amide, to a process for its preparation, to pharmaceutical compositions containing it and uses thereof. The invention is an improvement in, or modification of, the invention of PatonL Specification No. Lf-oOSO .
The above Valent Specification discloses compounds of general formula (I)
B-OC^'x (I) wherein B is an -NR
R„ group wherein R is a hydrogen atom 1 z 1
1() linear or branched alkyl group or an unsaturated, linear or branched aliphatic hydrocarbon group, and Rg is a linear or branched alkyl group or an unsaturated, linear or branched
C„ . aliphatic hydrocarbon group, a phenyl-C . alkyl or a cycloz—4· i“*4 alkyl-C^ alkyl group; or B is a pyrrolidin-l-yl, piperidine,
1$ perhydroazcpi.n-1-yl, morpholino, thio morpholino, piperazin-1yl or 4-methyl piperazin-l-yl group, and pharmaceutically acceptable acid addition salts thereof.
I t has now been found I.ha I. one oi’ the compounds oi' general formula (I) unexpectedly pyssesses an activity that is markedly grealer than that of the others. This compound is N-methyl-16,
17—dihydro-apovincamide which has the formula (II)
It is a compound of general formula (I) wherein R^ is a hydrogen atom and R2 is a methyl group.
Accordingly, the present invention provides N-methyl-l6,17dihydro-apovincamide or an addition salt thereof with a pharmaceutically acceptable acid; the compounds can in particular be used in the cardio-vascular field.
The preparation of the compound of formula II can be carried out in accordance with the method described in the Patent Specification mentioned above; i.e. 16,17-dihydroapovincaminic acid or a functional derivative thereof can be reacted with methylamine.
Thus, 16,17-dihydroapovincaminic acid or one of its alkali metal salts is converted to the acid halide, for example using an oxalyl halide, such as oxalyl chloride, or a thionyl halide, such as thionyl chloride, or a halogen derivative of phosphorus.
This reaction is preferably carried out at ambient temperature, in a non-polar solvent, such as an aromatic hydrocarbon, e.g. benzene, toluene or xylene._ However, it is possible to add to the solvent an acceptor for a hydrogen halide; an example of the acceptor is a tertiary organic base. The acid halide can be isolated from the solvent or used, in the solvent, for the next stage.
The conversion of the acid halide to the amide of formula II can be carried out by reacting the halide with methylamine at ambient temperature, in a neutral medium, or preferably, a basic medium.
The following Example illustrates the invention.
- 3 41495
ΚΧΛΜΓΙ.Ι·..
N-Mcthyl-1 6, 17-
2.2 Ml of oxalyl chloride (0.0256 mole) are added, all at once, to a suspension of 7-580 g (0.0233 mole) of 16.17-dihydroapovincaminic acid in 200 ml of dry benzene. The flask is closed with a calcium chloride guard tube and the mixture is left in darkness for 1 hour, with magnetic stirring. The flask is cooled and a solution in bpnzene of methylamine is then added until the
Ιθ mixture gives a basic reaction; the reactants are left in contact for two hours, with magnetic stirring. The solution obtained is rendered alkaline with 5/ ammonia and is extracted with chloroform. The chloroform solution is washed twice with water, dried over dry magnesium sulphate and evaporated to dryness. After 15 standing overnight in a desiccator, I.48 g (yield: 20/) of pale yellow crystals of N-methyl-l6,17-dlhydroapovincamide, m.p. 194-195°C are obtained.
Analysis:
Calculated: C,74-59; Η, 8.12; N, 12.52;
0, 4.70/.
Found C, 74.74; H, 8.06; N, 12.45;
4.74/.
Hemi-malato:
1.35 G of the amide base are dissolved in methanol and 0.536 g of malic acid in 23 ml of the same solvent is added. After leaving the reactants in contact for 10 minutes, tile mixture is evaporated to dryness to give 1.85 g of N - methyl - 16,17- dihydro apovincamidc hcmi-malate as an amorphous yellow product, m.p. 126-127°.
Analysis:
Calculated: C, 63.62; ii, 7.05; N, 8.91/
Calculated (with 1.80/ of water):
- 4 4149 ft
C, 62.48; H,7.13; N, 8.74$
Found: C, 62.43; H,7.9O; N, 8.29$
I.R, spectrum (KBr)
N-H band = 3,290 cm-1
C=0 band — 1,650 cm 1
NMR spectrum (CDCl^iST.M.S. = 0) broad signal centred on 6 ppm = H of N-H
4.6 ppm (9) = H in 16 position
Broadened peak centred on 3.9 ppm = H in 21 position
Acid oxalate;
14.6 G of oxalic acid dihydrate in 300 ml of ethyl acetate are added to 39 g of the base in 1.5 litres of ethyl acetate. This mixture is stirred for 30 minutes and the crystals which have precipitated are filtered off, washed with ethyl acetate and dried first for 1 hour in an oven at 5θ-60° and then for hours at 55° under a residual vacuum of 0.1 mm of mercury to give 44.35 g (yield = 91$ ) of N-methyl-l6,17-dihydro-apovincamide acid oxalate.
Analysis: ^3^29^5^3 (427)
Calculated (dry) C, 64.63; H, 6.79; N, 9.83$. Calculated (with 2.6$ of water): C, 62.92, H, 6.90; N, 9.57$. Found C, 62.82; H, 6.62; N, 10.02$. The compound of the invent Lon was subjected to various
pharmacological tests. It was compared firstly with vincamine and secondly with piperidyl - 16,17 - dihydro - apovincamide and N,N - diethyl - 16,17 - dihydroapovincamide, described in the Patent Specification mentioned above.For all these tests, the compounds were dissolved in a solution of ascorbic acid [the
- 5 4149S weight of the latter corresponding to twice the weight of vincamine equivalent ( in moles) to the weight of the compound testedj. The results are listed in Table f below.
Acute toxicity
The compound of the invention and the reference substances wore administered by various routes to mice of the CDX strain.
The mortality was recorded for a period of observation of 7 days and the 50% lethal doses (Ι,ϋ^θ) were determined graphically.
Low oxygen pressure anoxia best on mice
Mice of the GDI strain were kept in an atmosphere of reduced oxygen content by setting up a partial vacuum (19» mm ol' mercury, corresponding to 5-25% of oxygen).
The survival time of the animals is noted. This time is increased by agents able to assist the tissue oxygenation and in particular the cerebral oxygenation. The compounds studied were administered at various doses, intraperitoneally, 10 minutes before the test. The percentage increases in the survival time relative to the values obtained with control animals are calculated The mean active dose (M.A.D.) namely the dose which increases the survival time by 100%, is determined graphically.
- 6 414 98
Low pressure anoxia test M.A.D., mg/kg. expressed as molecular equivalent of vineamine co 00 r* Tfr 04 1 base 00 04 oo m r-. 04 oral administration o O O' 1-M o Ό M· o o o O' 00 !>> +5 •H ϋ tw •Η Λ 0 bp intraperitoneal administration tn 04 04 LT> t—4 04 1 U-> 04 04 Acute t LD50’ “ intravenous administration LO 04 »—l Ό 1 Compounds 0 £< Ό >> XJ •ri {> 1—1 «> \O i—l ¢) I TJ •H s t—j 03 >> ϋ 42 a +> *rl & s 1 Di —*«— Vineamine 0 Li xJ >» Λ •H Ό 1 ι—1 Ό I Z o ** ft , 1 0 p Ό >» 42 *P tJ I ι—1 o' Q) 1 Ή rP S >> ¢0 Ό U •rl C Sm ·Ρ 0) > ft O •P ft fa
- 7 41495
It. can be seen from the Tabic· that N-mctliyl - 1(),17 ~ dihytlro - apovincamide is superior, as a tissue oxygenator, particularly with regard Lo the cerebral tissues, to the compounds with which it was compared.
N- Methyl - 16,17 - dihydro - apovincamide and its pharmaceutically acceptable acid addition salts can be used in human and veterinary medicine in the cardiovascular area and in particularin the area of cerebral circulation, because they in particular improve the blood flow in the brain and the use of oxygen by the
It) latter. furthermore·, the compounds are general cellular oxygenators.
The invention provides a pharmaceutical composition comprising the compound of formula (II) and/or a pharmaceutically acceptable acid addition salt thereof as the active principle, and a phar maccutically acceptable carrier or diluent, particularly those suitable for oral, endo-rectaI , parenteral or topical administr-al— ion. These pharmaceutical compositions can also contain other medicaments with which N - methyl - 16,17 - dihydro - apovincamide and its salts are pharmacologically and therapeutically compat20 ible. For oral administration in particular, it is also possible to add ascorbic acid or a derivative thereof, which facilitates resorption by the digestive tract.
For oral administration, all the usual forms suitable for such administration can be employed; examples are tablets, dragees, pills, capsules, cachets and potable solutions or suspensions.
The unit weight of active principle can be 0.5 to 20 mg and the daily dose can be 0.5 to 200 mg.
For endo-rectal administration, individual doses can contain 1 to 4-0 mg of the active principle which can be distributed in any carrier or diluent suitable for use as a suppository base.
to 5 suppositories can be administered per· 24 hours.
For parenteral administration, solutions prepared beforehand
- S _
41435 or at the time of use, and buffered to the physiological pH, can be used. These solutions can contain 0.5 to 20 mg of active principle in a volume of 1 to 5 ml. In practice, the solutions are divided into ampoules of 1 to 5 ml capacity, for intramuscular or intravenous administration, or for administration by slow intravenous infusion. The daily dose administered parenterally can be 0.5 to 100 mg.
For topical administration, lotions, emulsions, ointments or creams of such nature as to assist cutaneous penetration can be used.
The present invention also includes within its scope a method of treating cardiovascular disorders in mammals other than humans which comprises administering to the non-human mammal N - methyl 16,17 - dihydroapovincamide or a pharmaceutically acceptable acid addition salt thereof.
Claims (10)
1. A compound which is N-inethyl -16,17-d i hydroapo vi ncamide or a pharmaceutical Iy acceptable acid addition salt thereof.
2. ΙΊ- methyl - 1(),17 - dihydro - apov i ucami de hemi-inal ate. 5 ,
3. N - methyl - 16,17 - dihydro - apovi.neami.de acid oxalate.
4. A process for the preparation of N-methyl - 16,17 - dihydro apovincami.de or a pharmaceutically acceptable acid addition salt thereof, which process comprises reacting 16,17 - dihydroapovincaminic acid, or a functional derivative thereof, with methylamine, IO and optionally the reaction product is reacted with a pharmaceutically acceptable acid to give a salt.
5. A process according to claim 4, wherein the functional derivative is an acid halide
6. A process according to claim 4, substantially as described 15 in the Example.
7. - A compound or salt according to claim 1 prepared by a process according to any one of claims 4 to 6.
8. A pharmaceutical composition comprising a compound or salt according to any one of claims 1 to 3 and 7 and a pharmaceutically 20 acceptable carrier or diluent.
9. A composition according to claim 8 comprising also ascorbic acid or a derivative thereof.
10. A composition according to claim 8 substantially as hereinbefore described. 25 It. A method of treating cardiovascular disorders in mamma!s other than humans, which method comprises administering to the non-hqmari mammal a compound or salt according to any one of claims 1 to 3 and 7 ·
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR7518691A FR2314717A2 (en) | 1975-06-16 | 1975-06-16 | NEW AMIDS OF DIHYDROAPOVINCAMINIC ACID, THEIR SALTS, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM |
Publications (2)
Publication Number | Publication Date |
---|---|
IE41495L IE41495L (en) | 1976-12-16 |
IE41495B1 true IE41495B1 (en) | 1980-01-16 |
Family
ID=9156548
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE157175A IE41495B1 (en) | 1975-06-16 | 1975-07-15 | Dihydroapovincaminic acid amide |
Country Status (9)
Country | Link |
---|---|
JP (1) | JPS52299A (en) |
BE (1) | BE831236R (en) |
CA (1) | CA1031345A (en) |
DK (1) | DK324275A (en) |
FR (1) | FR2314717A2 (en) |
GB (1) | GB1472238A (en) |
IE (1) | IE41495B1 (en) |
LU (1) | LU73098A1 (en) |
NL (1) | NL7511543A (en) |
-
1975
- 1975-06-16 FR FR7518691A patent/FR2314717A2/en active Granted
- 1975-07-10 BE BE158186A patent/BE831236R/en active
- 1975-07-15 IE IE157175A patent/IE41495B1/en unknown
- 1975-07-16 DK DK324275A patent/DK324275A/en unknown
- 1975-07-17 GB GB3006975A patent/GB1472238A/en not_active Expired
- 1975-07-22 CA CA231,977A patent/CA1031345A/en not_active Expired
- 1975-07-30 LU LU73098A patent/LU73098A1/xx unknown
- 1975-10-01 NL NL7511543A patent/NL7511543A/en not_active Application Discontinuation
-
1976
- 1976-01-30 JP JP919376A patent/JPS52299A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
FR2314717B2 (en) | 1978-10-06 |
BE831236R (en) | 1976-01-12 |
LU73098A1 (en) | 1976-05-18 |
FR2314717A2 (en) | 1977-01-14 |
JPS52299A (en) | 1977-01-05 |
DK324275A (en) | 1976-12-17 |
IE41495L (en) | 1976-12-16 |
GB1472238A (en) | 1977-05-04 |
NL7511543A (en) | 1976-12-20 |
CA1031345A (en) | 1978-05-16 |
AU8333975A (en) | 1977-01-27 |
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