CA1268179C - .beta.-carboline-3-oxadiazolyl derivatives, method of preparing the same and their use - Google Patents
.beta.-carboline-3-oxadiazolyl derivatives, method of preparing the same and their useInfo
- Publication number
- CA1268179C CA1268179C CA486598 CA1268179C CA 1268179 C CA1268179 C CA 1268179C CA 486598 CA486598 CA 486598 CA 1268179 C CA1268179 C CA 1268179C
- Authority
- CA
- Canada
- Prior art keywords
- compound
- carboline
- set forth
- forth above
- ethyl
- 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.)
- Expired
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 45
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 125000005466 alkylenyl group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229910017912 NH2OH Inorganic materials 0.000 claims 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims 1
- 125000000392 cycloalkenyl group Chemical group 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims 1
- 230000000506 psychotropic Effects 0.000 abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
- -1 alkoxyalkyl gro Chemical compound 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 238000006073 displacement reaction Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 210000004129 Prosencephalon Anatomy 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1H-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 2
- FBAOVPVVMDOHPK-UHFFFAOYSA-N 2-(1H-imidazol-2-ylsulfinyl)-1H-imidazole Chemical compound N=1C=CNC=1S(=O)C1=NC=CN1 FBAOVPVVMDOHPK-UHFFFAOYSA-N 0.000 description 2
- 210000004556 Brain Anatomy 0.000 description 2
- 229960002200 Flunitrazepam Drugs 0.000 description 2
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- PPTYJKAXVCCBDU-UHFFFAOYSA-N Rohypnol Chemical compound N=1CC(=O)N(C)C2=CC=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1F PPTYJKAXVCCBDU-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000003345 scintillation counting Methods 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- ZVAPWJGRRUHKGP-UHFFFAOYSA-N 1H-1,5-benzodiazepine Chemical class N1C=CC=NC2=CC=CC=C12 ZVAPWJGRRUHKGP-UHFFFAOYSA-N 0.000 description 1
- BPMFPOGUJAAYHL-UHFFFAOYSA-N 9H-pyrido[2,3-b]indole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=N1 BPMFPOGUJAAYHL-UHFFFAOYSA-N 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- SMJGOYDMFXWHDF-UHFFFAOYSA-N C(C)(C)OC=1C=C2C=3C=CN=CC3NC2=CC1 Chemical compound C(C)(C)OC=1C=C2C=3C=CN=CC3NC2=CC1 SMJGOYDMFXWHDF-UHFFFAOYSA-N 0.000 description 1
- 210000003169 Central Nervous System Anatomy 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241000448280 Elates Species 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 229940031574 HYDROXYMETHYL CELLULOSE Drugs 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M Monopotassium phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- RLZPCFQNZGINRP-UHFFFAOYSA-N N'-hydroxypropanimidamide Chemical compound CCC(N)=NO RLZPCFQNZGINRP-UHFFFAOYSA-N 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N Propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N Propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 235000003846 Ricinus Nutrition 0.000 description 1
- 241000322381 Ricinus <louse> Species 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N Silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 125000004432 carbon atoms Chemical group C* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 201000002674 obstructive nephropathy Diseases 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 230000003204 osmotic Effects 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001184 potassium carbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002285 radioactive Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Abstract
ABSTRACT
New .beta.-Carboline-3-oxadiazolyl derivatives.
New .beta.-carboline-3-oxadiazolyl derivatives having the gene-ral formula I:
(I) wherein X is or and wherein R4, RA and R have specified meanings.
The new compounds which exhibit surprising psychotropic properties are prepared by analogy methods.
New .beta.-Carboline-3-oxadiazolyl derivatives.
New .beta.-carboline-3-oxadiazolyl derivatives having the gene-ral formula I:
(I) wherein X is or and wherein R4, RA and R have specified meanings.
The new compounds which exhibit surprising psychotropic properties are prepared by analogy methods.
Description
~2~ L79 This invention r elates to new ~-carboline-3-oxadiazolyl de-rivatives .
These new compounds possess valuable pharmacological properties which make them useful in psychopharmaceutical prepara-tions .
The new compounds of the invention are ~-carboline-3-oxa-diazolyl derivatives having the general formula 1:
~4 - .
wherein X is a oxadiazolyl group selected from the group consisting o~ .
~ L --< N=l ~ R
C3-~7 ~;_ wherein R is H, a lower alkyl or~cycloalkyl group, R is H, a lower alkyl or a lower alkoxyalkyl gro~lp, RA iq a lower alkyl group ; SCH3 ; SC2H~ ; OR 5 , wherein R15 is a lower alkyl ", cy~cloalkyl o~ c~cloalkenyl;
CH20R17, wherein R17 is H or a lower alkyl or phenyl group; -C--C-CH2N (CH3 ) 2; or O N
--< N ll R18 wherein R18 is a lower alkyl group, and wherein the cbmpound I may contain one or two RA groups, provided, however, that X is not 3-ethyl-1, 2, 4-oxadiazole-5-yl when R is H and RA is 5-CH20CH3, 5-OCH2C6H5, 6-sCH3, 6-oCH3 or 6-oCH2C6H5-2 ~L2,~8i~7g The term "lower alkyl group" means an alkyl group con-taining from 1 to 6 carbon atoms.
EP patent publications Nos. 30254 and 54507 disclose vari-ous substituted ~-carbolines including 3-oxadiazolyl derivatives which are related to the compounds of the invention.
However, surprisingly it has been found that the com-pounds of the invention exhibit psychotropic properties which are clearly superior to those of the prior art compounds.
The superior psychotropic properties of the compounds of the invention are evidenced by their improved capability for displac-ing radioactively labelled flunitrazepam from benzodiazepine recept-ors .
It is well known (Squires, R.F. and Braestrup,~ C., Nature (London) 266 (1977)) that specific sites in the central nervous systems of vertebrates exhibit a high specific affinity for binding 1,4- and 1,5-benzodiazepines. These sites are called benzodiazepine receptors.
The displacement activity of the compounds of the invention has been cletermined by determin7ng the IC50 value and ED50 value.
The IC50 value represents the concentration which causes a displacement of 50% of the specific binding of H-flunitrazepam (1.0 nM, 0C) in samples comprising a total volume of 0.55 ml of a su-spension of brain membrane, e. g . from rats.
The displacement test is performed as follows:
0,50 ml of a suspension of non-treated rat forebrain in 25 mM KH2PO4, pH = 7.1 (5-10 mg tissue/sample) i5 incubated for 40-60 minutes at 0C together with 3H-diazepam (specific activity 87 Ci/mmol, 1.0 nM) or 3H-flunitrazepam (specific activity 87 Ci/mmol, 1.0 nM). After incubation the suspension is filtered through "What-man GF/C" glass fibre filters, the residue washed twice with cold buffer solution and the radioactivity measured by scintillation count-ing .
The test is repeated except that prior to the addition of the radioactive labelled benzodiazepine a given amount ar an exces-sive amount of the compound, the displacement capability of which is to be determined, is added. Based on the data obtained the IC50 value can be calculated.
The EDSo value represents the dose (mg/kg) of a test sub-stance which causes the specific binding of flunitrazepam to benzo-3 ~1L2~ 7g diazepine receptors in a living brain to be reduced to 50% of thecontrol value~ Such an in vivo test is carried out as follows:
Groups oF mice are in~ected with the test substance at different doses and usually subcutaneously. 15 minutes later 3H-flu-nitrazepam is administered intravenously to the mice and after fur-ther 20 minutes the mice are killed. Their forebrain membranes are removed and the radioactivity of these forebrain membranes is mea-sured by scintillation counting. The ED50 value is determined from dose-response curves.
Test results obtained by testing some compounds of the invention will appear from the following table 1. :
.
(' ' " ~''' ' ' '" ' ' , , Table 1 Affinity for the benzodiazepine receptor inhibition of 3H-flunitraze-pam binding RA ~N J~
X ¦ R j RA I C 50 E D 50 . ng/ml ng/ml (in vitro) (in vivo) 1 2 3 ~ S-oC H 2P h O . 4 O . 9 _<N--O CH20CH3 5-OCH2Ph ~ 0.5 1 0 ~N ~ CH3- 5-CH20c2H5 0 . 26 O . 4 N ,~Et ~ ~ ~ O . 4 ~
~ON--~Et CH20CH3 5-0-~ O-Z ¦ O-Z _ Et¦ CH2CH3 5-ocH2cH2cH3 ¦ 0 3 ¦ 1.4 ¦ C H 2 C H 3 5 - ~ e> 4 ~E~ ¦ 6-c-c-cH2NMe2 0 . 4 E t ~ 2 3 1 5 - 0 ~ L o E I
~L26~3i.7g The invention also relates to a method of preparing the above mentioned compounds. This method comprises (a) reacting a reactive derivative of a compound of the -general formula 11 R _ ~COOH (I I) : - H
wherein R4 and RA have the meanings set forth above with a compound having the formula 111 .
NOH
R < . ( 111 ) wherein R has the meaning set forth above, to form a - compound of the general formula I in which X is O N
~N L R
wherein R has the meaning set forth above, (b) reacting a compound having the general formula IV
R
RA~ ~ J` CONH2 wherein R4 and RA have the meanings set forth above, with a compound V having the general formula R-C(OCH3)2N(CH3)2 (V) 6 ~2~ 79 wherein R has the meaning set forth above, to form a compoun~ having t~e general formula V
R
R __~CON=CRN (CH3) 2 H
wherein R, R4 and RA have the meanings set forth above and . by reacting the compound having the formula Vl with NH20H or another aminating agent, to form a compoutld having the formula I, wherein X is - O N
~N I~R
wherein R has the meaning set forth above or (c) reacting a compound having the formula Vl I
., ~A~ /~ CN (VII) wherein R4 and RA have the meanings set forth above with NHzOH, to form a compound having the general formula V l l l R
\NH (Vlll) . . ~
7 ~2~8179 wherein R4 and RA have the meanings set forth above, and by reacting the compound having the formula Vlll with a compound having the general formula IX
, (RC0)2o (IX) wherein R has the meaning set forth above, to form a compound having the formula 1, wherein X is .
~- 1 N I R
,- , - : ............... .
wherein R has the meaning set forth above.
The pharmacologically active compounds of the invention can be used for the formulation of pharmaceutical preparations, e.g.
for oral and parenteral administration to mammals including humans, in accordance with conventional methods of galenic pharmacy.
Conventional excipients are such pharmaceutically accept-able organic or inorganic carrier substances sùitable for parenterai or enteral application which do not deleteriously react with the active compound s .
Examples of such carriers are water, salt solutions, alco-hols, polyethylene glycols, polyhydroxyethoxylated castor oil, gela-tine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.
The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, such as lubricants, preser-vatives, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.
Injectable solutions or suspensions, preferably aqueous soiutions with the active compound dissolved in polyhydroxyethoxyl-ated ricinus oil, are particùlarly suitable for parenteral use.
Ampoules are conveniently unit dosages.
Tablets, dragees or capsules having talc and/or a carbo-hydrate carrier or binder or the like, the carrier preferably being 8 ~ 2~i8~79 .
lactose and/or corn starch and/or potato starch, are particularly suitable for oral application. A syrup, elixir or the like can be used wherein a sweetened vehicle can be employed.
Generally, the compounds of this invention are dispensed in unit dosage form comprising 0.05-100 mg in a pharmaceutically acceptable carrier per unit dosage.
The dosage of the compounds according to this invention is 0.1-300 mg/day, preferably 0.5-30 mg/day, when administered to patients, e.g. humans, as a drug.
The invention will now be described in further detail with reference to the following examp!es: - - -;, ~ -. .
3-[5-(3-ethyl-1 ,2,4-oxadiazole)-yl~-4-methoxymethyl-5-benzyloxy-~-carboline A: Pripionamide oxime A solution of 2.3 9 of sodium in 40 ml of methanol was - added dropwise to a solution of 6.9 9 of hydroxylamine hydrochloride in 100 ml of methanol. The reaction mixture was left for one hour before it was filtered. 0.11 mole propionnitrile was added dropwise to the filtrate, and the reaction mixture was allowed to stand for 2 days at room temperature with exclusion of water.
- B: 3-[5-(3-ethyl-1,2,4-oxadiazole)-yl]-4-methoxymethyl-5-benzyloxy-~-carboline -To 27.2 9 of imidazol in 300 ml of dry tetrahydrofuran (THF) was added dropwise 7.2 ml of thionylchloride in 100 ml of dry THF at room temperature while stirring. After the addition, stirring was continued for 0.5 hours, and the precipitate was removed by filtration. The filtrate contained 0.1 mole of thionyldiimidazole per 400 ml.
10 9 of 4-methoxymethyl-5-benzyloxy-~-carboline-3-carbox-ylic acid were suspended in 300 ml of dry THF. 200 ml of thionyldiimidazole in THF were added dropwise while stir-ring and stirring was continued until all acid had reacted.
9 ~8~7~-~
10 9 oF propionamide oxime were added dropwise during 5 minutes and stirring was continued for some hours. The mixture was leFt at room temperature until next day. The mixture was then evaporated and 200 ml of water and acetic acid were added. The mixture was filtered yielding 11.7 9 of product. This product was dissolved in 900 ml of xylene and heated to 155-165C while stirring for 6 hours.
The xylene phase was filtered giving 11.5 9 of crude product. The crude product was purified by chromatogra-phy on silica gel and CHCI3-Et3N-CH30 (1:1:1) yielding 9.0 9 of pure 4-methoxymethyl-5-benzyloxy-3- [5-(3-ethyl--1,2,4-oxadiazole)-yl]-~-carboline.
M . p . 182-7C .
!
The following cornpounds were prepared in an analogous . manner~
3- [5-(3-ethyl-1,2,4-oxadiazole)-yl]-4-methoxymethyl-6-benzyloxy-~-carboline. M.p. 169-73C.
3-[5-(3-methyl-1,2,4-oxadiazole)-yl]-4-methoxymethyl-5-benzyloxy-~-carboline. M.p. 236-39C.
3-[5-(3-cyclopropyl-1,2,4-oxadiazole)-yl]-4-methoxymethyl-5-benzyloxy-~-carboline. M. p . 214-9C .
3-[5-(3-ethyl-1,2,4-oxadiazole)-yl]-4-methyl-5-benzyloxy--~-carbGline. M. p . 224-7C .
. .
3-[5-(3-ethyl-1,2,4-oxadiazole)-yl~-4-methoxymethyl-6--methylthio-~-carboline.
3-~5-(3-ethyl-1,2,4-oxadiazole)-yl]-6,7-dimethoxy-4-ethyl--,B-carboline .
~.2;~3~79 3,6-di-[5-(3-ethyl-1,2,4-oxadiazole)-yl]-4-methyl-~-carb-oline . ..
3-[5-(3-ethyl-1,2,4-oxadiazole)-yl~-4-methyl-5-ethoxymeth-yl.~,M p. 192-4C.
,~- ca~ bo/;J7e 3-[5-(3-ethyl-1,2,4-oxadiazole)-yl]-4-ethyl-5-methoxy-~--carboline. M.p. 120-4C.
3- [5-(3-ethyl-1,2,4-oxadiazole)-yl]-4-ethyl-6-methoxy-~i--carboline . M . p . 186-215C .
- .................... .. _ . ~
3-[5-(3-ethyl-1,2,4-oxadiazole)-yl]-4-ethyl-6-(3-dimethyl-aminopropargyl)-,8-carboline. M.p. 148-56C.
3- [5-(3-ethyl-1,2,4-oxadiazole)-yl] -4-methyl-6-methylthio--~-carboline . M . p . 260-5C .
3^[5-(3-ethyl-1,Z,4-oxadiazole)-yl]-6-(3-dimethylaminopro-pargyl )-~-carboline . M . p . 225-30C .
3-LS-(3-ethyl-1,2,4-oxadiazole)-yl]-6-ethylthio-~-carboline.
M . p . 188-93C .
i 2-[5-(3-ethyl-1,2,4-oxadiazole)-yl] -4-methyl-5-iso-propoxy--~-carboline. M . p . 232-5C .
.
3- [5-(3-ethyl-1,2,4-oxadiazole)-yl]-5-iso-propoxy-Ei-carb-oline. M . p . 267-71C .
.
3-[5-(3-ethyl-1,2,4-oxadiazole)-yl]-5-ethoxymethyl-~i-carb-oline. M. p. 105-12C .
3-[5-(3-ethyl-1,2,4-oxadiazole)-yl]-4-methoxymethyl-5-eth-oxymethyl-~-carboline. M.p. 105-12 C.
11 ~,2~ t'9 3- [5-(3-ethyl-1,2,4-oxadiazole)-yl]-4-methoxymethyl-5-eth-oxy~ carboline. M . p . 74-88C .
3-[5-(3-ethyl-1,2,4-oxadiazole)-yl]-6-ethoxy-~-carboline.
M . p . 243-53C .
3- [5-(3-ethyl-1,2,4-oxadiazole)-yl] -6-(hydroxybutyl)-~-carboline. M . p. 176-9 C .
. . ~
3- [5-(3-ethyl-1,2,4-oxadiazole)-yl]-4-methoxymethyl-6-iso-propyl-~-carboline. M . p. 174 C .
_;
3-[5-(3-ethyl-1,2,4-oxadiazole)-yl]-4-methoxymethyl-S-(cyc-lohexen-3-yl )oxy-~-carboline .
3- ~5-(3-ethyl -1,2,4-oxadiazole)-yl ] -4-methoxymethyl-;-iso-butoxy-~-carboline . M . p . 93.8C .
3- [5-(3-ethyl-1,2,4-oxadiazole)-yl]-4-methoxymethyl-6-eth-oxymethyl-~-carboline: M . p . 168-71C .
3- [5-(3-ethyl-t ,2,4-oxadiazole)-yl]-4-methoxymethyl-5-iso-propoxy-~-carboline . M . p . 138-42C .
3- 15-(3-ethyl-1,2,4-oxadiazole)-yl] -4-methoxymethyl-5--propoxy-~-carboline. M. p . 104-22C .
3-[.-,-(3-ethyl-1,2,4-oxadiazole)-yl]-4-methyl-5-methoxy-methyl-,3-carboline. M.p. 205-10 C.
_ _ . _ .
3- [5-(3-ethyl-1,2,4-oxadiazole)-yl]-4-methyl-5-methyl-~--carboline . M. p . 242-4 C .
3- [S-(3-ethyl -1,2,4-oxadiazole)-yl ] -4-ethyl-5-ethoxymethyl--~-carboline. M.p. 156-63C.
12 ~ 9 3-[5-(3-ethyl-1,2,4-oxadiazo!e)-yl]-4-methyl-5-ethoxyethyl--~-carboline. M.p. 180-4C.
3,5-di-15-(3-ethyl-1,2,4-oxadiazole)-yl~-~-carboline.
M . p . 226-30 C .
.
3-[5-(3-ethyl-1,2,4-oxadiazole)-yl]-4-methoxymethyl-5-cyc-lo-butoxy-~-carboline. M. p . 107-11C
.. . .. . . _ _ _ .. . _ . . _ . _ _ _ .. _ _ . _ . .. _ . _ .. _ . .. _ .. _ _ . _ .... . . . . . . . .
and 3-~5-~3-ethyl-1,2 t 4-oxadiazole)-yl~-4-methoxymethyl-. 6-iso-propyloxy-B-carboline. M.p. 176-9 C.
ExAMpL-E--?
These new compounds possess valuable pharmacological properties which make them useful in psychopharmaceutical prepara-tions .
The new compounds of the invention are ~-carboline-3-oxa-diazolyl derivatives having the general formula 1:
~4 - .
wherein X is a oxadiazolyl group selected from the group consisting o~ .
~ L --< N=l ~ R
C3-~7 ~;_ wherein R is H, a lower alkyl or~cycloalkyl group, R is H, a lower alkyl or a lower alkoxyalkyl gro~lp, RA iq a lower alkyl group ; SCH3 ; SC2H~ ; OR 5 , wherein R15 is a lower alkyl ", cy~cloalkyl o~ c~cloalkenyl;
CH20R17, wherein R17 is H or a lower alkyl or phenyl group; -C--C-CH2N (CH3 ) 2; or O N
--< N ll R18 wherein R18 is a lower alkyl group, and wherein the cbmpound I may contain one or two RA groups, provided, however, that X is not 3-ethyl-1, 2, 4-oxadiazole-5-yl when R is H and RA is 5-CH20CH3, 5-OCH2C6H5, 6-sCH3, 6-oCH3 or 6-oCH2C6H5-2 ~L2,~8i~7g The term "lower alkyl group" means an alkyl group con-taining from 1 to 6 carbon atoms.
EP patent publications Nos. 30254 and 54507 disclose vari-ous substituted ~-carbolines including 3-oxadiazolyl derivatives which are related to the compounds of the invention.
However, surprisingly it has been found that the com-pounds of the invention exhibit psychotropic properties which are clearly superior to those of the prior art compounds.
The superior psychotropic properties of the compounds of the invention are evidenced by their improved capability for displac-ing radioactively labelled flunitrazepam from benzodiazepine recept-ors .
It is well known (Squires, R.F. and Braestrup,~ C., Nature (London) 266 (1977)) that specific sites in the central nervous systems of vertebrates exhibit a high specific affinity for binding 1,4- and 1,5-benzodiazepines. These sites are called benzodiazepine receptors.
The displacement activity of the compounds of the invention has been cletermined by determin7ng the IC50 value and ED50 value.
The IC50 value represents the concentration which causes a displacement of 50% of the specific binding of H-flunitrazepam (1.0 nM, 0C) in samples comprising a total volume of 0.55 ml of a su-spension of brain membrane, e. g . from rats.
The displacement test is performed as follows:
0,50 ml of a suspension of non-treated rat forebrain in 25 mM KH2PO4, pH = 7.1 (5-10 mg tissue/sample) i5 incubated for 40-60 minutes at 0C together with 3H-diazepam (specific activity 87 Ci/mmol, 1.0 nM) or 3H-flunitrazepam (specific activity 87 Ci/mmol, 1.0 nM). After incubation the suspension is filtered through "What-man GF/C" glass fibre filters, the residue washed twice with cold buffer solution and the radioactivity measured by scintillation count-ing .
The test is repeated except that prior to the addition of the radioactive labelled benzodiazepine a given amount ar an exces-sive amount of the compound, the displacement capability of which is to be determined, is added. Based on the data obtained the IC50 value can be calculated.
The EDSo value represents the dose (mg/kg) of a test sub-stance which causes the specific binding of flunitrazepam to benzo-3 ~1L2~ 7g diazepine receptors in a living brain to be reduced to 50% of thecontrol value~ Such an in vivo test is carried out as follows:
Groups oF mice are in~ected with the test substance at different doses and usually subcutaneously. 15 minutes later 3H-flu-nitrazepam is administered intravenously to the mice and after fur-ther 20 minutes the mice are killed. Their forebrain membranes are removed and the radioactivity of these forebrain membranes is mea-sured by scintillation counting. The ED50 value is determined from dose-response curves.
Test results obtained by testing some compounds of the invention will appear from the following table 1. :
.
(' ' " ~''' ' ' '" ' ' , , Table 1 Affinity for the benzodiazepine receptor inhibition of 3H-flunitraze-pam binding RA ~N J~
X ¦ R j RA I C 50 E D 50 . ng/ml ng/ml (in vitro) (in vivo) 1 2 3 ~ S-oC H 2P h O . 4 O . 9 _<N--O CH20CH3 5-OCH2Ph ~ 0.5 1 0 ~N ~ CH3- 5-CH20c2H5 0 . 26 O . 4 N ,~Et ~ ~ ~ O . 4 ~
~ON--~Et CH20CH3 5-0-~ O-Z ¦ O-Z _ Et¦ CH2CH3 5-ocH2cH2cH3 ¦ 0 3 ¦ 1.4 ¦ C H 2 C H 3 5 - ~ e> 4 ~E~ ¦ 6-c-c-cH2NMe2 0 . 4 E t ~ 2 3 1 5 - 0 ~ L o E I
~L26~3i.7g The invention also relates to a method of preparing the above mentioned compounds. This method comprises (a) reacting a reactive derivative of a compound of the -general formula 11 R _ ~COOH (I I) : - H
wherein R4 and RA have the meanings set forth above with a compound having the formula 111 .
NOH
R < . ( 111 ) wherein R has the meaning set forth above, to form a - compound of the general formula I in which X is O N
~N L R
wherein R has the meaning set forth above, (b) reacting a compound having the general formula IV
R
RA~ ~ J` CONH2 wherein R4 and RA have the meanings set forth above, with a compound V having the general formula R-C(OCH3)2N(CH3)2 (V) 6 ~2~ 79 wherein R has the meaning set forth above, to form a compoun~ having t~e general formula V
R
R __~CON=CRN (CH3) 2 H
wherein R, R4 and RA have the meanings set forth above and . by reacting the compound having the formula Vl with NH20H or another aminating agent, to form a compoutld having the formula I, wherein X is - O N
~N I~R
wherein R has the meaning set forth above or (c) reacting a compound having the formula Vl I
., ~A~ /~ CN (VII) wherein R4 and RA have the meanings set forth above with NHzOH, to form a compound having the general formula V l l l R
\NH (Vlll) . . ~
7 ~2~8179 wherein R4 and RA have the meanings set forth above, and by reacting the compound having the formula Vlll with a compound having the general formula IX
, (RC0)2o (IX) wherein R has the meaning set forth above, to form a compound having the formula 1, wherein X is .
~- 1 N I R
,- , - : ............... .
wherein R has the meaning set forth above.
The pharmacologically active compounds of the invention can be used for the formulation of pharmaceutical preparations, e.g.
for oral and parenteral administration to mammals including humans, in accordance with conventional methods of galenic pharmacy.
Conventional excipients are such pharmaceutically accept-able organic or inorganic carrier substances sùitable for parenterai or enteral application which do not deleteriously react with the active compound s .
Examples of such carriers are water, salt solutions, alco-hols, polyethylene glycols, polyhydroxyethoxylated castor oil, gela-tine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.
The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, such as lubricants, preser-vatives, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.
Injectable solutions or suspensions, preferably aqueous soiutions with the active compound dissolved in polyhydroxyethoxyl-ated ricinus oil, are particùlarly suitable for parenteral use.
Ampoules are conveniently unit dosages.
Tablets, dragees or capsules having talc and/or a carbo-hydrate carrier or binder or the like, the carrier preferably being 8 ~ 2~i8~79 .
lactose and/or corn starch and/or potato starch, are particularly suitable for oral application. A syrup, elixir or the like can be used wherein a sweetened vehicle can be employed.
Generally, the compounds of this invention are dispensed in unit dosage form comprising 0.05-100 mg in a pharmaceutically acceptable carrier per unit dosage.
The dosage of the compounds according to this invention is 0.1-300 mg/day, preferably 0.5-30 mg/day, when administered to patients, e.g. humans, as a drug.
The invention will now be described in further detail with reference to the following examp!es: - - -;, ~ -. .
3-[5-(3-ethyl-1 ,2,4-oxadiazole)-yl~-4-methoxymethyl-5-benzyloxy-~-carboline A: Pripionamide oxime A solution of 2.3 9 of sodium in 40 ml of methanol was - added dropwise to a solution of 6.9 9 of hydroxylamine hydrochloride in 100 ml of methanol. The reaction mixture was left for one hour before it was filtered. 0.11 mole propionnitrile was added dropwise to the filtrate, and the reaction mixture was allowed to stand for 2 days at room temperature with exclusion of water.
- B: 3-[5-(3-ethyl-1,2,4-oxadiazole)-yl]-4-methoxymethyl-5-benzyloxy-~-carboline -To 27.2 9 of imidazol in 300 ml of dry tetrahydrofuran (THF) was added dropwise 7.2 ml of thionylchloride in 100 ml of dry THF at room temperature while stirring. After the addition, stirring was continued for 0.5 hours, and the precipitate was removed by filtration. The filtrate contained 0.1 mole of thionyldiimidazole per 400 ml.
10 9 of 4-methoxymethyl-5-benzyloxy-~-carboline-3-carbox-ylic acid were suspended in 300 ml of dry THF. 200 ml of thionyldiimidazole in THF were added dropwise while stir-ring and stirring was continued until all acid had reacted.
9 ~8~7~-~
10 9 oF propionamide oxime were added dropwise during 5 minutes and stirring was continued for some hours. The mixture was leFt at room temperature until next day. The mixture was then evaporated and 200 ml of water and acetic acid were added. The mixture was filtered yielding 11.7 9 of product. This product was dissolved in 900 ml of xylene and heated to 155-165C while stirring for 6 hours.
The xylene phase was filtered giving 11.5 9 of crude product. The crude product was purified by chromatogra-phy on silica gel and CHCI3-Et3N-CH30 (1:1:1) yielding 9.0 9 of pure 4-methoxymethyl-5-benzyloxy-3- [5-(3-ethyl--1,2,4-oxadiazole)-yl]-~-carboline.
M . p . 182-7C .
!
The following cornpounds were prepared in an analogous . manner~
3- [5-(3-ethyl-1,2,4-oxadiazole)-yl]-4-methoxymethyl-6-benzyloxy-~-carboline. M.p. 169-73C.
3-[5-(3-methyl-1,2,4-oxadiazole)-yl]-4-methoxymethyl-5-benzyloxy-~-carboline. M.p. 236-39C.
3-[5-(3-cyclopropyl-1,2,4-oxadiazole)-yl]-4-methoxymethyl-5-benzyloxy-~-carboline. M. p . 214-9C .
3-[5-(3-ethyl-1,2,4-oxadiazole)-yl]-4-methyl-5-benzyloxy--~-carbGline. M. p . 224-7C .
. .
3-[5-(3-ethyl-1,2,4-oxadiazole)-yl~-4-methoxymethyl-6--methylthio-~-carboline.
3-~5-(3-ethyl-1,2,4-oxadiazole)-yl]-6,7-dimethoxy-4-ethyl--,B-carboline .
~.2;~3~79 3,6-di-[5-(3-ethyl-1,2,4-oxadiazole)-yl]-4-methyl-~-carb-oline . ..
3-[5-(3-ethyl-1,2,4-oxadiazole)-yl~-4-methyl-5-ethoxymeth-yl.~,M p. 192-4C.
,~- ca~ bo/;J7e 3-[5-(3-ethyl-1,2,4-oxadiazole)-yl]-4-ethyl-5-methoxy-~--carboline. M.p. 120-4C.
3- [5-(3-ethyl-1,2,4-oxadiazole)-yl]-4-ethyl-6-methoxy-~i--carboline . M . p . 186-215C .
- .................... .. _ . ~
3-[5-(3-ethyl-1,2,4-oxadiazole)-yl]-4-ethyl-6-(3-dimethyl-aminopropargyl)-,8-carboline. M.p. 148-56C.
3- [5-(3-ethyl-1,2,4-oxadiazole)-yl] -4-methyl-6-methylthio--~-carboline . M . p . 260-5C .
3^[5-(3-ethyl-1,Z,4-oxadiazole)-yl]-6-(3-dimethylaminopro-pargyl )-~-carboline . M . p . 225-30C .
3-LS-(3-ethyl-1,2,4-oxadiazole)-yl]-6-ethylthio-~-carboline.
M . p . 188-93C .
i 2-[5-(3-ethyl-1,2,4-oxadiazole)-yl] -4-methyl-5-iso-propoxy--~-carboline. M . p . 232-5C .
.
3- [5-(3-ethyl-1,2,4-oxadiazole)-yl]-5-iso-propoxy-Ei-carb-oline. M . p . 267-71C .
.
3-[5-(3-ethyl-1,2,4-oxadiazole)-yl]-5-ethoxymethyl-~i-carb-oline. M. p. 105-12C .
3-[5-(3-ethyl-1,2,4-oxadiazole)-yl]-4-methoxymethyl-5-eth-oxymethyl-~-carboline. M.p. 105-12 C.
11 ~,2~ t'9 3- [5-(3-ethyl-1,2,4-oxadiazole)-yl]-4-methoxymethyl-5-eth-oxy~ carboline. M . p . 74-88C .
3-[5-(3-ethyl-1,2,4-oxadiazole)-yl]-6-ethoxy-~-carboline.
M . p . 243-53C .
3- [5-(3-ethyl-1,2,4-oxadiazole)-yl] -6-(hydroxybutyl)-~-carboline. M . p. 176-9 C .
. . ~
3- [5-(3-ethyl-1,2,4-oxadiazole)-yl]-4-methoxymethyl-6-iso-propyl-~-carboline. M . p. 174 C .
_;
3-[5-(3-ethyl-1,2,4-oxadiazole)-yl]-4-methoxymethyl-S-(cyc-lohexen-3-yl )oxy-~-carboline .
3- ~5-(3-ethyl -1,2,4-oxadiazole)-yl ] -4-methoxymethyl-;-iso-butoxy-~-carboline . M . p . 93.8C .
3- [5-(3-ethyl-1,2,4-oxadiazole)-yl]-4-methoxymethyl-6-eth-oxymethyl-~-carboline: M . p . 168-71C .
3- [5-(3-ethyl-t ,2,4-oxadiazole)-yl]-4-methoxymethyl-5-iso-propoxy-~-carboline . M . p . 138-42C .
3- 15-(3-ethyl-1,2,4-oxadiazole)-yl] -4-methoxymethyl-5--propoxy-~-carboline. M. p . 104-22C .
3-[.-,-(3-ethyl-1,2,4-oxadiazole)-yl]-4-methyl-5-methoxy-methyl-,3-carboline. M.p. 205-10 C.
_ _ . _ .
3- [5-(3-ethyl-1,2,4-oxadiazole)-yl]-4-methyl-5-methyl-~--carboline . M. p . 242-4 C .
3- [S-(3-ethyl -1,2,4-oxadiazole)-yl ] -4-ethyl-5-ethoxymethyl--~-carboline. M.p. 156-63C.
12 ~ 9 3-[5-(3-ethyl-1,2,4-oxadiazo!e)-yl]-4-methyl-5-ethoxyethyl--~-carboline. M.p. 180-4C.
3,5-di-15-(3-ethyl-1,2,4-oxadiazole)-yl~-~-carboline.
M . p . 226-30 C .
.
3-[5-(3-ethyl-1,2,4-oxadiazole)-yl]-4-methoxymethyl-5-cyc-lo-butoxy-~-carboline. M. p . 107-11C
.. . .. . . _ _ _ .. . _ . . _ . _ _ _ .. _ _ . _ . .. _ . _ .. _ . .. _ .. _ _ . _ .... . . . . . . . .
and 3-~5-~3-ethyl-1,2 t 4-oxadiazole)-yl~-4-methoxymethyl-. 6-iso-propyloxy-B-carboline. M.p. 176-9 C.
ExAMpL-E--?
4-methoxymethyi-5-benzyloxy-3-[-(S-ethyl-1,2,4-oxadiazole)-yl]-~--carboline A: 4-methoxymethy!-5-benzyloxy-~-carboline-3-carboxamide oxime A mixture of 0.0125 mol and 3-cyano-4-methoxymethyl-S-benzoloxy-~-carboline, 1.1 9 of hydroxylamine hydrochlor-ide, 200 ml of 99% ethanol and 5.2 ml of a 20% potassium carbonate solution in water was refluxed for 22 hours. The reaction mixture was filtered and the filtrate was concen-trated. The residue was treated with 100 ml of water and the crystalline solid was filtered off and washed with water .
B: 4-methoxymethyl-5-benzyloxy-3- [-3-(5-ethyl-1, 2, 4-oxadia-zole)-yl ~ -~-carboline A mixture of 5. 6 mmol of the product of A and 10 ml of propionic acid anhydride was stirred for 2 hours at 20C
.2~ 79 . 13 and thereafter for 5 hours at 120C. After evaporation 100 ml of THF were added and the mixture was allowed to ? stand overnight at room temperature whereafter the mix-ture was concentrated in vacuo. 100 ml of methylene ch!or-ide were added and the mixture was filtered leaving the title compound. M.p. 173.7C.
The following compounds were prepared in an analogous manner:
.. . _ .. . . . . . . .
- 3- [3-(5-methyl-1 ,2,4-oxadiazole)-yl]-4-methoxymethyl-5-^benzyloxy-~-carboline. M.p. 168.5C.
3- [-3-(S-ethyl-1 ,2,4-oxadiazole)-yl]-4-methyl-5-ethoxy-methyl-~-carboline . M . p . 152-65C .
B: 4-methoxymethyl-5-benzyloxy-3- [-3-(5-ethyl-1, 2, 4-oxadia-zole)-yl ~ -~-carboline A mixture of 5. 6 mmol of the product of A and 10 ml of propionic acid anhydride was stirred for 2 hours at 20C
.2~ 79 . 13 and thereafter for 5 hours at 120C. After evaporation 100 ml of THF were added and the mixture was allowed to ? stand overnight at room temperature whereafter the mix-ture was concentrated in vacuo. 100 ml of methylene ch!or-ide were added and the mixture was filtered leaving the title compound. M.p. 173.7C.
The following compounds were prepared in an analogous manner:
.. . _ .. . . . . . . .
- 3- [3-(5-methyl-1 ,2,4-oxadiazole)-yl]-4-methoxymethyl-5-^benzyloxy-~-carboline. M.p. 168.5C.
3- [-3-(S-ethyl-1 ,2,4-oxadiazole)-yl]-4-methyl-5-ethoxy-methyl-~-carboline . M . p . 152-65C .
Claims (7)
1. .beta.-Carboline-3-oxadiazolyl derivatives, c h a r a c t -e r i z e d in that they have the general formula I:
(I) wherein X is an oxadiazolyl group selected from the group consist-ing of and wherein R is H, a lower alkyl or C3-C7 cycloalkyl group, R4 is H, a lower alkyl or a lower alkoxyalkyl group, RA is a lower alkyl ,group; SCH3; SC2H5; OR15, wherein R15 is a lower alkyl, C3-C7 cycloalkyl or, C3-C7 cycloalkenyl;
CH2OR17, wherein R17 is H or a lower alkyl or phenyl group; C?C-CH2N(CH3)2; or wherein R18 is a lower alkyl group, and wherein the compound I may contain one or two RA groups, provided, however, that X is not 3-ethyl-1,2,4-oxcadiazole-5-yl when R4 is H and RA is 5-CH2OCH3, 5-OCH2C6H5, 6-SCH3, 6-OCH3 or 6-OCH2C6H5.
(I) wherein X is an oxadiazolyl group selected from the group consist-ing of and wherein R is H, a lower alkyl or C3-C7 cycloalkyl group, R4 is H, a lower alkyl or a lower alkoxyalkyl group, RA is a lower alkyl ,group; SCH3; SC2H5; OR15, wherein R15 is a lower alkyl, C3-C7 cycloalkyl or, C3-C7 cycloalkenyl;
CH2OR17, wherein R17 is H or a lower alkyl or phenyl group; C?C-CH2N(CH3)2; or wherein R18 is a lower alkyl group, and wherein the compound I may contain one or two RA groups, provided, however, that X is not 3-ethyl-1,2,4-oxcadiazole-5-yl when R4 is H and RA is 5-CH2OCH3, 5-OCH2C6H5, 6-SCH3, 6-OCH3 or 6-OCH2C6H5.
2. 4-Methoxymethyl-5-benzyloxy-3-[5-(3-ethyl-1,2,4-oxadiazole)-yl]-.beta.-carboline.
3. 4-Methoxymethyl-5-benzyloxy-3-[5-(3-methyl-1,2,4-oxadiazole)-yl]-.beta.-carboline.
4. 3-[5-(3-Ethyl-1,2,4-oxadiazole)-yl]-5-isoprop-oxy-.beta.-carboline.
5. 3-[5-(3-Ethyl-1,2,4-oxadiazole)-yl]-4-methyl-5-methoxymethyl-.beta.-carboline.
6. A method of preparing a compound according to claim 1, c h a r a c t e r i z e d in (a) reacting a reactive derivative of a compound of the general formula II
(II) wherein R4 and RA have the meanings set forth above with a compound having the formula III
(III) wherein R has the meaning set forth above, to form a compound of the general formula I in which X is wherein R has the meaning set forth above, (b) reacting a compound having the general formula IV
(IV) wherein R4 and RA have the meanings set forth above, with a compound V having the general formula R-C(OCH3)2N(CH3)2 (V) wherein R has the meaning set forth above, to form a compound having the general formula VI
(VI) wherein R, R4. and RA have the meanings set forth above and by reacting the compound having the formula VI with NH2OH or another aminating agent, to form a compound having the formula I, wherein X is wherein R has the meaning set forth above or (c) reacting a compound having the formula VII
(VII) wherein R4 and RA have the meanings set forth above with NH2OH, to form a compound having the general formula VIII
(VIII) wherein R4 and RA have the meanings set forth above, and by reacting the compound having the formula VIII with a compound having the general formula IX
(RCO)2O (IX) wherein R has the meaning set forth above, to form a compound having the formula 1, wherein X is wherein R has the meaning set forth above.
(II) wherein R4 and RA have the meanings set forth above with a compound having the formula III
(III) wherein R has the meaning set forth above, to form a compound of the general formula I in which X is wherein R has the meaning set forth above, (b) reacting a compound having the general formula IV
(IV) wherein R4 and RA have the meanings set forth above, with a compound V having the general formula R-C(OCH3)2N(CH3)2 (V) wherein R has the meaning set forth above, to form a compound having the general formula VI
(VI) wherein R, R4. and RA have the meanings set forth above and by reacting the compound having the formula VI with NH2OH or another aminating agent, to form a compound having the formula I, wherein X is wherein R has the meaning set forth above or (c) reacting a compound having the formula VII
(VII) wherein R4 and RA have the meanings set forth above with NH2OH, to form a compound having the general formula VIII
(VIII) wherein R4 and RA have the meanings set forth above, and by reacting the compound having the formula VIII with a compound having the general formula IX
(RCO)2O (IX) wherein R has the meaning set forth above, to form a compound having the formula 1, wherein X is wherein R has the meaning set forth above.
7. A pharmaceutical preparation comprising a compound of claim 1 in admixture or conjunction with a pharmaceuti-cally acceptable carrier.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK2400/84 | 1984-05-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1268179C true CA1268179C (en) | 1990-04-25 |
Family
ID=
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