US3894001A - 11-Aminoalkyl- and 11-cyclicaminomorphanthridines - Google Patents
11-Aminoalkyl- and 11-cyclicaminomorphanthridines Download PDFInfo
- Publication number
- US3894001A US3894001A US307933A US30793372A US3894001A US 3894001 A US3894001 A US 3894001A US 307933 A US307933 A US 307933A US 30793372 A US30793372 A US 30793372A US 3894001 A US3894001 A US 3894001A
- Authority
- US
- United States
- Prior art keywords
- hydrogen
- chloro
- morphanthridine
- methyl
- dihydromorphanthridine
- 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 - Lifetime
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- 239000001257 hydrogen Substances 0.000 claims description 33
- 150000002431 hydrogen Chemical class 0.000 claims description 21
- -1 4-PIPERIDYL Chemical class 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 11
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- IDWNSAXOQLJYOF-UHFFFAOYSA-N 11h-benzo[c][1]benzazepine Chemical compound C1=NC2=CC=CC=C2CC2=CC=CC=C21 IDWNSAXOQLJYOF-UHFFFAOYSA-N 0.000 abstract description 9
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 abstract description 4
- 239000003874 central nervous system depressant Substances 0.000 abstract description 3
- 238000000034 method Methods 0.000 abstract description 3
- 230000002936 tranquilizing effect Effects 0.000 abstract description 3
- 239000000730 antalgic agent Substances 0.000 abstract description 2
- 229940035363 muscle relaxants Drugs 0.000 abstract description 2
- 239000003158 myorelaxant agent Substances 0.000 abstract description 2
- 230000003647 oxidation Effects 0.000 abstract description 2
- 238000007254 oxidation reaction Methods 0.000 abstract description 2
- 125000000217 alkyl group Chemical group 0.000 description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 239000002253 acid Substances 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 125000005936 piperidyl group Chemical group 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- VYZPXGMSAOCYOL-UHFFFAOYSA-N 2-[2-(2-aminoethyl)phenyl]ethanamine Chemical compound NCCC1=CC=CC=C1CCN VYZPXGMSAOCYOL-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 206010001488 Aggression Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000016571 aggressive behavior Effects 0.000 description 1
- 208000012761 aggressive behavior Diseases 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- NEHMKBQYUWJMIP-NJFSPNSNSA-N chloro(114C)methane Chemical compound [14CH3]Cl NEHMKBQYUWJMIP-NJFSPNSNSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- QXUAFCKBYYPTPQ-ZWKAXHIPSA-L magnesium (2R,3R,4S,5R,6S)-2-(hydroxymethyl)-6-[(2R,3S,4R,5R)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol octadecanoate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O QXUAFCKBYYPTPQ-ZWKAXHIPSA-L 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000004014 thioethyl group Chemical group [H]SC([H])([H])C([H])([H])* 0.000 description 1
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/20—Dibenz [b, e] azepines; Hydrogenated dibenz [b, e] azepines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Definitions
- AESTMW continuatiomimpart of Ser. No. 848,355, Aug. 7, The compounds are 1l-ammoalkylm0rphanthrldmes 1969, Pat 3,699,099, and a continuatiomimpart and ll-cyclicaminomorphanthridines which are useful f 48506, J 22 97 abandoned as central nervous system depressants of the tranquilizing type, muscle relaxants and analgetic agents.
- X and Y are members of the group consisting of hydrogen, halogen such as chloro, bromo and fluoro, an alkyl of l to 4 carbon 'atoms'such as'methyl and ethyl, an alkoxy of l to 3 carbon atoms such as methoxy, ethoxy and propo'xy, a thio-lower alkyl such, as thiomethyl and thioethyl and trifluoromethyl, R, R and R are hydrogen or a lower alkyl of--1 :to 4 carbon atoms, n is 0 to 4 and Am is se'lectedfrom't.
- R and R are selected from hydrogen, lower alkyl of l to 4 carbon atoms such as methyl, ethyl or isopropyl and a phenyl-lower alkyl of 7 to '13 carbon atoms such as benzyl, phenethyl or phenyliso'propyl, or
- a heterocyclicamino group suchlas morpholino, pyrrolidino, piperidino, N-lower alkyl piperazino in which the lower alkyl is 1 to 4'carbon atoms such as N- methyl piperazino, N-phenyl-lower alkyl piperazino in which the lower alkyl is l to 4 carbon atorns such as N- benzyl piperazino and N-(hydroXy-lower alkyl)- piperazino groups in which the lower alkyl is Ho 4 carbon atoms such as 4-(B-hydroxyethyl piperazino), and
- a c yclicamino group such as 3-'piper idyl', 4-pi peridyl, 3-pyrrolidyl, 3-homopiperidyl and 4-homopiperidyl.
- the compounds of the present invention may be conveniently prepared from the corresponding 1 laminoalkyl-S,o-dihydromorphanthridines and the 11- cyclicamino -5,o dihydromorphanthrid ines which have the following formulae in w 'ch X, Y, R, R 1R n, Am and -C are as previously defined.
- Representative of the compounds which may be employed as starting materials are l 1-( 3-dimethylaminopropyl )-5 ,-dihydromorphanthridine, 2-chloro-1 l-( 3-dimethylaminopropyl)-5 ,6-dihydromorphanthridine, S-chloro-l l-(3-dimethylaminopropyl)-5,6-dihydromorphanthridine, Z-trifluoromethyl-l l-( 3-dimethylaminopropyl )-5 ,6- dihydromorphanthridine, l 1-(3-diethylaminopropyl)-5,o-dihydromorphanthridine, Z-chloro-l l-(3diethylaminopropyl)-5,6-dihydromorphanthridine, 8-chloro-1 1-(3-diethylaminopropyl)-5,6-dihydromorphanthridine, Z
- dihydromorphanthridine l 1,-(3-methylarninopropyl)-5,6-dihydromorphanthridine, 2-chloro-l l-(3-methylaminopropyl)-5,6-dihydromorphanthridine, S-chloro-l l-(3-methylaminopropyl)-5 ,6-dihydromorphanthridine, 2-trifluoromethyl-l l-(3-methylaminopropyl)-5,6-
- dihydromorphanthridine 2-trifluoromethyl-l l-( N-methyl-N- benzylaminopropyl)-5,6-dihydromorphanthridine, l l-(N-methyl-piperazinopropyl)-5 ,6-dihydromorphanthridine, 2-chloro-1 l-(N-methyl-piperazinopropyl)-5 ,6-dihydromorphanthridine,
- the compounds of the present invention have been found to possess utility as pharmaceutical and veterinary agents, especially as central nervous system depressants.
- central nervous system depressants for example, in mouse behavioral studies the compound 1 1-(3-dimethylaminopropyl) morphanthridine was found in a dose of 10 mg/kg intraperitoneally to cause central nervous system depression. The studies also indicated that the compound had an LD in excess of 100 mg/kg intraperitoneally.
- the forementioned compound was also tested for tranquilizing activity in mice which had been isolated to induce an antisocial aggressive behavior. in the tests the compound was administered to the mice in doses of 5 and 20 mg/kg intraperitoneally and found to have an E10 of about 20 mg/kg. The compound was also tested for analgetic activity in mice and was found to be effective against the effects of electrical stimulation in doses of 40 mg/lcg intraperitoneally.
- the compounds When employed as pharmaceutical agents the compounds are preferably used in the form of acid addition salts.
- Such acid addition salts may be conveniently prepared by conventional means such as by contacting the compounds with a suitable acid in a mutual solvent and then removing the solvent to obtain the desired salt.
- acids which may be used are hydrochloric acid, succinic acid, tartaric acid, benzoic acid or fumaric acid.
- Quarternary ammonium salts of the compounds may be formed by conventional techniques employing a suitable alkylating agent such as methyl chloride, methyl iodide or ethyl bromide.
- Pharmaceutical dosage forms containing the active ingredients are generally prepared by combining the active ingredient or ingredients with a major amount of one or more suitable pharmaceutical diluents and then forming the resulting mixture into unit dosage forms suitable for oral or parenteral administration.
- the unit dosage forms will generally contain from 5 to 250 mg. of the active ingredients. One or more of such units may be administered daily depending upon the patients physical size and the severity of the condition being treated. However, generally the daily dosage will not exceed 150 mg. of the active ingredient per kilogram of the patients body weight.
- Suitable pharmaceutical composition which may be prepared are the following:
- EXAMPLE 1 l 1-(3-Dimethylaminopropyl)morphanthridine Active manganese dioxide (25 grams) is refluxed with 250 ml. of benzene using a water separator. After 2 hours, 5.3 grams (0.019 mole) of 11-(3- dimethylaminopropy1)-5,6-dihydromorphanthridine in ml. of benzene is added and the suspension stirred and refluxed for 18 hours. The Mn0 is filtered off, rinsed with benzene, and the filtrate concentrated to yield the crude base. Chromatography over silica gel using benzene-methanol (19:1) as eluent followed by benzene-diethylamine (40: 1) affords 1 1-(3- dimethylaminopropyl)morphanthridine.
- Example 2 The process of Example 1 is repeated employing in place of l 1-(3-dimethylaminopropyl)-5,o-dihydromorphanthridine one of the following:
- R;, and R are hydrogen, alkyl of l to 4 carbons 0T p y alkyl 0f 7 to 13 carbons and R and R are hydrogen, alyl of 1 to 4 carbons or or benzyl.
- yq r amlrw rq p Selected from q P o.
- lino, pyrrolidlno, prperldino, N-lower alkyl pipera- Y, R R d R are hydrogen, n is 0, Am is zino, N-phenyl-lower alkyl piperazino and N- LhyfIlroxy-lower alkyl) -piperazino, and
- cyclicamino group selected from 3-piperidyl, 4- ⁇ R1 piperidyl, 3-pyrrolidyl, 3-homopiperidyl and 4- homopiperidyl and pharmaceutically acceptable acid addition salts thereof,
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The compounds are 11-aminoalkylmorphanthridines and 11cyclicaminomorphanthridines which are useful as central nervous system depressants of the tranquilizing type, muscle relaxants and analgetic agents. Representative of the compounds disclosed are 11-(3-dimethylaminopropyl)morphanthridine and 11-(N-methyl-4piperidyl)morphanthridine. The method of preparing the compounds is by the oxidation of the corresponding 5,6dihydromorphanthridine with active manganese dioxide.
Description
United States Patent [1 1 [111 33%,001 Drukker July 8 1975 ll-AMINOALKYL- AND [56] References Cited 11 l-CYCLICAMINOMORPHANTHRIDINES UNITED STATES PATENTS [7 5] Inventor: Alexander E. Drukker, Milwaukee, 3,317,537 5/1967 Drukker 260/239 D Wis.
[73] Assignee: Colgate-Palmolive Company, New Primary Examifer Henry mes York Assistant Exammer-Robert T. Bond Attorney, Agent, or Firm-T. F. Kryshak; M. L. [22] Filed: Nov. 20, 1972 Youngs [21] Appl. No: 307,933
Related U.S. Application Data [57] AESTMW [63] continuatiomimpart of Ser. No. 848,355, Aug. 7, The compounds are 1l-ammoalkylm0rphanthrldmes 1969, Pat 3,699,099, and a continuatiomimpart and ll-cyclicaminomorphanthridines which are useful f 48506, J 22 97 abandoned as central nervous system depressants of the tranquilizing type, muscle relaxants and analgetic agents. Rep- [52] Us. C1 ..260/239 D; 260/247.1 M; resentative 0f the Compounds disclosed are H 260/247.5 R; 260/326.5 CA; 260/326.81; dimethylaminopropyl)morphanthridine and 260/268 TR; 424/244; 424/248; 424/250; methyl-4-piperidyl)morphanthridine. The method of 424/2 7; 424/274; 2 0/293 59 preparing the compounds is by the oxidation of the [51] Int. Cl C07d 41/08 Corresponding y 0 p r n w [58] Field of Search. 260/239 D, 247.1 M, 247.5 R, rive manganese dioxide- 260/326.5 CA, 326.81, 268 TR, 293.59
11% Claims, No Drawings RELATED CASES This application is a continuation in-part of my pending applications Ser. Nos. 848,355 now U.S. Pat. No. 3,699,099 and 48,506, now abandoned, filed Aug.
7, 1969, and June 22, 1970, respectively.
DESCRIPTION OF Til-IE INVENTION The compounds of the present invention may be represented by the following formulae:
in which X and Y are members of the group consisting of hydrogen, halogen such as chloro, bromo and fluoro, an alkyl of l to 4 carbon 'atoms'such as'methyl and ethyl, an alkoxy of l to 3 carbon atoms such as methoxy, ethoxy and propo'xy, a thio-lower alkyl such, as thiomethyl and thioethyl and trifluoromethyl, R, R and R are hydrogen or a lower alkyl of--1 :to 4 carbon atoms, n is 0 to 4 and Am is se'lectedfrom't.
in which R and R; are selected from hydrogen, lower alkyl of l to 4 carbon atoms such as methyl, ethyl or isopropyl and a phenyl-lower alkyl of 7 to '13 carbon atoms such as benzyl, phenethyl or phenyliso'propyl, or
b. a heterocyclicamino group suchlas morpholino, pyrrolidino, piperidino, N-lower alkyl piperazino in which the lower alkyl is 1 to 4'carbon atoms such as N- methyl piperazino, N-phenyl-lower alkyl piperazino in which the lower alkyl is l to 4 carbon atorns such as N- benzyl piperazino and N-(hydroXy-lower alkyl)- piperazino groups in which the lower alkyl is Ho 4 carbon atoms such as 4-(B-hydroxyethyl piperazino), and
is a c yclicamino group such as 3-'piper idyl', 4-pi peridyl, 3-pyrrolidyl, 3-homopiperidyl and 4-homopiperidyl.
The compounds of the present invention may be conveniently prepared from the corresponding 1 laminoalkyl-S,o-dihydromorphanthridines and the 11- cyclicamino -5,o dihydromorphanthrid ines which have the following formulae in w 'ch X, Y, R, R 1R n, Am and -C are as previously defined.
Representative of the compounds which may be employed as starting materials are l 1-( 3-dimethylaminopropyl )-5 ,-dihydromorphanthridine, 2-chloro-1 l-( 3-dimethylaminopropyl)-5 ,6-dihydromorphanthridine, S-chloro-l l-(3-dimethylaminopropyl)-5,6-dihydromorphanthridine, Z-trifluoromethyl-l l-( 3-dimethylaminopropyl )-5 ,6- dihydromorphanthridine, l 1-(3-diethylaminopropyl)-5,o-dihydromorphanthridine, Z-chloro-l l-(3diethylaminopropyl)-5,6-dihydromorphanthridine, 8-chloro-1 1-(3-diethylaminopropyl)-5,6-dihydromorphanthridine, Z-trifluoromethyl-l l-( 3-diethy laminopropyl)-5 ,6-
dihydromorphanthridine, l 1,-(3-methylarninopropyl)-5,6-dihydromorphanthridine, 2-chloro-l l-(3-methylaminopropyl)-5,6-dihydromorphanthridine, S-chloro-l l-(3-methylaminopropyl)-5 ,6-dihydromorphanthridine, 2-trifluoromethyl-l l-(3-methylaminopropyl)-5,6-
dihydromorphanthridine, l l-(N-methyl-N-benzylaminopropyl)-5,6-dihydromorphanthridine, 2-chloro-l 1-(N-methyl-N-benzylaminopropyl)-5 ,6- dihydromorphanthridine, 8-chloro-1 1-(N-methyl-N-benzylaminopropyl)-5 ,6-
dihydromorphanthridine, 2-trifluoromethyl-l l-( N-methyl-N- benzylaminopropyl)-5,6-dihydromorphanthridine, l l-(N-methyl-piperazinopropyl)-5 ,6-dihydromorphanthridine, 2-chloro-1 l-(N-methyl-piperazinopropyl)-5 ,6-dihydromorphanthridine,
5 8-chloro-l l-(N-methyl-piperazinopropyl)-5 ,6-dihydromorphanthridine,
Z-trifluoromethyl-l 1-( N-methyl-piperazinopropyl)- 5 ,6-dihydromorphanthridine,
1 1-[ 3-(4-hydroxyethylpiperazinopropyl) ]-5 ,6-dihydromorphanthridine, I
l l-[ 3-(4-hydroxyethylpiperazinopropyl)]- morphanthridine,
Z-chloro-l l-[ 3-(4-hydroxyethylpiperazinopropyl) morphanthridine,
8-chloro-l 1-[3-(4-hydroxyethylpiperzinopropyl)]- morphanthridine,
Z-trifluoromethyl-l 1-[3-(4- hydroxyethylpiperazinopropyl) ]-morphanthridine,
l l-(N-methyl-4-piperidyl)-morphanthridine, 2-chloro-1 1-(N-methyl-4-piperidyl)- morphanthridine,
8-chloro-l l-( N-methyl-4-piperidyl morphanthridine,
2-trifluoromethyl- 1 l-(N-methyl-4-piperidyl morphanthridine,
1 l-(N-benzyl-4-piperidyl)-morphanthridine, 2-chloro-1 1(N-benzyl-4-piperidyl)- morphanthridine,
8-chloro-1 l-(N-benzyl-4-piperidyl)- morphanthridine,
2-trifluoromethyl-1 1-( N-benZyl-4-piperidyl morphanthridine,
l l-(l\l-methyl-3-piperidyl)-morphanthridine,
2-chloro-l l-(N-methyl-3-piperidyl)- moi-phanthridine,
8-chloro-l 1-(N-methyl-3-piperidyl)- morphanthridine,
Z-trifluoromethyl-l 1-( N-methyl-3-piperidyl morphanthridine,
1 l-(N-ethyl-3-pyrrolidyl)-morphanthridine,
l l-(N-benzyl-3-pyrrolidyl)-morphanthridine, and
l l-(N-methyl-3-homopiperidyl)-morphanthridine.
The compounds of the present invention have been found to possess utility as pharmaceutical and veterinary agents, especially as central nervous system depressants. For example, in mouse behavioral studies the compound 1 1-(3-dimethylaminopropyl) morphanthridine was found in a dose of 10 mg/kg intraperitoneally to cause central nervous system depression. The studies also indicated that the compound had an LD in excess of 100 mg/kg intraperitoneally.
The forementioned compound was also tested for tranquilizing activity in mice which had been isolated to induce an antisocial aggressive behavior. in the tests the compound was administered to the mice in doses of 5 and 20 mg/kg intraperitoneally and found to have an E10 of about 20 mg/kg. The compound was also tested for analgetic activity in mice and was found to be effective against the effects of electrical stimulation in doses of 40 mg/lcg intraperitoneally.
When employed as pharmaceutical agents the compounds are preferably used in the form of acid addition salts. Such acid addition salts may be conveniently prepared by conventional means such as by contacting the compounds with a suitable acid in a mutual solvent and then removing the solvent to obtain the desired salt. Examples of acids which may be used are hydrochloric acid, succinic acid, tartaric acid, benzoic acid or fumaric acid.
Quarternary ammonium salts of the compounds may be formed by conventional techniques employing a suitable alkylating agent such as methyl chloride, methyl iodide or ethyl bromide.
Pharmaceutical dosage forms containing the active ingredients are generally prepared by combining the active ingredient or ingredients with a major amount of one or more suitable pharmaceutical diluents and then forming the resulting mixture into unit dosage forms suitable for oral or parenteral administration.
The unit dosage forms will generally contain from 5 to 250 mg. of the active ingredients. One or more of such units may be administered daily depending upon the patients physical size and the severity of the condition being treated. However, generally the daily dosage will not exceed 150 mg. of the active ingredient per kilogram of the patients body weight.
Representative of a suitable pharmaceutical composition which may be prepared are the following:
TABLETS l l-(3-Dimethylaminopropyl) morphanthridine 2 Methyl cellulose, 400 cps. Lactose Magnesium stearate Starch The powders, other than magnesium stearate, are granulated with water, passed through a No. 16 mesh screen and dried at 50 C. Magnesium stearate is mixed in and 40 mg. tablets are pressed.
The practice of the invention is further illustrated by the following examples:
EXAMPLE 1 l 1-(3-Dimethylaminopropyl)morphanthridine Active manganese dioxide (25 grams) is refluxed with 250 ml. of benzene using a water separator. After 2 hours, 5.3 grams (0.019 mole) of 11-(3- dimethylaminopropy1)-5,6-dihydromorphanthridine in ml. of benzene is added and the suspension stirred and refluxed for 18 hours. The Mn0 is filtered off, rinsed with benzene, and the filtrate concentrated to yield the crude base. Chromatography over silica gel using benzene-methanol (19:1) as eluent followed by benzene-diethylamine (40: 1) affords 1 1-(3- dimethylaminopropyl)morphanthridine.
Anal. Calcd. for C l-ll N C, 81.97; H, 7.97; N, 10.06.
Found: C, 82.24; H, 8.31; N, 10.22.
EXAMPLE 2 The process of Example 1 is repeated employing in place of l 1-(3-dimethylaminopropyl)-5,o-dihydromorphanthridine one of the following:
2-chloro-1 l-(3-dimethylaminopropyl)-5,6-dihydromorphanthridine,
8-chloro-1 1-( 3-dirnethylaminopropyl )-5 ,6-dihydromorphanthridine,
2-trifluoromethyl-l l-(3-dimethylaminopropyl)-5,6-
9 W R R Y X Y CHR (CHR Am c I II in which X and Y are hydrogen, halo, alkoxy of 1 to 3 and R and R are hydrogen, alkyl of l to 4 carbons or carbons, alkyl of l to 4 carbons, thio-lower alkyl or tribenzyl. fluoromethyl, n is to 4, R, R and R are hydrogen or 5. A compound of Formula II of claim 1 in which X, alkyl of 1 to 4 carbon atoms, Am is Y, R, R and R are hydrogen, n is 0, Am is a. N R,,
in which R;, and R are hydrogen, alkyl of l to 4 carbons 0T p y alkyl 0f 7 to 13 carbons and R and R are hydrogen, alyl of 1 to 4 carbons or or benzyl. yq r amlrw rq p Selected from q P o. A compound of Formula 1 of claim 1 m which x,
lino, pyrrolidlno, prperldino, N-lower alkyl pipera- Y, R R d R are hydrogen, n is 0, Am is zino, N-phenyl-lower alkyl piperazino and N- LhyfIlroxy-lower alkyl) -piperazino, and
is a cyclicamino group selected from 3-piperidyl, 4- \R1 piperidyl, 3-pyrrolidyl, 3-homopiperidyl and 4- homopiperidyl and pharmaceutically acceptable acid addition salts thereof,
2. A compound of Formula I of claim 1 in which X and Y are hydrogen or chloro.
and 1R and R are methyl.
7. A compound of Formula I of claim l in which X is hydrogen, Y is chloro, R, R and R are hydrogen, n
3. A compound of Formula I of claim 1 in which X is Am is and Y are hydrogen or chloro, R, R and R are hydrogen, n is 0, Am is R3 R a R and R and R are methyl.
and 3 and 4 are hydrogen, alkyl of 1 t0 4 carbons 8. A compound of Formula II of claim l in lwhich X benzyl. and Y are hydrogen.
A Compound of Formula I of clam 1 Whlch X 9. A compound of Formula II of claim 1 in which X is hydrogen, Y is chloro, R, R and R are hydrogen, n is hydrogen and Y is ch10r0 IS 0, Am 1s 10. A compound of Formula II of claim 1 in which X andxare hydrogen or chloro, /Rn is 3 or 4-piperidyl and R is an alkyl of 1 to 4 carbons.
Claims (10)
1. A COMPOUND SELECTED FROM COMPOUNDS OF THE FORMULAE:
2. A compound of Formula I of claim 1 in which X and Y are hydrogen or chloro.
3. A compound of Formula I of claim 1 in which X and Y are hydrogen or chloro, R, R1 and R2 are hydrogen, n is 0, Am is
4. A compound of Formula I of claim 1 in which X is hydrogen, Y is chloro, R, R1 and R2 are hydrogen, n is 0, Am is
5. A compound of Formula I of claim 1 in which X, Y, R, R1 and R2 are hydrogen, n is 0, Am is
6. A compound of Formula I of claim 1 in which X, Y, R, R1 and R2 are hydrogen, n is 0, Am is
7. A compound of Formula I of claim 1 in which X is hydrogen, Y is chloro, R, R1 and R2 are hydrogen, n is 0, Am is
8. A compouNd of Formula II of claim 1 in lwhich X and Y are hydrogen.
9. A compound of Formula II of claim 1 in which X is hydrogen and Y is chloro.
10. A COMPOUND OF FORMULA II OF CLAIM 1 IN WHICH X AND Y ARE HYDROGEN OR CHLORO, -C NIS 3 OR 4-PIPERIDYL AND R1 IS AN ALKYL OF 1 TO 4 CARBONS.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US307933A US3894001A (en) | 1969-08-07 | 1972-11-20 | 11-Aminoalkyl- and 11-cyclicaminomorphanthridines |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US84835569A | 1969-08-07 | 1969-08-07 | |
| US307933A US3894001A (en) | 1969-08-07 | 1972-11-20 | 11-Aminoalkyl- and 11-cyclicaminomorphanthridines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3894001A true US3894001A (en) | 1975-07-08 |
Family
ID=26976008
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US307933A Expired - Lifetime US3894001A (en) | 1969-08-07 | 1972-11-20 | 11-Aminoalkyl- and 11-cyclicaminomorphanthridines |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US3894001A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2624487A1 (en) * | 1976-06-01 | 1977-12-15 | Richardson Merrell Inc | 11-Amino-alkyl-morphanthridine derivatives - with selective antidepressant activity |
| US4117122A (en) * | 1974-11-25 | 1978-09-26 | Richardson-Merrell Inc. | 11-aminoalkylmorphanthridin-11-ols |
| US4434171A (en) | 1980-11-28 | 1984-02-28 | Sandoz Ltd. | Dibenzazepine derivatives, pharmaceutical compositions containing them, and pharmaceutical methods using them |
| CN108331546A (en) * | 2018-02-11 | 2018-07-27 | 义乌市绿美生物科技有限公司 | A kind of novel oilfield chemicals equipment |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3317537A (en) * | 1965-06-25 | 1967-05-02 | Colgate Palmolive Co | Piperazinoalkyl-morphanthridines |
-
1972
- 1972-11-20 US US307933A patent/US3894001A/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3317537A (en) * | 1965-06-25 | 1967-05-02 | Colgate Palmolive Co | Piperazinoalkyl-morphanthridines |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4117122A (en) * | 1974-11-25 | 1978-09-26 | Richardson-Merrell Inc. | 11-aminoalkylmorphanthridin-11-ols |
| DE2624487A1 (en) * | 1976-06-01 | 1977-12-15 | Richardson Merrell Inc | 11-Amino-alkyl-morphanthridine derivatives - with selective antidepressant activity |
| US4434171A (en) | 1980-11-28 | 1984-02-28 | Sandoz Ltd. | Dibenzazepine derivatives, pharmaceutical compositions containing them, and pharmaceutical methods using them |
| CN108331546A (en) * | 2018-02-11 | 2018-07-27 | 义乌市绿美生物科技有限公司 | A kind of novel oilfield chemicals equipment |
| CN108331546B (en) * | 2018-02-11 | 2018-11-20 | 义乌市绿美生物科技有限公司 | A kind of novel oilfield chemicals equipment |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE2760372C2 (en) | ||
| DE2915318C2 (en) | ||
| CH667657A5 (en) | CARBOCYCLIC AND HETEROCYCLIC CARBONYL METHYLENE AND METHYL PIPERIDINE AND PYRROLIDINE. | |
| IL32853A (en) | 5,11-dihydro-6h-pyrido(2,3-b)-(1,4)benzodiazepine-6-ones substituted in 11-position and processes for the production thereof | |
| US3663696A (en) | Treatment of depression with 2-chloro-11 - (piperazinyl)dibenz - (b,f)(1,4)oxazepines and acid addition salts thereof | |
| US3712898A (en) | Benzoheterocyclicalkyl derivatives of 4-(2-keto-1-benzimidazolinyl)-piperidine | |
| IE44330B1 (en) | 1-aminoalkanoyl-2-(10,11-dihydrodibenz /b,f//1,4/oxazepine-10-carbonyl)hydrazines. | |
| US4434171A (en) | Dibenzazepine derivatives, pharmaceutical compositions containing them, and pharmaceutical methods using them | |
| DE2708913A1 (en) | BENZOYL PIPERIDYALKYL INDOLES AND RELATED COMPOUNDS | |
| US3894001A (en) | 11-Aminoalkyl- and 11-cyclicaminomorphanthridines | |
| US3803154A (en) | 11-cyclicaminoalkylidenemorphanthridines | |
| JPH02256676A (en) | Pteridines and pharmaceutical compositions containing the compounds | |
| DE1801523A1 (en) | New Tricyclic Enamines and Processes for Making New Tricyclic Enamines | |
| US3699099A (en) | 11-aminoalkylidenemorphanthridines | |
| DE2601262A1 (en) | 1-R-4- (OMEGA-SUBSTITUTED ALKYL) -3, 3-DIPHENYL-2-PYRROLIDINONE AND THE METHOD FOR THEIR MANUFACTURING | |
| US3859439A (en) | 2,3-dihydro-5 -trifluoromethyl-1h-dibenzo(2,3:6,7) thiepino (4,5-c) pyrroles as cns-depressants | |
| US3489836A (en) | 5-amino - 10,11-dihydro - 5h - dibenzo (a,d)-cycloheptenes and derivatives in pharmaceutical compositions and the use thereof for the treatment of epilepsy | |
| DE69617001T2 (en) | (2-morpholinylmethyl) benzamide derivatives | |
| US3767659A (en) | Derivatives of 3,4-dihydrobenzothieno(2,3-c)pyridine | |
| US3632653A (en) | Ethano-anthracenes | |
| EP0270692A1 (en) | Antiarrhythmic agent | |
| US3753992A (en) | Process and intermediates for quinine,quinidine and derivatives thereof | |
| US3282943A (en) | N-substitution products of polymethylene-tetrahydroquinolines | |
| US4101671A (en) | Aminobenzyl-amines and salts thereof | |
| US3786148A (en) | Method of treating hypertension with morphanthridines |