CA1077929A - Methanodibenzocycloheptapyrroles - Google Patents
MethanodibenzocycloheptapyrrolesInfo
- Publication number
- CA1077929A CA1077929A CA221,222A CA221222A CA1077929A CA 1077929 A CA1077929 A CA 1077929A CA 221222 A CA221222 A CA 221222A CA 1077929 A CA1077929 A CA 1077929A
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- Prior art keywords
- carbon atoms
- compound
- hydrogen
- prepared
- carbons
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/70—[b]- or [c]-condensed containing carbocyclic rings other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
- C07C2603/24—Anthracenes; Hydrogenated anthracenes
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Disclosed are compounds of the formula wherein R1, R2 are H, lower alkyl, lower alkoxy, hydroxyl, fluorine, chlorine, bromine, trifluoromethyl, 2,2,2-trifluoroethyl, methylthio, trifluoromethyl-thio, trifluoromethylsulfonyl, methylsulfonyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, car-bamoyl, sulfamyl, N-methylsulfamyl, N,N-dimethyl-sulfamyl, methylsulfinyl, hydrazinocarbonyl, hy-droxylamincarbonyl, lower alkylcarbonyl, cyclo-alkylcarbonyl of 4-7 carbons, nitro, and where R is H, alkyl of uo to 10 carbon atoms, alkenyl of 3-7 carbon atoms attached by a saturated carbon atom to N, cyclo-alkyl, of 3-5 carbon atoms, propargyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-penta-fluoropropyl, .alpha.-furylmethyl, .alpha.-thienyl-methyl, -(CH2)nCN, -(CH2)nCO2H, -(CH2)qOR3, -(CH2)nCO2 (lower alkyl) and -CH(R4) (CH2)pR5 of uo to 14 carbons, where q is 2-6;
n is 1-6;
p is 0-5;
R3 is lower alkyl, phenyl or lower alkylphenyl;
R4 is H or n-lower alkyl;
R5 is a hydrocarbyl group containing at least one ring of 3-9 carbon atoms attached to alkylene by a ring carbon atom, with the proviso that when p is O, the carbon atom attached to -CH(R4)- is not a quaternary carbon atom; and, when R is other than H, the nitrogen atom can be additionally substituted with oxygen to form a tertiary amine oxide, made by rearrangement of 9,12-bridged ethencanthracenes. The com-pounds where R is other than H are useful as tranquilizing agents and analgesics in warm-blooded animals.
- 1a -
Disclosed are compounds of the formula wherein R1, R2 are H, lower alkyl, lower alkoxy, hydroxyl, fluorine, chlorine, bromine, trifluoromethyl, 2,2,2-trifluoroethyl, methylthio, trifluoromethyl-thio, trifluoromethylsulfonyl, methylsulfonyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, car-bamoyl, sulfamyl, N-methylsulfamyl, N,N-dimethyl-sulfamyl, methylsulfinyl, hydrazinocarbonyl, hy-droxylamincarbonyl, lower alkylcarbonyl, cyclo-alkylcarbonyl of 4-7 carbons, nitro, and where R is H, alkyl of uo to 10 carbon atoms, alkenyl of 3-7 carbon atoms attached by a saturated carbon atom to N, cyclo-alkyl, of 3-5 carbon atoms, propargyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-penta-fluoropropyl, .alpha.-furylmethyl, .alpha.-thienyl-methyl, -(CH2)nCN, -(CH2)nCO2H, -(CH2)qOR3, -(CH2)nCO2 (lower alkyl) and -CH(R4) (CH2)pR5 of uo to 14 carbons, where q is 2-6;
n is 1-6;
p is 0-5;
R3 is lower alkyl, phenyl or lower alkylphenyl;
R4 is H or n-lower alkyl;
R5 is a hydrocarbyl group containing at least one ring of 3-9 carbon atoms attached to alkylene by a ring carbon atom, with the proviso that when p is O, the carbon atom attached to -CH(R4)- is not a quaternary carbon atom; and, when R is other than H, the nitrogen atom can be additionally substituted with oxygen to form a tertiary amine oxide, made by rearrangement of 9,12-bridged ethencanthracenes. The com-pounds where R is other than H are useful as tranquilizing agents and analgesics in warm-blooded animals.
- 1a -
Description
1~77gZ9 NOVEL TRhNQUILIZER-ANALGESICS AND PROCESSES FOR MAKING THEM
Related Patent The ethenoanthracenes from which the compounds of this invention are prepared, are disclosed by the inventor in ; U.S. Patent 4 077 977 which issued March 7, 1978.
. .
BACKGROUND OF THE INVENTION
Field of the Invention mis invention relates to novel polycyclic compounds conta~ning N, to methods of making the compou~ds~ and to the use of certain of the compounds as tranquilizing agents and as ' analgesics.
;,.' . De~cri~tion of the Prior Art There is no known art describing compounds of the type dlsclosed ln th$s invention. The closest known art ~ describes the following structures which lack one or more : features of the compounds of the invention.
.:
r1t1sh Patent 1 336 634 R
..`
'~
., .
., ~.~
~JS`
Related Patent The ethenoanthracenes from which the compounds of this invention are prepared, are disclosed by the inventor in ; U.S. Patent 4 077 977 which issued March 7, 1978.
. .
BACKGROUND OF THE INVENTION
Field of the Invention mis invention relates to novel polycyclic compounds conta~ning N, to methods of making the compou~ds~ and to the use of certain of the compounds as tranquilizing agents and as ' analgesics.
;,.' . De~cri~tion of the Prior Art There is no known art describing compounds of the type dlsclosed ln th$s invention. The closest known art ~ describes the following structures which lack one or more : features of the compounds of the invention.
.:
r1t1sh Patent 1 336 634 R
..`
'~
., .
., ~.~
~JS`
- 2-. , ',''.''.' ,, ,., )7~9~9 U.S. P~tent 3 687 936 V ~ ~ (4/10/73) , SUMMARY OF THE INVENTION
This invention i9 directed to co~pounds of the I orm~la S ~ A2 ~ 3 .., .':
_ 3 --.,, ~' ~ ' , '; .
, . .. . :
1~677929 whereln Rl, R2 are H, lower alkyl, lower alkoxy, hydroxyl, rluorine, chlorlne~ bromlne, trifluoromethyl, 2,2,2-tri.r}uoroethyl, methylthio, trlrluoromethylthio, tri-~luoromethylsulronyl, methylsulronyl, carboxyl, methoxy-carbonyl, ethoxycarbonyl, carbamoyl, ~ul~amyl, N-methyl-sulramyl, N,N-dimethylsul~amyl, methylsulrinyl, hydrazlno-carbonyl, hydroxylamlnocarbonyl, lower alkylcarbonyl, cycloalkylcarbonyl Or 4-7 carbons, nitro, and where R ls H, aIkyl of up to 10 carbon atoms, alkenyl of 3-7 carbon atoms attached by a saturated carbon atom to N, cycloalkyl of 3-5 carbon atoms, propargyl, . . , . _ . .
2,2,2-trl~luoroethyl, 2,2,3,3,3-penta-fluoropropyl, ~-furylmethyl, -thlenyl-methyl, -(CH2)nCN, -(CH2)nC02H, ~(CH2)qOR3~
-(CH2)nCO2 (lower alkyl) and -CH(R4)(CH2)pR5 o~ up to 14 carbons, where q is 2-6;
n 18 1-6;
~1~ 0-5~
R3 1B lower alkyl, phenyl or lower alkylphenyl;
. R4 ls H or n-lower alkyl;
R i8 a hydrocarbyl group containlng at least .. one ring Or 3-9 carbon atom~ attached eo alkylene by a rlng carbon atom, wlth the provlso that when ~ ls O, the carbon atom attached to -CH(R4)- ls not a quaternary carbon atom, . ' .
.. 4 `~
, 107~Y~.3 and, when R is other than H, espec~ally lower alkyl or cycloalkylmethyl of 5-10 carbon atoms, the nitrogen atom can be additionally substituted with oxygen to form a tertiary amine oxide. The invention al50 includes pharmaceutically acceptable acid addition salts of the amines.
While the compounds of formula (I) hereinabo~e are illustrative of one stereoisomer only, it shall be understood that the for~ula is intended to cover both stereoisomers and their racemic mixture.
Preferred are the amines of structure I which have the trans configuratlon at the 3a-12b ring fusion with respect to the 12b hydrogen atom and the 13 methano bridge (or in th~
alternative, and equivalent thereto, the five-membered nitrogen-containing ring is fused trans to the seven-membered ring) as expressed by the formula i~l N
R
wherein Rl and R2 are H and R is alkyl of 1-10 carbon atoms, especially n-alkyl of 2-8 carbons, alkenyl of 3-7 carbons attached to N by a saturated carbon atom, ; especially allyl, ~ -furylmethyl;
~(CH2)q-0-lower alkyl;
-(CH2)q-0-phenyl; and -CH(R4)(CH2)pR5 wherein p is 0 to 3;
q is 2 to 6;
R4 is H or CH3;
. .
, ~
:: ~0~9~5' R5 1~ cycloalkyl o~ 3-8 carbon atoms; cgcloalkenyl of
This invention i9 directed to co~pounds of the I orm~la S ~ A2 ~ 3 .., .':
_ 3 --.,, ~' ~ ' , '; .
, . .. . :
1~677929 whereln Rl, R2 are H, lower alkyl, lower alkoxy, hydroxyl, rluorine, chlorlne~ bromlne, trifluoromethyl, 2,2,2-tri.r}uoroethyl, methylthio, trlrluoromethylthio, tri-~luoromethylsulronyl, methylsulronyl, carboxyl, methoxy-carbonyl, ethoxycarbonyl, carbamoyl, ~ul~amyl, N-methyl-sulramyl, N,N-dimethylsul~amyl, methylsulrinyl, hydrazlno-carbonyl, hydroxylamlnocarbonyl, lower alkylcarbonyl, cycloalkylcarbonyl Or 4-7 carbons, nitro, and where R ls H, aIkyl of up to 10 carbon atoms, alkenyl of 3-7 carbon atoms attached by a saturated carbon atom to N, cycloalkyl of 3-5 carbon atoms, propargyl, . . , . _ . .
2,2,2-trl~luoroethyl, 2,2,3,3,3-penta-fluoropropyl, ~-furylmethyl, -thlenyl-methyl, -(CH2)nCN, -(CH2)nC02H, ~(CH2)qOR3~
-(CH2)nCO2 (lower alkyl) and -CH(R4)(CH2)pR5 o~ up to 14 carbons, where q is 2-6;
n 18 1-6;
~1~ 0-5~
R3 1B lower alkyl, phenyl or lower alkylphenyl;
. R4 ls H or n-lower alkyl;
R i8 a hydrocarbyl group containlng at least .. one ring Or 3-9 carbon atom~ attached eo alkylene by a rlng carbon atom, wlth the provlso that when ~ ls O, the carbon atom attached to -CH(R4)- ls not a quaternary carbon atom, . ' .
.. 4 `~
, 107~Y~.3 and, when R is other than H, espec~ally lower alkyl or cycloalkylmethyl of 5-10 carbon atoms, the nitrogen atom can be additionally substituted with oxygen to form a tertiary amine oxide. The invention al50 includes pharmaceutically acceptable acid addition salts of the amines.
While the compounds of formula (I) hereinabo~e are illustrative of one stereoisomer only, it shall be understood that the for~ula is intended to cover both stereoisomers and their racemic mixture.
Preferred are the amines of structure I which have the trans configuratlon at the 3a-12b ring fusion with respect to the 12b hydrogen atom and the 13 methano bridge (or in th~
alternative, and equivalent thereto, the five-membered nitrogen-containing ring is fused trans to the seven-membered ring) as expressed by the formula i~l N
R
wherein Rl and R2 are H and R is alkyl of 1-10 carbon atoms, especially n-alkyl of 2-8 carbons, alkenyl of 3-7 carbons attached to N by a saturated carbon atom, ; especially allyl, ~ -furylmethyl;
~(CH2)q-0-lower alkyl;
-(CH2)q-0-phenyl; and -CH(R4)(CH2)pR5 wherein p is 0 to 3;
q is 2 to 6;
R4 is H or CH3;
. .
, ~
:: ~0~9~5' R5 1~ cycloalkyl o~ 3-8 carbon atoms; cgcloalkenyl of
3-8 carbons, me~hylenecycloalkyl Or 4-9 carbon~;
polycycloalkyl o~ 7 to 9 carbons, polycyclo alkenyl o~ 7 to 9 carbon atoms; or phenyl;
Most pre~erred R groups are the cycloalkylmethyl groups o~ 5-1~ carbon atoms and alkyl of 4-8 carbon atoms.
The compounds where R is other than H have been found to be tranqu~lizers for warm-blooded animals and this invention further includes compositions of the active compounds with pharmaceutically acceptable inert carriers and to the use of an effective dose of these compounds to tranquilize warm-blooded animals either alone or, with the amines, ~n the ; form of their pharmaceutically acceptable salts.
The compound wherein R is H is a valuable inter-mediate for making other members o~ the class.
The term "lower alkyl" means an alkyl group Or 1-4 carbon atoms, including branched alkyl groups.
The term "cycloalkyl group" ls employed ln the :
llmlted sense Or a radical derlved rrom a ring of -CH2- groups by removal o~ a hydrogen atom.
".. ~ .
- The term "quaternary carbon atom" rerers to a ; carbon atom Joined dlrectly to rour other carbon atoms.
. .
; The term "cycloalkenyl" rerer~ to a cyclic hydro-carbon group contalnlng one or more double bonds rormally derlved ~rom a cycloalkyl group by removal Or hydrogen.
, .
DE~ILED DESCRIPTION OF THE INVENTION
.~. The present invention ls dlrected to certain _ 6 -.. ~, .
:
. 1~779~g ;
methanodibenzocycloheptapyrroles which can be made by a rearrangement reaction of bridge~ ethenoanthracenes.
me latter compounds are made by an internal Diels-Alde~r reaction o~ propargyl-substituted 9-anthracenemethylen-imines, 9-anthracenemethylamines and 9-anthramides as disclosed in the commonly assigned, aforementioned U.S. Patent 4 077 977.
In one procedure a substit~ted anthracene R1 ~ ~2 where Rl and R2 can be hydrogen, lower alkyl, lower alkoxy, - fluorine~ chlorine, bromine, trifluoromethyl~
2,2,2-trifluoroethyl or other partially fluori-nated lower alkyl groups~ trifluoromethylsulfonyl, methylsulfonyl, carboxyl, alkoxycarbonyl, sulfamyl, N-methylsulfamyl, N,N-dimethylsulfamyl, methylsul-finyl, or alkylcarbonyl groups, is reacted with ` oxalyl chloride in the presence of a catalyst to obtain the corresponding 9Danthroyl chloride. The ~ubstituted 9-anthroyl chloride iæ reacted with propargylamine per se or substituted on the nitro-~en atom wlth the aforesaid R groups. These com-pounds undergo an internal Diel~-Alder reaction to give ~ubstituted, 9,12-bridged ethenoanthracenes 1, -.
, according to the equationO
'.' ~9 C~I2 ~CC~-C~2-CsC~ CO ~2 1R
R II
. ~
:
1~77~9 This process can be carried out by heating the alkynylanthramlde, either neat or ln a suitable inert solvent, preferably an aromatic hydrocarbon at ~ temperature of 80 to 250C for a time sufficient to effect cyclization, generally from l to 48 hours depending on the conditions.
Reaction of II with bromine leads to a ring rearrangement reaction to produce products with the skeletal ~tructure of I substituted with bromine at the 12b and 13 positions, and contain~ng a l~arbonyl group. Bromination may be carried out in any inert solvent, preferably a chlorinated aliphatic hydrocarbon with methylene chloride and chloroform being especially preferred. The reaction temperature should be from about -20C to 100C, preferably 20-~5C.
. The bromine atoms are readily removed from the intermediate by reductive dehalogenation with a trialkyltin hydride, either neat, or dissolved in an aromatic hydrocarbon ~olvent. It is preferred to use tributyltir. hydride in benzene or toluene. The reaction is carried out at a tempera-ture in t~e range of 50-180C to give compounds having the skeletal structure of I which contain a l-carbonyl group.
;~ Alternatively the bromine atoms can be removed by reaction with zinc and acetic acld at 25 to 120 or ~lth zlnc and aqueou~ dlmethylformamlde.
The amides containing the l-carbonyl ~roup arc readily converted to the corresponding amines of structure I
by reduction o~ the carbonyl group, pre~erably ~th diborane dissolved in an ether solvent such as tetrahydrofuran, at a temperature of 0-100C.
Another procedure ls to start with an ethenoanthra-cene Or the ~ormula ' ~077g'~g ~ CH~
Rl = ~ R2 ¦
III
which can be prepared ~rom the corre~pondlng 9-anthraldehyde b~ reaction with propargylamine, ~ollaw~d by lnternal Diels-Alder reaction, reductlon o~ the carbon-nltrogen double bond, and alkylation o~ III(R2H) to obtain th~ derived N~ ubstituted compGund. Alternatively, III(R=H) may be acylated by conre~tional procedures, ~nd the acyl derl~a-tire~ may then be reduced with lithiu~ alu~inum hgdride to obtain the corre~ponding N-substituted compound~.
In a pre~erred process ~or the preparation o~
III shown in the ~ollowing equatlon~, tho 9-anthraldehyde ~ :
compound i~ react~d with a suitable amine at 25 to 150 ln an alcohol ~ol~ent to rorm an imlne. Th~ imine i~ then reduced wlth a metal hydride reducing agent such a8 ~od~um borohydride or Rodium cya~oborohgdrid~ ln an alc~hol such . ~
.~. a~ methanol, ethanol, or i~opropanol, ~hich can be th~ same ~olvent that iB employed to form the imine, at a temperature betweon 0C and 100C. me resultant secondary amine iB
`-~ 20 then condensed with a propargyl haltde~ pre~erably propargyl ; bro~ide, ln the pre~ence of an inorganic base such a~ an . .
., aqueous ~olution of an alkali metal carbonate or an organic .
: ba~e which does not react sub~tantially with propargyl . bromide, e.g., certain hindered umines including diisopropyl-.. ethyla~ine, at a te~perature of O to 100C, preferably ~ amOlent temperature~.
''' - 9 _ , .~
,'' . ' ' ~077g;~
me alkyngl-substituted anthraceneR are then cyclized to co~pound~ of Fo~ula ITI as described herein-above for the cyclizat~on o~ the alkynylanthra~ides.
~ ~ ~1 ~ ~ ~2 R C~O ~=N-R
: ~ ~ ~ Br-CHz C-=CH ~ ~
~ Rl ~ ~ 2 < Rl ~ R2 :. CH27-R H2~ R
"'' CH2C~CH
. .
.~ Ring rearrangement occur~ in the presence of strong acids ~uch as p-toluene~ulfonic acld and trifluoro~cetic acid . at about 70 to 200C to give product~ havlng the ~keletal structure of compound I but containing a double bond in the . ..
1-12b po~ltlon. The rearrangement i~ preferably carr~ed out with tri~luoroacetic acid. Thi~ reagent may al~o be em-plo~ed ~or the rearrangement of compound~ of structure III
~1~
whereln R 1~ an acyl group.
.: me double bond can be reduced to produce the deslred trans ~tructure at the 3a-12b carbon atoms by such reagent~ a~ ~odium cyanoborohgdrlde in acetlc acid or by catalytic hydrogenation ~ith a palladium cataly~t in acetlc acid sol~ent, or a platinum or rhodium catalgst in tetrahy-:~.
.
'' .''' ~0779~g drofuran. All of the abo~e reductions are conveniently run at ambient temperatures, but temperatures between 0C and 60(' are sultable. When catalytic hydrogenatlon i8 employed, the pres~ure of hydrogen should be from about 1 to about 10 atmosphere$.
In this method R must be other than H and Rl and R2 can be hydrolytically ~table group~, including carboxyl groups ~hich can be 6ubsequently esterified and converted to alkoxy-carbonyl, hydrazinocarbonyl, hydroxylaminocarbonyl, carbamoyl, or other derlved substituents Prod~ct~ substituted w~th methylthio and trifluoromethylthio groups are obtalned by reduction of the correspondlng methylsulfonyl and tri~luoro-methyl~ulfonyl compounds by conventlonal method~. EYdroxYl-substltuted compounds are obtained by eleavage of the corres-pondlng alkoxy compound~.
Examples Or ~uitable anthracenes which can be . employed a~ ~tarting materials lnclude:
:' l-methylanthracene - 2-methylanthracene 2,6-dimethylanthracene 2,7-dlme~hylanthracene 2-isopropylanthracene 2-t-butylanthracene 1,8-dlmethylanthracene l-chloroanthracene : 2-chloroanthracene . . .
~7~9~9 q ~
1,5-dichloro~nthracene 1~8-dlchloro~nthracene 2-methoxyanthracene 1~5-dlmethoxyanthracen~
l-bromoanthracene 2-bromoanthracene 3,6-dlchloroanthracene l-fluoroanthracene - 2-fluoroanthracene 2,6-dimethoxyanthracene - trl~luoromethylanthrac~ne 2-acetylanthracene . ., l-proplonylanthracene . 1,5-diacctylanthracene .... 1,8-dlacetyl~nthracene l-anthroic acid .; . , ~-anthrolc acld :.
l-anthracene~ulfonlc acld .~ 2-anthracen~sulfonlc acid . ~, ~,8-anthr~cenedlsulfonlc acld ; 2,6-anthracenedl~ulfonlc acld ' -~
Compounds Or structuro I wherein R i8 H can be alkylated or acylated accordlnK to conventional procedure~.
.: The acyl derlvative~ may then be roduced with ltthlum alumlnum hydride to obtaln th~ corre~pondlng N-~ubstltut0d compounds, for ex~mple cycloalkylmothyl groups may be - lntroduced onto the nitrogen atom by acylation with a .
:
```'`
.. - 12 -`:
`', ~, .
7~75~
cycloalkanecarbonyl chloride followed by reductlon o~ the carbonyl group. The -rurylmethyl and ~-thlenylmethyl derivatlves are obtained ln a similar manner.
Alkylatlon Or the R - H compound~ is pre~erred for the lntroduction of propargyl, ~-cyano lower alkyl, ~-carbomethoxy lower alkyl, ~-carboethoxy lower alkyl, and 2,2,2-tri Muroethyl substltuents.
In general, the 8, 3a and 12b carbon atoms are asymmetric carbon atoms. Depending on the method of 19 synthesizing the compounds of this invention, there are obtained mixtures Or racemates, pure racemates or optlcal antipodes.
The pharmacologlcally actlve compounds of the invention are trans at the 3a-12b rlng fusion wlth respect to the 12b-hydrogen atom and the 13-methano bridge as depicted ln structure I. The stereochemistry Or the 3a-12b ring ruslon was determined ~rom the crystal structure o~ the methlodlde salt of the compound Or str~cture I, R - CH
l = R2 = H. Crystals of thls compound are monoclinlc, space group P21/c, with cell dimensions of a = 10.219 i 0. oo8, b = 14.759 i 0.026, c = 12.902 i 0.012~, and ~ = 100.64 ~ 0.06.
The C(l)C(12b)C(3a)C(13) torsion angle is -~0.6 ~ 1.0 and the ; HC (12b)C(3a)C(13) torslon angle ls 162.2 + 5.0 where H ls the hydrogen on C(12b). The C(l)C(12b)C(3a)C(13) torslon angle ls the angle between the C(12b)-C(l) and C(3a)-C(13) ~ bonds in the C(12b)-C-(3a) pro~ectlon (clockwlse posltive).
; These data establlsh that the 3a-12b ring ~usion ls trans with respect to the 12b-hydrogen atom and the 13-methano bridge.
... .
~ - 13 -:
1[)779~9 .
/ \ I~
C~3 C~3 ., Mixture~ Or racemates can be separated into the stereolsomeric pure racemates (diasteriolsomers) by the use Or known physical procedures, e.g., by chromato~raphy or rractional distlllatlon. Pure racemates can be ~eparated into the optical antipodes by conventional methods such as combination wlth an optlcally actlve acid rollowed by sep-aratlon by physical means such as recrystallizatlon of the resultant salts.
Reduction wlth sodium cyanoborohydrlde in acetlc acid, catalytic hydrogenation wlth Pd in acetic acid, or with Pt or Rh ln tetrahydro~uran descrlbed above ~ields the desired 20 trans structure at the rlng Junction 3a-12b.
The amine compounds Or the present lnventlon can be converted to the amine o~ides by oxldatlon o~ the parent amine wlth hydrogen peroxlde, peracetic acid, perbenzolc acld or the llke at ambient temperature or between about 20C and 6~C.
` The amine or amine oxldes can be used as such;
...
- however, ln the case Or the amlnes, addltion salts Or the , actlve compound with pharmaceutlcally acceptable acids can be used for admlnlstratlonto warm-blooded anlmals alone or 3 with an inert carrler. Such salts lnclude hydrochlorldes, .. , _ 14 -,, '`' .
:
~(:1 779~5~
sulrates, nitrates, phosphates, acetates, tartrate9, cltrate~, lactates, maleates and rumarates o~ the amine compounds of this inventlon. The salt~ can be made, and the free bases can be recovered from the salts by conventlonal methods includlng the use Or ion exchange resln~, metathetical reactions and the like.
EI~BO~IMENT~ OF T~i~ INVENTION
The following examples are intended to illustrate this invention but should not be construed as fully delineating the scope thereof. The compounds of the invention described in the examples have the trans configuration at the 3a - 12b ring -fusion with respect to the 12b-hydrogen atom and the 13-methano bridge.
Example 1 2-Methyl-,2 3,8,12b-tetrahydro-lH-3~8-methanodibenzo ~,4:6,77-cyclohepta ~ ,2-c~pyrrole _ _ _ ~ ~GH~
la : ,. .
[~~~~ ~
N
; 30 CH3 CH3 lb lC
' '' .',' ,.
1~ 7 ~ g ~
To a ~olution Or O.88 g of 2-methyl~3,5-dlhydro-5~9b-o-benzenobenz~e]isoindol-1-(2H)-one in 10 ml of methylene chloride is added 0.58 g o~ bromine in 10 ml of methylene chloride. Removal of the solvent lea~es 1.42 g of 12b, 13-~lbromo-2-me~hyl-2,3,~,i2b-tetrahydro-lH-3a,8-methanodibenzo[3,4:6,7]-cyclohepta[1,2-c]pyrr~l-1-one, (la), mp 215-216 (dec). A ~ample crystallized from acetonitrile melted at 221-222 (dec); nmr spectrum:
~ 1.6-1.8 (m, 1); 2.3-2.8 (m, 7); 5.1 (d, J = 4.5 Hz, l);
5.7 (d, J = 10.5 Hz, 1); 5.8 (d, J - 4.5 Hz, 1); 6.6 (d, ~ - 10.5 Hz, 1) and 6.9 (s, 3).
Ar.al. Calcd for Cl9Hl5Br2N0: C, 52.68; H, 3.49, N, ~.24 Found: C, 52.83; H, ~.43; N, 3.34 - A mixture of 8.07 g of la, 17.2 g of freshly distilled tributyltin hydride and 50 ml o~ anhydrous benzene is heated under reflux under n~trogen for ~ days.
Most of the benzene is removed and the residue is distilled through a short-path column (to 125 bath temperature, 1 micron). The pot residue is crystallized from lsopropyl alcohol tc give 3,63 ~ t71~ yield) of 2-methyl-2,3,8,12b-tetrahydro-lH-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]
pyrrol-l-one (lb), mp 141-146. A sample crystalliæed once ; ~rom isopropyl alcohol has mp 147-157.
Anal. Calcd for ClgHl7N0: C, 82.8~; H, 6.22; N, 5.09 Found: C, 82.31; H, 6.18; N, 5.18.
A mixture of 1.65 g of lb and 50 ml of lM
diborane 1n tetrahydrofuran is heat~d under reflux for 24 hours. To the cooled mlxture is added slowly 10 ml o~ concentrated hydrochloric acid; the tetrahydrofuran is removed under vacuum; concentrated hydrochlorlc acid (10 ml) ls added to the residue, and the mixture is heated 1~7~9~g under reflux for 7 hours. After concentration to a small volume the mixture is made basic and extracted with methy-lene chloride. Removal o~ the solvent from the dried extract gives 1.57 g of an oil, the main constituent of which ls 2-methyl-2,3,8,12b-tetrahydro-lH-3a,8-methanodibenzo[3,4:6,7]
cyclohepta/~,2-c7pyrrole (lc); nmr spectrum (220 mc~: T 2.6-3.1 (m, 8); 5.9 (d, 4 Hz, 1); 6.o (d, 10 Hz, 1); 6.3 (t, probably d/d, l); 6.6 (d/d, 8/10 Hz, 1); 7.0 (d, 10 Hz +
additional bands, 2); 7.2 (s, 3); 7.4 (d/d, 10/4 Hz, 1) and 7.5 (d, 10 Hz, 1). The product is converted to the hydrochloride salt which melts at 255-257 (dec) after crystallization from acetonitrile.
Anal. Calcd for C19H20ClN: C, 76,62; H, 6.77; N, 4.70 Found: C, 76.77; H, 6.~6; N, 4.70.
The 2-methyl-3,5-dihydro-5,9b-o-benzenobenzre7 lsoindol-l-(2H)-one starting material was prepared as follows: a mixture of 25 g of 9-anthroic acid and 75 ml Or thionyl chloride is heated under reflux for 1 hour. The excess thionyl chloride is removed under vacuum (~0 mm;
90 bath temperature); 50 ml of toluene is added and the mixture is concentrated again. This operation is repeated onee more to give 28.3 g of 9-~nthroyl chloride as a very ; moisture-sensitive, ycllo~ solid.
.
A solution of 20.8 ~ of 9-anthroyl chloride in 100 ml o~ tetrahydro~uran is added ~ 10-15 to a solution of 14.2 g of N-methylpropargylamine in 5~ ml Or tetra-hydro~uran. A~ter stirring ~t room temperature for 3 , .i hours, the solvent ls re~oved and the residue ls stirred ; 30 with methylene chloride and 5~ a~ueous sodium bicarbon~te ~ solution. The methylene chlorlde L1yer is dried ~nd cnn-,`"`',, ;'., , .i .
~779~9 centrated to give 23.3 g of crude N-methyl-N-propargyl-9-anthramide as an oil. H nmr spectrum: ~ 1.7-2.9 (m, 9); 5.4 (d, 2.5 Hz, 1.3); 6.4 (d, 2.5 Hz, 0.7);
6.7 (s, 0.9); 7.4 (s, 2.1); 7.7 (t, 2.5 Hz, 0.7) and 8.~ (t, 0.3). The spectrum shows the presence of two rotamers.
A mlxture of 23.2 g of crude N-methyl-N-propargyl-9-anthramide and 200 mi o~ p-xylene is heated under reflux for ?.25 hrs, The solvent is removed and t~e residue is crystallized from 300 ml of acetonitrile to g~ve 16.4 ~ of 2 methyl-3,5-dihydro-5,9b-o-benzeno-b~nz~e]iscindol-1-(2H)-one, mp, 250-255; nmr spectrum:
~ 2.3~3.3 (m, 9); 4.8 (d, J = 6 Hz, 1); 5.9 (d, J - 2 Hz, 2) and 6.9 (s, 3).
~nal. Ca~cd ~or elsHlsN~: C, 83.kg; H, 5.5~; N, 5.1~
Found: C, 83.84; N, 5.66; ~, 5.10 , , ',~
.`.
` : ~
77~'~9 Exampl~ 2 2-M[et 1-2 3,8,12b-tetr~hYdro-lH-3a,8-methanodiben2o-~,4:~ ~cyclohepta~,2-c~pyrrole b~ Acid-C~talgzed ~ea~rangement _ _ _ - HO CH--NC ~C-=CH
.' : 2a ,CH2 F"CH2 ~L~
: 2 . . .
, ., , 2b 2c . .
,:
' '-. . , , CH3 CH3 ....
` 2d lc , ..
s` ~, .~..................................................................... .
:;
,~. - 19 -~,:
':
.
'';
., .:
. . . ' .: ~
~077929 A mixture of 16.7 g of 9-anthraldehyde, 5 g of propRrgylamine and 100 ml of ethanol i~ heated ~nder re~lux for 1 hour. The ~olvent is removed and the r~idue i8 crygtal-llzed from 100 ml Or acetonitrlle to glve 16.1 g (82%) of N-pro~pargyl-9-anthracenemethylenlmine; (2a), mp, 143-144; nmr ~pectrum: t 0.2 (~, 2 Hz, 1); 1.7-3.0 (m, 9); 5.1 (t, 2 Hz~
2) and 7.3 (t, 2 Hz, 1).
Anal. Calcd for C18H13N: C, 88.86; H, 5.39; N, 5-76 Found: C, 88.83; ~, 5.56; N, 5~87.
A mlxture of 19.4 g of crude N-propargyl-9-anthracene-methylenlmlne and 200 ml o~ ~-xylene i8 he~ted under reflux for 3 hour~. On coollng, 14.6 g of 3,5-dihydro-~,9b-o-benzenobenz-~ej~soindole (2b~, mp, 212-214, pr~cipitates. Another 1.4 g of product 18 obtQlned by removlng the solvent rrom the mother liquor and crystallizing the resldue fro~ 50 ~1 of acetonitrile;
nmr 3pectrum: T 1.1 (m, 1), 2.5-3.5 (m, 9); 4.8 (d, J ~ 6 Hz, 1) and 5.4 (t, J ~ 2 Hz, 2).
. .
~nal. Calcd for C18H13N: C, 88.86; ~, 5.39; N~ 5-76 Found: C, 89.10; H, 5.58; N, 5.66.
A mlxture of 8.19 g of 3,5-dlhydro-5,9b-c-benzeno-benz~qJisoindol~, 25 ml of formlc ~cid and 25 ml o~ aqueous form~ldehyde solutlon i~ hoated under re~lux for 3 hours.
Concentrated hydrochlorlc ~cid (10 ml) i8 added, and the ~olatlle~ ~re re~oved. The resldue 1~ stirred with aqueous sodium hydroxide 801utlon ~nd methylene chlorlde. Removal of the sol~ent from the drled methylene chlorlde extracts ~nd crystallizQtlon of the re3idue ~rom acetonltrile glves, ln two crops~ 5.04 g (58%) of 2-methyl-1~2,3,5-tetr~hydro-., ;' .
ilO779Z9 5,9b-o-benzenobenz~e~soindole (2c), mp 196-197; n~r ~pectrum:
~ 2 4-3.1 (m, 8); 3.3 (d of t~ J c 6/2 Hz, 1); 4.8 (d, 6 Hz, l);
6.1 (8, 2); 6.6 (d, 2 Hz~ 2) and 7.3 (8, 3).
Ana~L- Calcd for ClgH17N: C, 87.99; H, 6.61, N, 5.40 Found: C, 88.o5; H, 5.91; N, 5,32.
A se~led Carlus tube containing 20. 0 g of 2-methyl-1,2,3,5-t~trahydro-5,9b-o-benzenobenz~e~isolndole and 80 ml of trifluoroacetic acid 18 heated at 150 rOr 8 hours. me acid i8 distilled the re~ldue is dlssolved in met~ylene chlorlde and the ~olution i8 add~d 810wly to a 3tlrred, cooled, excess ; 15% aqueous sodlum hy~roxide ~olution. The layers are sepa-rated and the agueous phase i8 extracted once with methylene chlorlde. Removal of the solvent from the combined drled ~xtract~ give~ 19.6 g of 2-methyl-2,3-dihydro-8H-3a,8-methano-dibcnzo~3,4:6,7~cyclohepta~,2-c,7pyrrole (2d); nmr ~pectrum:
2.5-3.3 (m, 8); 3.9 ~, 1); 6.1 (d 10 Hz, 1); 6.1 (d, 4 Hz, 8pllt further; 1); 6.9 (d, 10 Hz, 1); 7.3 (~ 3) and 7.4-7.9 (AB quartet, J - 9 Hz, the lower-field component i3 8plit again by 4 Hz; the high-field component by ca. 1 Hz; 2). A
',A` 20 8ample crystallized twlce rrom l~opropyl alcohol melted at 119.5-120.
Anal. Calcd rOr ClgH17N C, 87.99, H, 6.61; N, 5.40 Found: C, 87.66; H, 6.74; N, 5.45.
. . .
!, i~
The above re~rrangement may al80 be carrled out with p-toluenesulfonic acid ln acetic acid ~t 165.
A mixture o~ 13.6 g o~ 2-methyl-2,3-dlhydro-8H-3a, 8-methanodlbenzo~,4:6.7~cyclohepta~ ,2-c~pyrrole, 100 ml of acetlc acid and 2 g of 10% palladium-on-charcoal cataly8t i8 ; ~, .~
; .
10'779~9 ~haken under 40 psi hydrogen pressure at room temperature until the pressure remains const~nt. The filter2d mixture is concentrated, the residue is ~.ade basic and e~tracted several t~mes with methylene chloride. Re~oval of the sol~en~ from the dr~ed extracts gi~es 13.7 g of 2-r~ethyl-2,~,8,12b-tetrahydro-lH-3a~8-methanodibenz~3~4:6~73 cyclonept3[1,2-c]pyrrol~
identical by nmr SpectrOSCopy with the product obtained in ~x~ple 1.
The hydrogenation of 2d to give lc may also be carr~ed out with a platinu~ cat~lyst ln tetrahydrofuran.
WhPn tetrahydrofuranis used as a solvent with a palladiu~
catalyst,so~e o~ the steroiso~.er of 1~J is also formed.
: The reduction of ~ to give lc may elso be effected with sodium cyanoborohydride in acetic acid-methanol at room temperature.
Examole ~
2,3,8,12b-Tetrahydro-lH-3a,8-~ethanodiberzo~3,4:6,73-cyclohe~tar 1. 2 -c ? P~lrrol e _ _ .. :
.. . .
~ , ~C~
. . ~
; ~N~
~r . H
The procedure of ~xample 1 is employed with `` 3,5-dihydro-5,9b-o-benzenobenz~e]isoindol-1-(2H)-one replacing its N-met`nyl homologue. Th~re is obtained 2,3,8,12b-tetrahydro-lH-3~ 8-methanodibenzo~3,4:6,7~cyclo-hepta~l,2-c]pyrrole as an oil that slowly for~s a solid `` ~ 7929 carbonate on exposur~ to air. Nmr spectrum: ~ 2.6-3.1 (m~ 8); 6-o-6~4 (m, 3); 6.5-7.1 (m, 3) and 7.5-8.o (m, 3).
The hydrochloride m21ts with decomposltion at 311-~12.
Anal. Calcd for C18~1gClN: -C, 76-18;
H, 6.~9; N~ 4.94.
Found: C, 76.60; H, 6.52;
~ - N, 4:87., The starting material is prepared as described for the starting material of Exam~le 1 but replacing N-19 methylpropargylamine with proparylamine.
.~ .
2,3,8,12b-Tetrahydro-lH-3a,8-methanodibenzo-[3,4:6,7]cyclohept2[1,2-c]pyrrole is prefera~ly prepared by : hydrogenolysis ol 2-benzyl-2,3,8,12b-~etr2hydro-lH-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole ~Exam~les 4 ar.d 5) with palladium on charcoal in acetic acid at room temperature and about40 psi hydrogen pr~ssure.
' Example 4 ~-Benzyl-2,3,8,12b-tetrahydro-lH-3a,8-methanodi-,;`: ,~ benzo~,4:6,71cyclohepta~1,2-clpyrrole , .
,j ,~ . , .
~ ,`. 20 ,~ CH 2 r~ / NCHzC6H5 ~ ,~
,, ~o~
` ",.` CH2C~H5 . . ~,. .
.~ , , .
;. . .
~.............. . .
.
~, ((~t~
2-~enzyl-3,5-di~ydro-5,9b-o-benzenobenz[e]-isoindol-l t2H)-one, prepared as described below, ls converted in three steps to 2-benzyl-2,3,8,12b-tetrahydro " lH-3a,8-methanodiben~o[3,4:6,7]cyclGhepta~1,2-c]pyrrole us~ng the procedure of EY~ample 1. The free base is obtained as an oil; lt has the following nmr spectrum:
2.5-3.~ (m, 13) and 6.0-8.0 (m, 10); at 220 MXz, the 6.o-8.o reg~on resolves (from lower t? hi~her field) into a four-proton mult plet, a one-proton tr~plet, a one-proton multiplet, a two-proto:l multiplet and a .
; two-proton AB quartet (J = 10 Hz) with one component split again (J = 4 Hz).
',''` '' ~ .
The startin~ m~terial is prepared as follows: -To a mlxture of 30 ml o~ benzylamine and 60 ml of tetrahydrofuran is added drop~ise with coolin~, a solution of 9.86 g of 9-anthroyl chloride in ~0 ml of tetrahy~rofuran. After stirring at room temperature overnight, the mixture is concentrated, and the residue is dissol~ed in methylene chloride. The solution is washed wlth dilute acid and dilute base, dried, and ,, , concentrated to give 12.45 g of crude N-benzyl-9-anthramide.
The product is added to a slurry of 2.50 g of sodium hydride (50~ ~n ~l, previously washed with hexane) in 80 ml of tetrahydrofuran and the m~xture is heated to '', , -. . . ~ ' . :
:, ' - .. ,. '' '' 1~779~9 reflux for 30 min and cooled. Propargyl bromide (6.o g) in 10 ml o~ tetrahydrofuran is added, and the reaction mixture is he~ted under reflux for 2 hours. Water and ~ethylene chloride are added; the layers are separated, and the dried organic layer is concentrated. The residue (crude N-benzyl-~-propargyl-9~Qnthramide) is heated under reflux with 100 ml of ~-xylene for 2.5 hr.
On cooling, 9.81 g of 2-~enzyl-~,5-dihydro-5,9b-o-benzeno-benz ~e~isoindol-1-(2H)-one prec~pitates.
EY~a~ol~ 5 .
2-B~nzyl-2,~,8,12b-tetrahydro-lH-~a,8-~e~hanodibenzo~3,4:6,7]cyclohepta~1,2-c] pyrrole ~,~' b!~ Acid-CatalY ZQd Rearran~ment .. .
.. . .
CHO CH-NCH2CaHs CH2~rHCH2CsHs 5a 5b ~~ / CH2 ~
~/ NCHzC~Hs `i--~ )(~2J `' .. ~H2N-CH2CdHs ;, ~d .:
'`
~77929 CH2CCH5 . CH2C8H5 5e A mixture of 100 g of 9-an~Lralde~ de, 53 g of benzyl-amine and 300 ml of ethanol is ~ea~ed under re~lux un~er nitrogen for ~ 2.5 hours. Th~ solution of IJ-ber.zyl-9-anthraeenemethylenimine - (5 ) so obtained is cooled to 60, and 18.78 g of sodium borohydride is added slowly, ~eeping the temper3~ure at 60-65. After stirring at room te~erature overnignt the excess hydride is des~royed by the slo~ addition ol conc.
hydrochloric acid. Th s mixture is then made basic and is extracted several times with ~ethylenQ chloride. Rerovzl of the solvent from the dried extracts gives 139.9 g of N-benzyl-9-anthracenemethylamine ( ~ ). Nmr s~ectrum: T 1.8-3.0 (m, -14);
5.5 (s, 2); 6.2 (s, 2) and 8.5 (s, 1).
; The product isdissolved in 300 ml of methylene chloride;
200 ml o~ lO~o aqueous potassiu~ carbonate solution and 100 ml of propar~yl bromide is added, and the mixture is stirred vigorously undernitrogen at roon temperature for 3 hours. The layers are separated, the aqueous layer is extracted once with methylene ~hloride, the combined extr2cts are washed with conc. sodium chloride solution, and dried. Removal o~ the solvent gives 153.5 g Or N-benzyl-N-propargyl-9-anthracenQmethylamine (5c). Nmr spec~rum:
~ 1-5-3-0 (m ,14); 5-5 (s, 2); 6-3 (s, 2); 6-9 ( d,J=2.5 Hz, 2) and 7.7 (t, J=2.5 Hz, 1~.
. . ~
~0~79;~9 Th~ product is h~ated under reflux with 1 liter o~ toluene for 2.25 hours. Removal of the sol~ent gives crude 2-ben2yl-1,2,3,5-tetrahydro-5,9b,o-benz2nob~nz~e]isoindole (5d3. A sa~ple crystallize fro~ isopropyl alco~ol was identical by nmr s~ectroscopy with the product obta~ned by benzoylat on o~ 1,2,3~5-tetrahydro-5,9b-o-benzeno-benzEe]isoindole~followed by reduct~on (see below).
A ~.ixture of ~8.9 g 2-benzyl-1,2,3,5-tetr2hydro-5,9b-o-benzenobenz~e]isoindole (~d) and 150 ml of trifluoroacetic acid, contained in three sealed C~rius tubes, is heated at 150 for 12 hours. The excess ~cid is distilled under vacu~m, the residue is dissolved ~n methylene chloride, and the solution is added slowly ~o cold, stirred, excess 15~ aqueous sodium hydroxide ~olution. The layers are sepqra~ed, the aqueous phzse is extracted once ~rith ~ethylene chloride, and the comoined extracts ; are dried. Removal of the solvent and crystalliza~ion of the residue from 150 ~1 OL acetonitrile gives 38.3 g of 2-benzyl-2,3-dihydro-8H-3a,8-methanodib2~.zo~3,4:6,7~cyclohept2[1,2-c]pyrrole (5e). ~Jmr spectru~: ~ 2.~-3.1 (m, 13); 3.7 (s, 1); 5.7-7.8 (m, 7).
An analytical sam?le, ?reDared by crystalli~ation ,ro~ acetonitrile, had m.p. 135-1~5.
Anal. Calcd for C25H2~N: C, 89.51; H, 6.31; N, 4.18 Found: C, 89.56; ~, 6.45; ~J 4.~6.
A mixture o, 37.7 g of finely po~dered 2-benzyl-2,3-dihydro 8~-3a, o-methanadiben~ot3~4:6~7~cyclohe~t~ 2-c~pyrrole ( ~e), 300 ml of meth2nol, and 40 ml o~ acetic acid is cooled with ice, and 1~.8 g of sodi~m cya~bborohydride is added slo~ly wi~h stirring. The mixtuLre is s~irred at room tem~erature for 3 hours, cooled, and trea~ed with 5~ ~ of conc. hydrochloric acid.
After stirri~g at roo~ temperature for 0.5 hour the mixture 3 is made basic and extracted several tlmes with ~ethylene chloride.
:.
~' '' .
1077g~9 Removal of the solven~ from ~he dried extracts gives 37.5 g of 2-benzyl-2,3,8,1~b-tetr~hydro-1~-32,8-me~hanodiDenzo[3,4:6,7]-cycloheptaLl,2-cJp~rro'e , identlcal by nmr spectroscopy w th the product obtalned in Ex.ample 4. The hydrochloride melts with decompo~itlon at 195-200 after cry~tallizatlon rrom ethanol.
Anal. Calcd. for C H 4Cl~J: C, 80.30; H, 6.47; N, 3.75.
Found: C, 79.92; H, 6.80; r~ 4~13 The in~ermediate, 2-benzyl-1,2,3,5-tetrahydro-5,9b-o-ben2enobenz[e]isoindole (5d) ~2y also be pr~pared as follows:
To a slurry of 10.19 g of 3,5-dihydro-5,9b-o-benzenobenz-te]iSoindole (Exa~ple 2) in 50 ml of methanol and 10 ml of acetic acid is added slowly, with cooling, 4.70 g of sodium ~, cyanoborohydride. The ~.ixture is stirred at room te~perature overnight, the excess hydride is destroyed with concentra~ed hydro-chloric acid (ice bath), and the mixture is made basic and extracted w~th methylene chloride. Re~oval of the solvent fro~ the dried extr~ct gives 10.~9 g of 1,2,3,5-tetrahydro-5~b-o-benzenobenz[eJiso-indole as an oil; nmr spectrum: T 2.6-3.7 (m, 9); ~.9 (d, 6 Hz, l); 6.o (s, 23; 6.5 (d, 2 Hz, 2) and 7.5 (s, 1).
To a m~xture of 4.60 g of 1,2,~,5-tetrahydro-~9b-o-benzenobenz~e~isoindole, 5 g of magneslum oxide, and 20 ml of tetrahydro~uran is added ~.19 g of benzoyl chloride. Af~er stirring . . .
at room temperature overnight the mix~ur2 is filtered, the filtrate i8 concentrated, and the residue is dissolved in me~hylene chloride.
The solution is washed in tuL~n, with lO~ potassium carbonatesolutlon and water, 2nd the solvent is removed. The residue,crude 2-benzoyl-1,2,3,5-tetrah~dro-5,9b-o-benzenobenz[e]isoindole,is heated under reflux with 2.83 g of lithium aluminu~ hydride in tetrahydrofuran for 4 hours. To th~ cooled mlxture is added slowly 2.8 ml of water, follo-~ed by 2.8 ml of 15~o aqueous "
s ' . - ,~
107~9 ~9 sodium hydro~ide solution, 2nd finally ~.4 ~1 of water. The miY.~ure is filtered, i~nd the filtrate is concentrated to giv~
5.45 g of crv.~e 2-benz~ 2~5-te~rahydro-5~9b-o-benzenober~z[e]
isoindole (5~). Crystallization of 1.06 g of this ~terial from isopropyl alcohol gives o.60 ~ o~ Fure 5d, m.p. 125-125~, M~r spectr~m: T 2.4-3.6 (m, 1'~); 5.0 (d, 6 Hz, 1); 6.2 (s, 2);
6.3 (s, 2) and 6.7 (d, 2 HZJ 2).
Anal- C21cd for C25H21N: C, 83-51; H, 6.31; ~J, 4.18.
Found: C, 89.77; H, 6.26; N, ~.26.
Example 6 2-CyclopropYlmethYl-2,3,8,12b-tetrahydro-lH-3a,8-methanodib~nzo~3,4:6,7~cycloher)ta~1,2-clpyrrole .
. N N ~CH2 . H C0-CH I
~ CH2 p / CH2 . ' To a slurry of 1.3~ g 0~2,3,8,12b-tetrah~dro-lH-,' 3A,8-methanodibenzo/~,4:6,77cyclohepta/~,2-c7pyrrole ' (Example 3) and ~ g of magnes~um oxide is added 0.93 g of cyclopropanecarbonyl chloride,and the mixture is st~rred :
iO7~9~9 .
at room temperature overnight. The filtered mixture is concentrated; the residue i~ dissolved in methylene chloride~ and the solution is washed with base~ dried, ~nd concentrated. The residue is heated under reflux ~rith 0.57 g of lithium ai~min~ hydride in tetrahydro-~uran overnight. To the cooled mlxture is added, in turn, o.6 ml of ~ater, o.6 ml o~ 15~ aqueous sodium hydroxide solution, and 1.8 ml of water; the mixture is filtered, and the filtrate is concentrated to give 1.~5 g o~ 2-cyclc~rop~Jlmethyl 2,3,~,12b-tetrahy~ro~ a,8-methanodibenzo~3,~:6,7]cyclohepta[1,2-c]pyrrole as an oil; nmr spectr~ 2.7-3.2 (~, 8); 6.0-8.o (m, 8) and 8.8-10.0 (m, 5). It is con~erted to the hydrochloride ~hich is crystallized from isopropyl alcohol. The melting point o~ the h~drochloride is erratic and depends upon the rate of heating. E2tended drying Or the hydro-chloride at 120-130 for 8 hours at 0.1 mlcron glves a ~olvent-~ree product, m. p. 251-252, wlth decompos1 tion.
Anal. Calc'd. ~or C22H24ClN: C, 78.20; H, 7-16; N, 4-14 . 20 Found: C, 7~.01; H, 6.91; N, 4.50.
Exa!nple 7 2-Cyclopentylmethyl-2,3,8,~2b-tetrahydro-lH-3a,8-methano~
d~benzo[~,4:6,7]cyclohe~ta[1,2-c~pyrrole by Ac~lation of ., 2,3,8,12b-Tetrahydro-lH-,~a,8-methanodibenZo~3,4:6,7]cyclo-e~tarl 2-clD~rrole Followed by Reduction '~' ' , . ..
., ' ~ ~ . .
CH2 ~
"' Following the procedure of Example 6, but using cyclopentanecarbonyl chloride in place of cycloprop~necarbonyl chloride, there is obtained 2-cyclopentylme~hyl-2,3,8,12b-tetrah~-dro-lX 3a,8-~ethanodibenzo[3,4:6,7]cyclohepta[1,2-c~-pyrrole as on oil th~t s10~,11y cr~stallizes. Nmr spectr~m:
T 2~5-~.0 (m, 8) ænd 6~o-g.o (m, 19); at 220 MHz the ~ 6.o-g.o Prea rPsolves, from lo-.~ to high field, into a doublet ~J = 4 Hz, 1) a doublet (J = 10 ~z, 1); a doublet of doublets(J ~ 7 and 8 Hz; l);
~ doublet of doublets (J=7 and 11 Hz; l); a four-pro~on multi~let;
10 a doublet of doublets (J = 4 and 10 Hz, l); a doublet (J = 10 Hz; 1) and mul~iplets (1, 2, 4, and 2 protons). The hydrochloride m~'ts wi~h decomoo~ition at 250-253 ~fter cryst~llizati~n from :.i is3p~0pyl 21coh31 and dryi~ at 110-115~ under 0.2 ~icr~n pressure for 9 hours.
Anal. Calcd. for C24H28ClN: C, 78.77; H, 7-71; ~, 3-83-Found: C, 78.52; H, 7.83; N, 3.72.
The N-Oxide of 2-cy^lopentylmethyl-~,3,8,12b-tetr2hydrQ-lH-3z,8-m~thanodibenzo~3,l~:6,7]cyclohep~ 2-c3pyrrole -is prepared as follows: A solution ~f 3.92 g of the free base in 20 20mlofchloro~orm is added slo~rly to a cool~d mixture ol 10 ~1 of 40~ per~cetic zcid and 2 g of anhydrous sodium ace~a~e. The miXture is stirred at room temp rature ~or 90 minutes,.cooled, and made basic by the æddition of 15~ aqueous sodiu~ `n~d~oxide ~; solution. The 12y~rs are separated and the aqueous ph~se is x~racted once with chloroform. The combined organic phases are dri i ed and concen~ratea to give 3.80 g`D~ crude product 3till retain~ng some solven~; the nmr spec~rum indicates t~e presence ol two iso~ers. Addition of hot etnyl acetate causes one isomor to crystzllize; it is purified b~ recrystallization from z~etonitrile 30N~r sp~c~r~m (220 MHz) from low to high field: Aromatic r~gion 2.3-3.3 (d, J = 7.5 Hzj 1 and m, 7); Alipha~ic region, 5.5-9.0 (m, 2; d, J = 4.5 Hz + m, 2; d, J = 12 Xz, l; m, 3;
~, l; d/d, J = 4.5/10 Hz, l; d, J = 10 Hz + m, 3; m, 4 and m, 2).
''.
, - 31 -:' , .
~)77gZ~
2-Cyclopentylmethyl-2,3,8,12b-tetrahydro-trans-lH-3a,8-methanodibenzo[3,4;6,7]cyclohepta[1,2-c]pyrrole is resolved into its optical antipodes by fractional crystallization of the (+) and (-) dibenzoyl (-) tartaric acid salts. The hydrochloride of the (~) isomer has [~]D = +125 (c-2.21 g/100 ml of chloroform); the hydrochloride of the (-) isomer has [a]D =-125 (c=2.00 g/100 ml of chloroform).
Exa~le 8 2-Cyclopentylneth.yl-2,3,8,12b-te~rah;dro-lH-3Q,8-~.ethano-~iOenzo[3,~:6,7]c;clo~.ept2[1,2-c~pyrrole by Acid-Catalyzed ~earrange~ent of 2-Cyclopentyl~.ot~yl-1,2,3,5-tetranydro-~b, o-benz~nobenzrelisoindole .
CRO CHaN-CH2--O .
. 8a CR2NH-CH2 ~ :- CH2l-CH
8~ 8c ~ CHz . ~ ) CH
CR
8d 8e ' ,'- ) ~ ' :,: . ~./
CH
8r 107'7g~9 .
.
~' Following the pro~edure of Example 5, but using cyclopentylmethyla~ine in place of benzylamine there is obtain~d, in turn:
N-cyclopentylmethyl-9-am hracenemethylenei~ine (8a);
nmr spectr~m: ~ 0.9 ~t, 1); 1.5-2.8 (m~ 9); 6.3 (d~ split further, 2) and 7.3-9 0 (~., 9) N-Cyclopentylmethyl-9-anthracenemethylamine (ôb);
nmr spectrum: T 1.8-~.1 (m, 9); 5.6 (s, 2)j 7.5 (d, 7 ~z, 2) ~ and 7.8-9-3 (m, 10)-,,~ 10 N-Cyclopentylr~Qthyl-N-proparg~fl-9-anthracenemethylamine (8c); nmr spectrum: ~ 2.3-3.0 (m, 9); 5.5 (s, ~); 6.8 (d, 2.5 Hz, 2); 7-5 (m, 2); 7-7 (t, 2.5 Hz, 1) and 7.5-9.2 (m, 9).
2 Cyclspentylmethyl-1,2,3,5-tetraAydro-5,9b-o-benze~o-benz~e~isoindole (8d); m.p. 110-111; nmr s~ectrum:~ 2.6-3.2 : (m, 8); ~.5 (d/t, 6/2 Hz, 1~; 4-.9 (d, 6 Hz, l); 6.2 (s; 2);
6.7 (d, 2 Hz, 2) and 7.3-9.0 (~, 11).
.. AnaI. Calcd for C2~H25N- C, 88.o3; H~ 7-70; N~ 4.28.
Found: C, 87.68; H, 7.75; N, 4.43~
2-Cyclopentylmethyl-2,3-dihydro-8H-3a,8-methanodibenzo-t3,~:6,7]cyclohepta[1,2-c~pyrrole (8ë), m.p. 103-104;
;~. 20 nmr spectru~: ~ 2.6-3.3 (m, 8); 3.9 (s, 1); 6.o-6.3 (d, 4 Hz, 1 and : d, 10 Hz, 1); 6.8 (~, 10 Hz, 1) and 7-9 (m, 13).
Anal. Calcd. for C2~H25N: C, 88.03; H, 7.70;N, 4.28.
. Found: C, 87.83; H, 8.o6; N, 4.34.
2-Cyclopentylmethyl-2, ~, ô, 12b -tetrahydro-lH-3a,8-methano-dibenzo~3,4:6,7~cyclohepta[1,2-c]pyrrole (8~), identical by 220 ~z nmr spectroscopy with the product of Example 7. The reduction ~ of 8e to 8~ may be carried out ~rith hydrogen in acetic acid using .~ pall&dium on charcoal as the catalyst as describ~d in . ., .......... Example 2.
,, ; -, ., `~' ' "'' .
,.- -EXB~P1e 9 2-Cyclopentyl~ethyl-2,~,8,12b-tetr?hydro-lH-3a,8-~ethano-albsnzo~3,4^5,7]cyclohop'2tl,2-c]plJrrole Via Acid-Cat21yzed Rear~an~e~er.t o~ 2-C~clo~en~,anecaroonlJl-1,2,3,5-tetrahydro-~9b-o-banzenoben7re ~so~.ndole ~3~
. C~2 CH2 ,. . . . .
:: 92 ,, . -:
',~ 10 ~ H
9b 8e , ' , , v 1~2~, .,.~ , .
:~ 8f :, . ' .~. .
'" , ~ 34 ~
10779~
A mixture of 12.07 g of 1,2,3,5-tetrahydro-5,9b-o-benzenobenz~ 2~ isoindole (Exam~le 5), 70 ml of chloroform, ~nd 55 ml of triethylamino is trealed with 10.5 g of cyclopen-~anec~rbonyl chloride, keeping the temperature below 20.
Afte.r stirring at room temperature for 2 hours, 10~ aqu~ous odium hydroxide solution is added with cooling, and the ~ixture is stirred at roo~ te~perature for 30 minutes. The ayers are separated, and the aqueous phase is extracted once ~ ith methylene chloride. Removal of the solvent from the dried lG extracts and crystallization of the residue from 50 ml of aceto-: ~itrile gives 13.14 g o~ 2-cyclopentanecarbonyl-1,2,3,5-tetra-ydro-5,9b~Q-benzenobenzle]isoindole ( ~ ). ~Tmr spectru~:
.5-~.5 (m, ~); 4.8 (d, 6 Hz, 1); 5.1 (s, 2); 5.8 (s, 2 Hz, 2) ~nd 6.7-8.7 (m, 9). An ~nalytical sample (acetonitrile) ~ ad m.p. 189-190.
. .
Anal. Calcd. for C2~23~0-: C, 84.42; H, 6.79; ~J, 4.10 Found: C, 84.o~; H, 6.79; N, 4.29.
A mixture of 11.67 g of the above product 2nd 60 ml 0~ tri~luoroacetic acid is heated under reflux for 2 hours. The e~cess acid is removed under vacuum, the residue is dissolved in ~e~hylene chloride and the solution is poured into cold, stirred, ~cess aqueous sodium hydroxide solution. The mixture is ~Xtracted several times with methylene chloride, the extracts ~e dr~ed, the solvent is re~o~ed and the residue is crystallized ~r~m ~0 ml of toluene to give 10.89 g of 2-cyclopentanecarbonyl-,3-dihydro-8H-3a,8-methanodibenzo~3,4:6,7]cyClohejpta~1,2~C]~yrrole (9b), I~r spectr~m: . 2.5-3.2 (m, 9); 5.0-6.1 (m, ~ and 6.6-8.
(h, 11). An analytical samD'e (~cetonitrile ) had m.p.l8~-186 .
"
.
:'', ' .
:. ' ....
., ., .
iO779Z9 Anal. Calcd. for C2~H2~N0: C, 84.42; H, 6.79; ~, 4.10.
Found: C, 8~.60; H, 6.93; M, 4.55.
To a cooled slurry of 0.40 g of lithium aluminum hydricle in 30 ~1 of ether is added 1.55 g of 9b and the mixture i5 stirred at roG~ temp2rature for 6 hours. The excess hydride is decomposed by the addition of 0.~ ml of water, follo.~ed by 0.4 ml of 15~ aqueous sodiu~ hydroxide solution and 1.2 ml of water. The ~ixture is f~ltered and the filtra~e is concentrated.
Crystalliz2tion of the residue from isopropyl alcohol gives o.89 g of 2-cyclooentylmethyl-2,~-dinydro-8X-3a,8-methanodibenzo-[3,4:6,7]cyclohepta~1,2-c]pyrrole (8e), identical by infrared and nmr spectroscopy ~lith the product ob~ained in Example 8.
R~du~tion of & as described in Exa~le 8 ~g~ves 2-cyclopenty methyl-2,3,8,12b-tetrahydro-lH-~a,8-mzthanodibenzo~3,4:6,7~cyclo-heptatl,2-c]pyrrole.
When 2-cyclopent2necarbonyl-2,3-dihydro-8H-3~,8-~.ethano-d$benzo~3S4:6,7]cyclohepta[1,2-c]pyrrole (9b) is hydro~enated with palladium-on-carbon catalyst intetr2hydrofur?n, 2-cyclopentane carbonyl-2~3~8~l2b-te~rahydro-lH-~8-methanodibenzo~3~:6~7J
~epta[1,2-c]pyrrole having the cis sterochemistry at the 3a-12b-ring fusion is formed.
Exam~le 10 2-Allyl-2,3,8,12b-tetrahydro-lH-3a,8-~.ethanodibenzo-L~-4~ .?lc~clohepta~l~2-cl~vrrole _ _ . , ' .
~ 30 . ~CHzCH=CH2 ., ,. - 36 -., 1077g2~ , A mixture of 2.19 g of 2,3,8,12b-tetrahydro-lH-3a,8-methanodibenzo~,4:6,7]cyclo~epta~1,2-c~pyrrole (Example ~, 20 ml of ch:Loroform, 20 ml ~f 10~ ~queous potassium carbonate solution and 4 ml of allyl bromide is st.irred v~ gorously under nitrogen at room temperature for 5 hours. A precipitate formed 1s brought into solution by addition of methanol; the layers are separated and the aqueous phase is extracted once with a mixture of methylene chloride and methanol. The solvent is removed from the dried extracts and the residue is heated with 15 ml o~ methanol and 6 g of trimethylamine in a sealed Carius tub~ at 110 for 8 hours; this trea~ment converts any quaternarys~
to the desi~ed tertiary amine. The solvent is removed and the resldue is dissolved in methylene chloride. The solution is washed with aqueous sodium hydroxide solution and dried. Rer..o~æl of the solvent gives 2~allyl-2,3,8,12b-te'ranydro-lH-3a,8-methano-dibenzo[3,4:6,7]cycloh~pta[1,2-c]~yrrole. The hydrochloride, after crystallization from isopropyl alcohol weighed,1.60 g;
m-p- 20a-209 (dec.) Anal. Calcd. for CzlH22ClN: C, 77.88;H,6.85; N, ~.33 Found: C,78.14;X, 7.02; N, 4.47-The free bæse h2s the following nmr s~eetru~: ~
2.7-3.2 (m, 8); 3.7-~.4 (m, 1); 4.6-5.1 (mJ 2) and ~.1-7.9 (m, 10).
Example 11 Ethyl 2,3,8,12b-Tetrahydro-lH-3a,8-methanodibanzo-6 ~ll cyclohePt2r 1 . 2-c~ rrol~-2-butvrate . .
,. . .
~\~
N
CH2CH2CH2C02C2Hg ',:
.
1(~779Z9 A mixture of 2.35 g of 2,3,8,12b-tetrahydro-lH-3a,8-~ethanodîbenzo[3,4:6,7~cycloheota~1,2-c]pyrrole, 25 ml o~
dimethyiformamide, 4 ml of trLe~hylamine and 2.55 g of ethyl
polycycloalkyl o~ 7 to 9 carbons, polycyclo alkenyl o~ 7 to 9 carbon atoms; or phenyl;
Most pre~erred R groups are the cycloalkylmethyl groups o~ 5-1~ carbon atoms and alkyl of 4-8 carbon atoms.
The compounds where R is other than H have been found to be tranqu~lizers for warm-blooded animals and this invention further includes compositions of the active compounds with pharmaceutically acceptable inert carriers and to the use of an effective dose of these compounds to tranquilize warm-blooded animals either alone or, with the amines, ~n the ; form of their pharmaceutically acceptable salts.
The compound wherein R is H is a valuable inter-mediate for making other members o~ the class.
The term "lower alkyl" means an alkyl group Or 1-4 carbon atoms, including branched alkyl groups.
The term "cycloalkyl group" ls employed ln the :
llmlted sense Or a radical derlved rrom a ring of -CH2- groups by removal o~ a hydrogen atom.
".. ~ .
- The term "quaternary carbon atom" rerers to a ; carbon atom Joined dlrectly to rour other carbon atoms.
. .
; The term "cycloalkenyl" rerer~ to a cyclic hydro-carbon group contalnlng one or more double bonds rormally derlved ~rom a cycloalkyl group by removal Or hydrogen.
, .
DE~ILED DESCRIPTION OF THE INVENTION
.~. The present invention ls dlrected to certain _ 6 -.. ~, .
:
. 1~779~g ;
methanodibenzocycloheptapyrroles which can be made by a rearrangement reaction of bridge~ ethenoanthracenes.
me latter compounds are made by an internal Diels-Alde~r reaction o~ propargyl-substituted 9-anthracenemethylen-imines, 9-anthracenemethylamines and 9-anthramides as disclosed in the commonly assigned, aforementioned U.S. Patent 4 077 977.
In one procedure a substit~ted anthracene R1 ~ ~2 where Rl and R2 can be hydrogen, lower alkyl, lower alkoxy, - fluorine~ chlorine, bromine, trifluoromethyl~
2,2,2-trifluoroethyl or other partially fluori-nated lower alkyl groups~ trifluoromethylsulfonyl, methylsulfonyl, carboxyl, alkoxycarbonyl, sulfamyl, N-methylsulfamyl, N,N-dimethylsulfamyl, methylsul-finyl, or alkylcarbonyl groups, is reacted with ` oxalyl chloride in the presence of a catalyst to obtain the corresponding 9Danthroyl chloride. The ~ubstituted 9-anthroyl chloride iæ reacted with propargylamine per se or substituted on the nitro-~en atom wlth the aforesaid R groups. These com-pounds undergo an internal Diel~-Alder reaction to give ~ubstituted, 9,12-bridged ethenoanthracenes 1, -.
, according to the equationO
'.' ~9 C~I2 ~CC~-C~2-CsC~ CO ~2 1R
R II
. ~
:
1~77~9 This process can be carried out by heating the alkynylanthramlde, either neat or ln a suitable inert solvent, preferably an aromatic hydrocarbon at ~ temperature of 80 to 250C for a time sufficient to effect cyclization, generally from l to 48 hours depending on the conditions.
Reaction of II with bromine leads to a ring rearrangement reaction to produce products with the skeletal ~tructure of I substituted with bromine at the 12b and 13 positions, and contain~ng a l~arbonyl group. Bromination may be carried out in any inert solvent, preferably a chlorinated aliphatic hydrocarbon with methylene chloride and chloroform being especially preferred. The reaction temperature should be from about -20C to 100C, preferably 20-~5C.
. The bromine atoms are readily removed from the intermediate by reductive dehalogenation with a trialkyltin hydride, either neat, or dissolved in an aromatic hydrocarbon ~olvent. It is preferred to use tributyltir. hydride in benzene or toluene. The reaction is carried out at a tempera-ture in t~e range of 50-180C to give compounds having the skeletal structure of I which contain a l-carbonyl group.
;~ Alternatively the bromine atoms can be removed by reaction with zinc and acetic acld at 25 to 120 or ~lth zlnc and aqueou~ dlmethylformamlde.
The amides containing the l-carbonyl ~roup arc readily converted to the corresponding amines of structure I
by reduction o~ the carbonyl group, pre~erably ~th diborane dissolved in an ether solvent such as tetrahydrofuran, at a temperature of 0-100C.
Another procedure ls to start with an ethenoanthra-cene Or the ~ormula ' ~077g'~g ~ CH~
Rl = ~ R2 ¦
III
which can be prepared ~rom the corre~pondlng 9-anthraldehyde b~ reaction with propargylamine, ~ollaw~d by lnternal Diels-Alder reaction, reductlon o~ the carbon-nltrogen double bond, and alkylation o~ III(R2H) to obtain th~ derived N~ ubstituted compGund. Alternatively, III(R=H) may be acylated by conre~tional procedures, ~nd the acyl derl~a-tire~ may then be reduced with lithiu~ alu~inum hgdride to obtain the corre~ponding N-substituted compound~.
In a pre~erred process ~or the preparation o~
III shown in the ~ollowing equatlon~, tho 9-anthraldehyde ~ :
compound i~ react~d with a suitable amine at 25 to 150 ln an alcohol ~ol~ent to rorm an imlne. Th~ imine i~ then reduced wlth a metal hydride reducing agent such a8 ~od~um borohydride or Rodium cya~oborohgdrid~ ln an alc~hol such . ~
.~. a~ methanol, ethanol, or i~opropanol, ~hich can be th~ same ~olvent that iB employed to form the imine, at a temperature betweon 0C and 100C. me resultant secondary amine iB
`-~ 20 then condensed with a propargyl haltde~ pre~erably propargyl ; bro~ide, ln the pre~ence of an inorganic base such a~ an . .
., aqueous ~olution of an alkali metal carbonate or an organic .
: ba~e which does not react sub~tantially with propargyl . bromide, e.g., certain hindered umines including diisopropyl-.. ethyla~ine, at a te~perature of O to 100C, preferably ~ amOlent temperature~.
''' - 9 _ , .~
,'' . ' ' ~077g;~
me alkyngl-substituted anthraceneR are then cyclized to co~pound~ of Fo~ula ITI as described herein-above for the cyclizat~on o~ the alkynylanthra~ides.
~ ~ ~1 ~ ~ ~2 R C~O ~=N-R
: ~ ~ ~ Br-CHz C-=CH ~ ~
~ Rl ~ ~ 2 < Rl ~ R2 :. CH27-R H2~ R
"'' CH2C~CH
. .
.~ Ring rearrangement occur~ in the presence of strong acids ~uch as p-toluene~ulfonic acld and trifluoro~cetic acid . at about 70 to 200C to give product~ havlng the ~keletal structure of compound I but containing a double bond in the . ..
1-12b po~ltlon. The rearrangement i~ preferably carr~ed out with tri~luoroacetic acid. Thi~ reagent may al~o be em-plo~ed ~or the rearrangement of compound~ of structure III
~1~
whereln R 1~ an acyl group.
.: me double bond can be reduced to produce the deslred trans ~tructure at the 3a-12b carbon atoms by such reagent~ a~ ~odium cyanoborohgdrlde in acetlc acid or by catalytic hydrogenation ~ith a palladium cataly~t in acetlc acid sol~ent, or a platinum or rhodium catalgst in tetrahy-:~.
.
'' .''' ~0779~g drofuran. All of the abo~e reductions are conveniently run at ambient temperatures, but temperatures between 0C and 60(' are sultable. When catalytic hydrogenatlon i8 employed, the pres~ure of hydrogen should be from about 1 to about 10 atmosphere$.
In this method R must be other than H and Rl and R2 can be hydrolytically ~table group~, including carboxyl groups ~hich can be 6ubsequently esterified and converted to alkoxy-carbonyl, hydrazinocarbonyl, hydroxylaminocarbonyl, carbamoyl, or other derlved substituents Prod~ct~ substituted w~th methylthio and trifluoromethylthio groups are obtalned by reduction of the correspondlng methylsulfonyl and tri~luoro-methyl~ulfonyl compounds by conventlonal method~. EYdroxYl-substltuted compounds are obtained by eleavage of the corres-pondlng alkoxy compound~.
Examples Or ~uitable anthracenes which can be . employed a~ ~tarting materials lnclude:
:' l-methylanthracene - 2-methylanthracene 2,6-dimethylanthracene 2,7-dlme~hylanthracene 2-isopropylanthracene 2-t-butylanthracene 1,8-dlmethylanthracene l-chloroanthracene : 2-chloroanthracene . . .
~7~9~9 q ~
1,5-dichloro~nthracene 1~8-dlchloro~nthracene 2-methoxyanthracene 1~5-dlmethoxyanthracen~
l-bromoanthracene 2-bromoanthracene 3,6-dlchloroanthracene l-fluoroanthracene - 2-fluoroanthracene 2,6-dimethoxyanthracene - trl~luoromethylanthrac~ne 2-acetylanthracene . ., l-proplonylanthracene . 1,5-diacctylanthracene .... 1,8-dlacetyl~nthracene l-anthroic acid .; . , ~-anthrolc acld :.
l-anthracene~ulfonlc acld .~ 2-anthracen~sulfonlc acid . ~, ~,8-anthr~cenedlsulfonlc acld ; 2,6-anthracenedl~ulfonlc acld ' -~
Compounds Or structuro I wherein R i8 H can be alkylated or acylated accordlnK to conventional procedure~.
.: The acyl derlvative~ may then be roduced with ltthlum alumlnum hydride to obtaln th~ corre~pondlng N-~ubstltut0d compounds, for ex~mple cycloalkylmothyl groups may be - lntroduced onto the nitrogen atom by acylation with a .
:
```'`
.. - 12 -`:
`', ~, .
7~75~
cycloalkanecarbonyl chloride followed by reductlon o~ the carbonyl group. The -rurylmethyl and ~-thlenylmethyl derivatlves are obtained ln a similar manner.
Alkylatlon Or the R - H compound~ is pre~erred for the lntroduction of propargyl, ~-cyano lower alkyl, ~-carbomethoxy lower alkyl, ~-carboethoxy lower alkyl, and 2,2,2-tri Muroethyl substltuents.
In general, the 8, 3a and 12b carbon atoms are asymmetric carbon atoms. Depending on the method of 19 synthesizing the compounds of this invention, there are obtained mixtures Or racemates, pure racemates or optlcal antipodes.
The pharmacologlcally actlve compounds of the invention are trans at the 3a-12b rlng fusion wlth respect to the 12b-hydrogen atom and the 13-methano bridge as depicted ln structure I. The stereochemistry Or the 3a-12b ring ruslon was determined ~rom the crystal structure o~ the methlodlde salt of the compound Or str~cture I, R - CH
l = R2 = H. Crystals of thls compound are monoclinlc, space group P21/c, with cell dimensions of a = 10.219 i 0. oo8, b = 14.759 i 0.026, c = 12.902 i 0.012~, and ~ = 100.64 ~ 0.06.
The C(l)C(12b)C(3a)C(13) torsion angle is -~0.6 ~ 1.0 and the ; HC (12b)C(3a)C(13) torslon angle ls 162.2 + 5.0 where H ls the hydrogen on C(12b). The C(l)C(12b)C(3a)C(13) torslon angle ls the angle between the C(12b)-C(l) and C(3a)-C(13) ~ bonds in the C(12b)-C-(3a) pro~ectlon (clockwlse posltive).
; These data establlsh that the 3a-12b ring ~usion ls trans with respect to the 12b-hydrogen atom and the 13-methano bridge.
... .
~ - 13 -:
1[)779~9 .
/ \ I~
C~3 C~3 ., Mixture~ Or racemates can be separated into the stereolsomeric pure racemates (diasteriolsomers) by the use Or known physical procedures, e.g., by chromato~raphy or rractional distlllatlon. Pure racemates can be ~eparated into the optical antipodes by conventional methods such as combination wlth an optlcally actlve acid rollowed by sep-aratlon by physical means such as recrystallizatlon of the resultant salts.
Reduction wlth sodium cyanoborohydrlde in acetlc acid, catalytic hydrogenation wlth Pd in acetic acid, or with Pt or Rh ln tetrahydro~uran descrlbed above ~ields the desired 20 trans structure at the rlng Junction 3a-12b.
The amine compounds Or the present lnventlon can be converted to the amine o~ides by oxldatlon o~ the parent amine wlth hydrogen peroxlde, peracetic acid, perbenzolc acld or the llke at ambient temperature or between about 20C and 6~C.
` The amine or amine oxldes can be used as such;
...
- however, ln the case Or the amlnes, addltion salts Or the , actlve compound with pharmaceutlcally acceptable acids can be used for admlnlstratlonto warm-blooded anlmals alone or 3 with an inert carrler. Such salts lnclude hydrochlorldes, .. , _ 14 -,, '`' .
:
~(:1 779~5~
sulrates, nitrates, phosphates, acetates, tartrate9, cltrate~, lactates, maleates and rumarates o~ the amine compounds of this inventlon. The salt~ can be made, and the free bases can be recovered from the salts by conventlonal methods includlng the use Or ion exchange resln~, metathetical reactions and the like.
EI~BO~IMENT~ OF T~i~ INVENTION
The following examples are intended to illustrate this invention but should not be construed as fully delineating the scope thereof. The compounds of the invention described in the examples have the trans configuration at the 3a - 12b ring -fusion with respect to the 12b-hydrogen atom and the 13-methano bridge.
Example 1 2-Methyl-,2 3,8,12b-tetrahydro-lH-3~8-methanodibenzo ~,4:6,77-cyclohepta ~ ,2-c~pyrrole _ _ _ ~ ~GH~
la : ,. .
[~~~~ ~
N
; 30 CH3 CH3 lb lC
' '' .',' ,.
1~ 7 ~ g ~
To a ~olution Or O.88 g of 2-methyl~3,5-dlhydro-5~9b-o-benzenobenz~e]isoindol-1-(2H)-one in 10 ml of methylene chloride is added 0.58 g o~ bromine in 10 ml of methylene chloride. Removal of the solvent lea~es 1.42 g of 12b, 13-~lbromo-2-me~hyl-2,3,~,i2b-tetrahydro-lH-3a,8-methanodibenzo[3,4:6,7]-cyclohepta[1,2-c]pyrr~l-1-one, (la), mp 215-216 (dec). A ~ample crystallized from acetonitrile melted at 221-222 (dec); nmr spectrum:
~ 1.6-1.8 (m, 1); 2.3-2.8 (m, 7); 5.1 (d, J = 4.5 Hz, l);
5.7 (d, J = 10.5 Hz, 1); 5.8 (d, J - 4.5 Hz, 1); 6.6 (d, ~ - 10.5 Hz, 1) and 6.9 (s, 3).
Ar.al. Calcd for Cl9Hl5Br2N0: C, 52.68; H, 3.49, N, ~.24 Found: C, 52.83; H, ~.43; N, 3.34 - A mixture of 8.07 g of la, 17.2 g of freshly distilled tributyltin hydride and 50 ml o~ anhydrous benzene is heated under reflux under n~trogen for ~ days.
Most of the benzene is removed and the residue is distilled through a short-path column (to 125 bath temperature, 1 micron). The pot residue is crystallized from lsopropyl alcohol tc give 3,63 ~ t71~ yield) of 2-methyl-2,3,8,12b-tetrahydro-lH-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]
pyrrol-l-one (lb), mp 141-146. A sample crystalliæed once ; ~rom isopropyl alcohol has mp 147-157.
Anal. Calcd for ClgHl7N0: C, 82.8~; H, 6.22; N, 5.09 Found: C, 82.31; H, 6.18; N, 5.18.
A mixture of 1.65 g of lb and 50 ml of lM
diborane 1n tetrahydrofuran is heat~d under reflux for 24 hours. To the cooled mlxture is added slowly 10 ml o~ concentrated hydrochloric acid; the tetrahydrofuran is removed under vacuum; concentrated hydrochlorlc acid (10 ml) ls added to the residue, and the mixture is heated 1~7~9~g under reflux for 7 hours. After concentration to a small volume the mixture is made basic and extracted with methy-lene chloride. Removal o~ the solvent from the dried extract gives 1.57 g of an oil, the main constituent of which ls 2-methyl-2,3,8,12b-tetrahydro-lH-3a,8-methanodibenzo[3,4:6,7]
cyclohepta/~,2-c7pyrrole (lc); nmr spectrum (220 mc~: T 2.6-3.1 (m, 8); 5.9 (d, 4 Hz, 1); 6.o (d, 10 Hz, 1); 6.3 (t, probably d/d, l); 6.6 (d/d, 8/10 Hz, 1); 7.0 (d, 10 Hz +
additional bands, 2); 7.2 (s, 3); 7.4 (d/d, 10/4 Hz, 1) and 7.5 (d, 10 Hz, 1). The product is converted to the hydrochloride salt which melts at 255-257 (dec) after crystallization from acetonitrile.
Anal. Calcd for C19H20ClN: C, 76,62; H, 6.77; N, 4.70 Found: C, 76.77; H, 6.~6; N, 4.70.
The 2-methyl-3,5-dihydro-5,9b-o-benzenobenzre7 lsoindol-l-(2H)-one starting material was prepared as follows: a mixture of 25 g of 9-anthroic acid and 75 ml Or thionyl chloride is heated under reflux for 1 hour. The excess thionyl chloride is removed under vacuum (~0 mm;
90 bath temperature); 50 ml of toluene is added and the mixture is concentrated again. This operation is repeated onee more to give 28.3 g of 9-~nthroyl chloride as a very ; moisture-sensitive, ycllo~ solid.
.
A solution of 20.8 ~ of 9-anthroyl chloride in 100 ml o~ tetrahydro~uran is added ~ 10-15 to a solution of 14.2 g of N-methylpropargylamine in 5~ ml Or tetra-hydro~uran. A~ter stirring ~t room temperature for 3 , .i hours, the solvent ls re~oved and the residue ls stirred ; 30 with methylene chloride and 5~ a~ueous sodium bicarbon~te ~ solution. The methylene chlorlde L1yer is dried ~nd cnn-,`"`',, ;'., , .i .
~779~9 centrated to give 23.3 g of crude N-methyl-N-propargyl-9-anthramide as an oil. H nmr spectrum: ~ 1.7-2.9 (m, 9); 5.4 (d, 2.5 Hz, 1.3); 6.4 (d, 2.5 Hz, 0.7);
6.7 (s, 0.9); 7.4 (s, 2.1); 7.7 (t, 2.5 Hz, 0.7) and 8.~ (t, 0.3). The spectrum shows the presence of two rotamers.
A mlxture of 23.2 g of crude N-methyl-N-propargyl-9-anthramide and 200 mi o~ p-xylene is heated under reflux for ?.25 hrs, The solvent is removed and t~e residue is crystallized from 300 ml of acetonitrile to g~ve 16.4 ~ of 2 methyl-3,5-dihydro-5,9b-o-benzeno-b~nz~e]iscindol-1-(2H)-one, mp, 250-255; nmr spectrum:
~ 2.3~3.3 (m, 9); 4.8 (d, J = 6 Hz, 1); 5.9 (d, J - 2 Hz, 2) and 6.9 (s, 3).
~nal. Ca~cd ~or elsHlsN~: C, 83.kg; H, 5.5~; N, 5.1~
Found: C, 83.84; N, 5.66; ~, 5.10 , , ',~
.`.
` : ~
77~'~9 Exampl~ 2 2-M[et 1-2 3,8,12b-tetr~hYdro-lH-3a,8-methanodiben2o-~,4:~ ~cyclohepta~,2-c~pyrrole b~ Acid-C~talgzed ~ea~rangement _ _ _ - HO CH--NC ~C-=CH
.' : 2a ,CH2 F"CH2 ~L~
: 2 . . .
, ., , 2b 2c . .
,:
' '-. . , , CH3 CH3 ....
` 2d lc , ..
s` ~, .~..................................................................... .
:;
,~. - 19 -~,:
':
.
'';
., .:
. . . ' .: ~
~077929 A mixture of 16.7 g of 9-anthraldehyde, 5 g of propRrgylamine and 100 ml of ethanol i~ heated ~nder re~lux for 1 hour. The ~olvent is removed and the r~idue i8 crygtal-llzed from 100 ml Or acetonitrlle to glve 16.1 g (82%) of N-pro~pargyl-9-anthracenemethylenlmine; (2a), mp, 143-144; nmr ~pectrum: t 0.2 (~, 2 Hz, 1); 1.7-3.0 (m, 9); 5.1 (t, 2 Hz~
2) and 7.3 (t, 2 Hz, 1).
Anal. Calcd for C18H13N: C, 88.86; H, 5.39; N, 5-76 Found: C, 88.83; ~, 5.56; N, 5~87.
A mlxture of 19.4 g of crude N-propargyl-9-anthracene-methylenlmlne and 200 ml o~ ~-xylene i8 he~ted under reflux for 3 hour~. On coollng, 14.6 g of 3,5-dihydro-~,9b-o-benzenobenz-~ej~soindole (2b~, mp, 212-214, pr~cipitates. Another 1.4 g of product 18 obtQlned by removlng the solvent rrom the mother liquor and crystallizing the resldue fro~ 50 ~1 of acetonitrile;
nmr 3pectrum: T 1.1 (m, 1), 2.5-3.5 (m, 9); 4.8 (d, J ~ 6 Hz, 1) and 5.4 (t, J ~ 2 Hz, 2).
. .
~nal. Calcd for C18H13N: C, 88.86; ~, 5.39; N~ 5-76 Found: C, 89.10; H, 5.58; N, 5.66.
A mlxture of 8.19 g of 3,5-dlhydro-5,9b-c-benzeno-benz~qJisoindol~, 25 ml of formlc ~cid and 25 ml o~ aqueous form~ldehyde solutlon i~ hoated under re~lux for 3 hours.
Concentrated hydrochlorlc ~cid (10 ml) i8 added, and the ~olatlle~ ~re re~oved. The resldue 1~ stirred with aqueous sodium hydroxide 801utlon ~nd methylene chlorlde. Removal of the sol~ent from the drled methylene chlorlde extracts ~nd crystallizQtlon of the re3idue ~rom acetonltrile glves, ln two crops~ 5.04 g (58%) of 2-methyl-1~2,3,5-tetr~hydro-., ;' .
ilO779Z9 5,9b-o-benzenobenz~e~soindole (2c), mp 196-197; n~r ~pectrum:
~ 2 4-3.1 (m, 8); 3.3 (d of t~ J c 6/2 Hz, 1); 4.8 (d, 6 Hz, l);
6.1 (8, 2); 6.6 (d, 2 Hz~ 2) and 7.3 (8, 3).
Ana~L- Calcd for ClgH17N: C, 87.99; H, 6.61, N, 5.40 Found: C, 88.o5; H, 5.91; N, 5,32.
A se~led Carlus tube containing 20. 0 g of 2-methyl-1,2,3,5-t~trahydro-5,9b-o-benzenobenz~e~isolndole and 80 ml of trifluoroacetic acid 18 heated at 150 rOr 8 hours. me acid i8 distilled the re~ldue is dlssolved in met~ylene chlorlde and the ~olution i8 add~d 810wly to a 3tlrred, cooled, excess ; 15% aqueous sodlum hy~roxide ~olution. The layers are sepa-rated and the agueous phase i8 extracted once with methylene chlorlde. Removal of the solvent from the combined drled ~xtract~ give~ 19.6 g of 2-methyl-2,3-dihydro-8H-3a,8-methano-dibcnzo~3,4:6,7~cyclohepta~,2-c,7pyrrole (2d); nmr ~pectrum:
2.5-3.3 (m, 8); 3.9 ~, 1); 6.1 (d 10 Hz, 1); 6.1 (d, 4 Hz, 8pllt further; 1); 6.9 (d, 10 Hz, 1); 7.3 (~ 3) and 7.4-7.9 (AB quartet, J - 9 Hz, the lower-field component i3 8plit again by 4 Hz; the high-field component by ca. 1 Hz; 2). A
',A` 20 8ample crystallized twlce rrom l~opropyl alcohol melted at 119.5-120.
Anal. Calcd rOr ClgH17N C, 87.99, H, 6.61; N, 5.40 Found: C, 87.66; H, 6.74; N, 5.45.
. . .
!, i~
The above re~rrangement may al80 be carrled out with p-toluenesulfonic acid ln acetic acid ~t 165.
A mixture o~ 13.6 g o~ 2-methyl-2,3-dlhydro-8H-3a, 8-methanodlbenzo~,4:6.7~cyclohepta~ ,2-c~pyrrole, 100 ml of acetlc acid and 2 g of 10% palladium-on-charcoal cataly8t i8 ; ~, .~
; .
10'779~9 ~haken under 40 psi hydrogen pressure at room temperature until the pressure remains const~nt. The filter2d mixture is concentrated, the residue is ~.ade basic and e~tracted several t~mes with methylene chloride. Re~oval of the sol~en~ from the dr~ed extracts gi~es 13.7 g of 2-r~ethyl-2,~,8,12b-tetrahydro-lH-3a~8-methanodibenz~3~4:6~73 cyclonept3[1,2-c]pyrrol~
identical by nmr SpectrOSCopy with the product obtained in ~x~ple 1.
The hydrogenation of 2d to give lc may also be carr~ed out with a platinu~ cat~lyst ln tetrahydrofuran.
WhPn tetrahydrofuranis used as a solvent with a palladiu~
catalyst,so~e o~ the steroiso~.er of 1~J is also formed.
: The reduction of ~ to give lc may elso be effected with sodium cyanoborohydride in acetic acid-methanol at room temperature.
Examole ~
2,3,8,12b-Tetrahydro-lH-3a,8-~ethanodiberzo~3,4:6,73-cyclohe~tar 1. 2 -c ? P~lrrol e _ _ .. :
.. . .
~ , ~C~
. . ~
; ~N~
~r . H
The procedure of ~xample 1 is employed with `` 3,5-dihydro-5,9b-o-benzenobenz~e]isoindol-1-(2H)-one replacing its N-met`nyl homologue. Th~re is obtained 2,3,8,12b-tetrahydro-lH-3~ 8-methanodibenzo~3,4:6,7~cyclo-hepta~l,2-c]pyrrole as an oil that slowly for~s a solid `` ~ 7929 carbonate on exposur~ to air. Nmr spectrum: ~ 2.6-3.1 (m~ 8); 6-o-6~4 (m, 3); 6.5-7.1 (m, 3) and 7.5-8.o (m, 3).
The hydrochloride m21ts with decomposltion at 311-~12.
Anal. Calcd for C18~1gClN: -C, 76-18;
H, 6.~9; N~ 4.94.
Found: C, 76.60; H, 6.52;
~ - N, 4:87., The starting material is prepared as described for the starting material of Exam~le 1 but replacing N-19 methylpropargylamine with proparylamine.
.~ .
2,3,8,12b-Tetrahydro-lH-3a,8-methanodibenzo-[3,4:6,7]cyclohept2[1,2-c]pyrrole is prefera~ly prepared by : hydrogenolysis ol 2-benzyl-2,3,8,12b-~etr2hydro-lH-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole ~Exam~les 4 ar.d 5) with palladium on charcoal in acetic acid at room temperature and about40 psi hydrogen pr~ssure.
' Example 4 ~-Benzyl-2,3,8,12b-tetrahydro-lH-3a,8-methanodi-,;`: ,~ benzo~,4:6,71cyclohepta~1,2-clpyrrole , .
,j ,~ . , .
~ ,`. 20 ,~ CH 2 r~ / NCHzC6H5 ~ ,~
,, ~o~
` ",.` CH2C~H5 . . ~,. .
.~ , , .
;. . .
~.............. . .
.
~, ((~t~
2-~enzyl-3,5-di~ydro-5,9b-o-benzenobenz[e]-isoindol-l t2H)-one, prepared as described below, ls converted in three steps to 2-benzyl-2,3,8,12b-tetrahydro " lH-3a,8-methanodiben~o[3,4:6,7]cyclGhepta~1,2-c]pyrrole us~ng the procedure of EY~ample 1. The free base is obtained as an oil; lt has the following nmr spectrum:
2.5-3.~ (m, 13) and 6.0-8.0 (m, 10); at 220 MXz, the 6.o-8.o reg~on resolves (from lower t? hi~her field) into a four-proton mult plet, a one-proton tr~plet, a one-proton multiplet, a two-proto:l multiplet and a .
; two-proton AB quartet (J = 10 Hz) with one component split again (J = 4 Hz).
',''` '' ~ .
The startin~ m~terial is prepared as follows: -To a mlxture of 30 ml o~ benzylamine and 60 ml of tetrahydrofuran is added drop~ise with coolin~, a solution of 9.86 g of 9-anthroyl chloride in ~0 ml of tetrahy~rofuran. After stirring at room temperature overnight, the mixture is concentrated, and the residue is dissol~ed in methylene chloride. The solution is washed wlth dilute acid and dilute base, dried, and ,, , concentrated to give 12.45 g of crude N-benzyl-9-anthramide.
The product is added to a slurry of 2.50 g of sodium hydride (50~ ~n ~l, previously washed with hexane) in 80 ml of tetrahydrofuran and the m~xture is heated to '', , -. . . ~ ' . :
:, ' - .. ,. '' '' 1~779~9 reflux for 30 min and cooled. Propargyl bromide (6.o g) in 10 ml o~ tetrahydrofuran is added, and the reaction mixture is he~ted under reflux for 2 hours. Water and ~ethylene chloride are added; the layers are separated, and the dried organic layer is concentrated. The residue (crude N-benzyl-~-propargyl-9~Qnthramide) is heated under reflux with 100 ml of ~-xylene for 2.5 hr.
On cooling, 9.81 g of 2-~enzyl-~,5-dihydro-5,9b-o-benzeno-benz ~e~isoindol-1-(2H)-one prec~pitates.
EY~a~ol~ 5 .
2-B~nzyl-2,~,8,12b-tetrahydro-lH-~a,8-~e~hanodibenzo~3,4:6,7]cyclohepta~1,2-c] pyrrole ~,~' b!~ Acid-CatalY ZQd Rearran~ment .. .
.. . .
CHO CH-NCH2CaHs CH2~rHCH2CsHs 5a 5b ~~ / CH2 ~
~/ NCHzC~Hs `i--~ )(~2J `' .. ~H2N-CH2CdHs ;, ~d .:
'`
~77929 CH2CCH5 . CH2C8H5 5e A mixture of 100 g of 9-an~Lralde~ de, 53 g of benzyl-amine and 300 ml of ethanol is ~ea~ed under re~lux un~er nitrogen for ~ 2.5 hours. Th~ solution of IJ-ber.zyl-9-anthraeenemethylenimine - (5 ) so obtained is cooled to 60, and 18.78 g of sodium borohydride is added slowly, ~eeping the temper3~ure at 60-65. After stirring at room te~erature overnignt the excess hydride is des~royed by the slo~ addition ol conc.
hydrochloric acid. Th s mixture is then made basic and is extracted several times with ~ethylenQ chloride. Rerovzl of the solvent from the dried extracts gives 139.9 g of N-benzyl-9-anthracenemethylamine ( ~ ). Nmr s~ectrum: T 1.8-3.0 (m, -14);
5.5 (s, 2); 6.2 (s, 2) and 8.5 (s, 1).
; The product isdissolved in 300 ml of methylene chloride;
200 ml o~ lO~o aqueous potassiu~ carbonate solution and 100 ml of propar~yl bromide is added, and the mixture is stirred vigorously undernitrogen at roon temperature for 3 hours. The layers are separated, the aqueous layer is extracted once with methylene ~hloride, the combined extr2cts are washed with conc. sodium chloride solution, and dried. Removal o~ the solvent gives 153.5 g Or N-benzyl-N-propargyl-9-anthracenQmethylamine (5c). Nmr spec~rum:
~ 1-5-3-0 (m ,14); 5-5 (s, 2); 6-3 (s, 2); 6-9 ( d,J=2.5 Hz, 2) and 7.7 (t, J=2.5 Hz, 1~.
. . ~
~0~79;~9 Th~ product is h~ated under reflux with 1 liter o~ toluene for 2.25 hours. Removal of the sol~ent gives crude 2-ben2yl-1,2,3,5-tetrahydro-5,9b,o-benz2nob~nz~e]isoindole (5d3. A sa~ple crystallize fro~ isopropyl alco~ol was identical by nmr s~ectroscopy with the product obta~ned by benzoylat on o~ 1,2,3~5-tetrahydro-5,9b-o-benzeno-benzEe]isoindole~followed by reduct~on (see below).
A ~.ixture of ~8.9 g 2-benzyl-1,2,3,5-tetr2hydro-5,9b-o-benzenobenz~e]isoindole (~d) and 150 ml of trifluoroacetic acid, contained in three sealed C~rius tubes, is heated at 150 for 12 hours. The excess ~cid is distilled under vacu~m, the residue is dissolved ~n methylene chloride, and the solution is added slowly ~o cold, stirred, excess 15~ aqueous sodium hydroxide ~olution. The layers are sepqra~ed, the aqueous phzse is extracted once ~rith ~ethylene chloride, and the comoined extracts ; are dried. Removal of the solvent and crystalliza~ion of the residue from 150 ~1 OL acetonitrile gives 38.3 g of 2-benzyl-2,3-dihydro-8H-3a,8-methanodib2~.zo~3,4:6,7~cyclohept2[1,2-c]pyrrole (5e). ~Jmr spectru~: ~ 2.~-3.1 (m, 13); 3.7 (s, 1); 5.7-7.8 (m, 7).
An analytical sam?le, ?reDared by crystalli~ation ,ro~ acetonitrile, had m.p. 135-1~5.
Anal. Calcd for C25H2~N: C, 89.51; H, 6.31; N, 4.18 Found: C, 89.56; ~, 6.45; ~J 4.~6.
A mixture o, 37.7 g of finely po~dered 2-benzyl-2,3-dihydro 8~-3a, o-methanadiben~ot3~4:6~7~cyclohe~t~ 2-c~pyrrole ( ~e), 300 ml of meth2nol, and 40 ml o~ acetic acid is cooled with ice, and 1~.8 g of sodi~m cya~bborohydride is added slo~ly wi~h stirring. The mixtuLre is s~irred at room tem~erature for 3 hours, cooled, and trea~ed with 5~ ~ of conc. hydrochloric acid.
After stirri~g at roo~ temperature for 0.5 hour the mixture 3 is made basic and extracted several tlmes with ~ethylene chloride.
:.
~' '' .
1077g~9 Removal of the solven~ from ~he dried extracts gives 37.5 g of 2-benzyl-2,3,8,1~b-tetr~hydro-1~-32,8-me~hanodiDenzo[3,4:6,7]-cycloheptaLl,2-cJp~rro'e , identlcal by nmr spectroscopy w th the product obtalned in Ex.ample 4. The hydrochloride melts with decompo~itlon at 195-200 after cry~tallizatlon rrom ethanol.
Anal. Calcd. for C H 4Cl~J: C, 80.30; H, 6.47; N, 3.75.
Found: C, 79.92; H, 6.80; r~ 4~13 The in~ermediate, 2-benzyl-1,2,3,5-tetrahydro-5,9b-o-ben2enobenz[e]isoindole (5d) ~2y also be pr~pared as follows:
To a slurry of 10.19 g of 3,5-dihydro-5,9b-o-benzenobenz-te]iSoindole (Exa~ple 2) in 50 ml of methanol and 10 ml of acetic acid is added slowly, with cooling, 4.70 g of sodium ~, cyanoborohydride. The ~.ixture is stirred at room te~perature overnight, the excess hydride is destroyed with concentra~ed hydro-chloric acid (ice bath), and the mixture is made basic and extracted w~th methylene chloride. Re~oval of the solvent fro~ the dried extr~ct gives 10.~9 g of 1,2,3,5-tetrahydro-5~b-o-benzenobenz[eJiso-indole as an oil; nmr spectrum: T 2.6-3.7 (m, 9); ~.9 (d, 6 Hz, l); 6.o (s, 23; 6.5 (d, 2 Hz, 2) and 7.5 (s, 1).
To a m~xture of 4.60 g of 1,2,~,5-tetrahydro-~9b-o-benzenobenz~e~isoindole, 5 g of magneslum oxide, and 20 ml of tetrahydro~uran is added ~.19 g of benzoyl chloride. Af~er stirring . . .
at room temperature overnight the mix~ur2 is filtered, the filtrate i8 concentrated, and the residue is dissolved in me~hylene chloride.
The solution is washed in tuL~n, with lO~ potassium carbonatesolutlon and water, 2nd the solvent is removed. The residue,crude 2-benzoyl-1,2,3,5-tetrah~dro-5,9b-o-benzenobenz[e]isoindole,is heated under reflux with 2.83 g of lithium aluminu~ hydride in tetrahydrofuran for 4 hours. To th~ cooled mlxture is added slowly 2.8 ml of water, follo-~ed by 2.8 ml of 15~o aqueous "
s ' . - ,~
107~9 ~9 sodium hydro~ide solution, 2nd finally ~.4 ~1 of water. The miY.~ure is filtered, i~nd the filtrate is concentrated to giv~
5.45 g of crv.~e 2-benz~ 2~5-te~rahydro-5~9b-o-benzenober~z[e]
isoindole (5~). Crystallization of 1.06 g of this ~terial from isopropyl alcohol gives o.60 ~ o~ Fure 5d, m.p. 125-125~, M~r spectr~m: T 2.4-3.6 (m, 1'~); 5.0 (d, 6 Hz, 1); 6.2 (s, 2);
6.3 (s, 2) and 6.7 (d, 2 HZJ 2).
Anal- C21cd for C25H21N: C, 83-51; H, 6.31; ~J, 4.18.
Found: C, 89.77; H, 6.26; N, ~.26.
Example 6 2-CyclopropYlmethYl-2,3,8,12b-tetrahydro-lH-3a,8-methanodib~nzo~3,4:6,7~cycloher)ta~1,2-clpyrrole .
. N N ~CH2 . H C0-CH I
~ CH2 p / CH2 . ' To a slurry of 1.3~ g 0~2,3,8,12b-tetrah~dro-lH-,' 3A,8-methanodibenzo/~,4:6,77cyclohepta/~,2-c7pyrrole ' (Example 3) and ~ g of magnes~um oxide is added 0.93 g of cyclopropanecarbonyl chloride,and the mixture is st~rred :
iO7~9~9 .
at room temperature overnight. The filtered mixture is concentrated; the residue i~ dissolved in methylene chloride~ and the solution is washed with base~ dried, ~nd concentrated. The residue is heated under reflux ~rith 0.57 g of lithium ai~min~ hydride in tetrahydro-~uran overnight. To the cooled mlxture is added, in turn, o.6 ml of ~ater, o.6 ml o~ 15~ aqueous sodium hydroxide solution, and 1.8 ml of water; the mixture is filtered, and the filtrate is concentrated to give 1.~5 g o~ 2-cyclc~rop~Jlmethyl 2,3,~,12b-tetrahy~ro~ a,8-methanodibenzo~3,~:6,7]cyclohepta[1,2-c]pyrrole as an oil; nmr spectr~ 2.7-3.2 (~, 8); 6.0-8.o (m, 8) and 8.8-10.0 (m, 5). It is con~erted to the hydrochloride ~hich is crystallized from isopropyl alcohol. The melting point o~ the h~drochloride is erratic and depends upon the rate of heating. E2tended drying Or the hydro-chloride at 120-130 for 8 hours at 0.1 mlcron glves a ~olvent-~ree product, m. p. 251-252, wlth decompos1 tion.
Anal. Calc'd. ~or C22H24ClN: C, 78.20; H, 7-16; N, 4-14 . 20 Found: C, 7~.01; H, 6.91; N, 4.50.
Exa!nple 7 2-Cyclopentylmethyl-2,3,8,~2b-tetrahydro-lH-3a,8-methano~
d~benzo[~,4:6,7]cyclohe~ta[1,2-c~pyrrole by Ac~lation of ., 2,3,8,12b-Tetrahydro-lH-,~a,8-methanodibenZo~3,4:6,7]cyclo-e~tarl 2-clD~rrole Followed by Reduction '~' ' , . ..
., ' ~ ~ . .
CH2 ~
"' Following the procedure of Example 6, but using cyclopentanecarbonyl chloride in place of cycloprop~necarbonyl chloride, there is obtained 2-cyclopentylme~hyl-2,3,8,12b-tetrah~-dro-lX 3a,8-~ethanodibenzo[3,4:6,7]cyclohepta[1,2-c~-pyrrole as on oil th~t s10~,11y cr~stallizes. Nmr spectr~m:
T 2~5-~.0 (m, 8) ænd 6~o-g.o (m, 19); at 220 MHz the ~ 6.o-g.o Prea rPsolves, from lo-.~ to high field, into a doublet ~J = 4 Hz, 1) a doublet (J = 10 ~z, 1); a doublet of doublets(J ~ 7 and 8 Hz; l);
~ doublet of doublets (J=7 and 11 Hz; l); a four-pro~on multi~let;
10 a doublet of doublets (J = 4 and 10 Hz, l); a doublet (J = 10 Hz; 1) and mul~iplets (1, 2, 4, and 2 protons). The hydrochloride m~'ts wi~h decomoo~ition at 250-253 ~fter cryst~llizati~n from :.i is3p~0pyl 21coh31 and dryi~ at 110-115~ under 0.2 ~icr~n pressure for 9 hours.
Anal. Calcd. for C24H28ClN: C, 78.77; H, 7-71; ~, 3-83-Found: C, 78.52; H, 7.83; N, 3.72.
The N-Oxide of 2-cy^lopentylmethyl-~,3,8,12b-tetr2hydrQ-lH-3z,8-m~thanodibenzo~3,l~:6,7]cyclohep~ 2-c3pyrrole -is prepared as follows: A solution ~f 3.92 g of the free base in 20 20mlofchloro~orm is added slo~rly to a cool~d mixture ol 10 ~1 of 40~ per~cetic zcid and 2 g of anhydrous sodium ace~a~e. The miXture is stirred at room temp rature ~or 90 minutes,.cooled, and made basic by the æddition of 15~ aqueous sodiu~ `n~d~oxide ~; solution. The 12y~rs are separated and the aqueous ph~se is x~racted once with chloroform. The combined organic phases are dri i ed and concen~ratea to give 3.80 g`D~ crude product 3till retain~ng some solven~; the nmr spec~rum indicates t~e presence ol two iso~ers. Addition of hot etnyl acetate causes one isomor to crystzllize; it is purified b~ recrystallization from z~etonitrile 30N~r sp~c~r~m (220 MHz) from low to high field: Aromatic r~gion 2.3-3.3 (d, J = 7.5 Hzj 1 and m, 7); Alipha~ic region, 5.5-9.0 (m, 2; d, J = 4.5 Hz + m, 2; d, J = 12 Xz, l; m, 3;
~, l; d/d, J = 4.5/10 Hz, l; d, J = 10 Hz + m, 3; m, 4 and m, 2).
''.
, - 31 -:' , .
~)77gZ~
2-Cyclopentylmethyl-2,3,8,12b-tetrahydro-trans-lH-3a,8-methanodibenzo[3,4;6,7]cyclohepta[1,2-c]pyrrole is resolved into its optical antipodes by fractional crystallization of the (+) and (-) dibenzoyl (-) tartaric acid salts. The hydrochloride of the (~) isomer has [~]D = +125 (c-2.21 g/100 ml of chloroform); the hydrochloride of the (-) isomer has [a]D =-125 (c=2.00 g/100 ml of chloroform).
Exa~le 8 2-Cyclopentylneth.yl-2,3,8,12b-te~rah;dro-lH-3Q,8-~.ethano-~iOenzo[3,~:6,7]c;clo~.ept2[1,2-c~pyrrole by Acid-Catalyzed ~earrange~ent of 2-Cyclopentyl~.ot~yl-1,2,3,5-tetranydro-~b, o-benz~nobenzrelisoindole .
CRO CHaN-CH2--O .
. 8a CR2NH-CH2 ~ :- CH2l-CH
8~ 8c ~ CHz . ~ ) CH
CR
8d 8e ' ,'- ) ~ ' :,: . ~./
CH
8r 107'7g~9 .
.
~' Following the pro~edure of Example 5, but using cyclopentylmethyla~ine in place of benzylamine there is obtain~d, in turn:
N-cyclopentylmethyl-9-am hracenemethylenei~ine (8a);
nmr spectr~m: ~ 0.9 ~t, 1); 1.5-2.8 (m~ 9); 6.3 (d~ split further, 2) and 7.3-9 0 (~., 9) N-Cyclopentylmethyl-9-anthracenemethylamine (ôb);
nmr spectrum: T 1.8-~.1 (m, 9); 5.6 (s, 2)j 7.5 (d, 7 ~z, 2) ~ and 7.8-9-3 (m, 10)-,,~ 10 N-Cyclopentylr~Qthyl-N-proparg~fl-9-anthracenemethylamine (8c); nmr spectrum: ~ 2.3-3.0 (m, 9); 5.5 (s, ~); 6.8 (d, 2.5 Hz, 2); 7-5 (m, 2); 7-7 (t, 2.5 Hz, 1) and 7.5-9.2 (m, 9).
2 Cyclspentylmethyl-1,2,3,5-tetraAydro-5,9b-o-benze~o-benz~e~isoindole (8d); m.p. 110-111; nmr s~ectrum:~ 2.6-3.2 : (m, 8); ~.5 (d/t, 6/2 Hz, 1~; 4-.9 (d, 6 Hz, l); 6.2 (s; 2);
6.7 (d, 2 Hz, 2) and 7.3-9.0 (~, 11).
.. AnaI. Calcd for C2~H25N- C, 88.o3; H~ 7-70; N~ 4.28.
Found: C, 87.68; H, 7.75; N, 4.43~
2-Cyclopentylmethyl-2,3-dihydro-8H-3a,8-methanodibenzo-t3,~:6,7]cyclohepta[1,2-c~pyrrole (8ë), m.p. 103-104;
;~. 20 nmr spectru~: ~ 2.6-3.3 (m, 8); 3.9 (s, 1); 6.o-6.3 (d, 4 Hz, 1 and : d, 10 Hz, 1); 6.8 (~, 10 Hz, 1) and 7-9 (m, 13).
Anal. Calcd. for C2~H25N: C, 88.03; H, 7.70;N, 4.28.
. Found: C, 87.83; H, 8.o6; N, 4.34.
2-Cyclopentylmethyl-2, ~, ô, 12b -tetrahydro-lH-3a,8-methano-dibenzo~3,4:6,7~cyclohepta[1,2-c]pyrrole (8~), identical by 220 ~z nmr spectroscopy with the product of Example 7. The reduction ~ of 8e to 8~ may be carried out ~rith hydrogen in acetic acid using .~ pall&dium on charcoal as the catalyst as describ~d in . ., .......... Example 2.
,, ; -, ., `~' ' "'' .
,.- -EXB~P1e 9 2-Cyclopentyl~ethyl-2,~,8,12b-tetr?hydro-lH-3a,8-~ethano-albsnzo~3,4^5,7]cyclohop'2tl,2-c]plJrrole Via Acid-Cat21yzed Rear~an~e~er.t o~ 2-C~clo~en~,anecaroonlJl-1,2,3,5-tetrahydro-~9b-o-banzenoben7re ~so~.ndole ~3~
. C~2 CH2 ,. . . . .
:: 92 ,, . -:
',~ 10 ~ H
9b 8e , ' , , v 1~2~, .,.~ , .
:~ 8f :, . ' .~. .
'" , ~ 34 ~
10779~
A mixture of 12.07 g of 1,2,3,5-tetrahydro-5,9b-o-benzenobenz~ 2~ isoindole (Exam~le 5), 70 ml of chloroform, ~nd 55 ml of triethylamino is trealed with 10.5 g of cyclopen-~anec~rbonyl chloride, keeping the temperature below 20.
Afte.r stirring at room temperature for 2 hours, 10~ aqu~ous odium hydroxide solution is added with cooling, and the ~ixture is stirred at roo~ te~perature for 30 minutes. The ayers are separated, and the aqueous phase is extracted once ~ ith methylene chloride. Removal of the solvent from the dried lG extracts and crystallization of the residue from 50 ml of aceto-: ~itrile gives 13.14 g o~ 2-cyclopentanecarbonyl-1,2,3,5-tetra-ydro-5,9b~Q-benzenobenzle]isoindole ( ~ ). ~Tmr spectru~:
.5-~.5 (m, ~); 4.8 (d, 6 Hz, 1); 5.1 (s, 2); 5.8 (s, 2 Hz, 2) ~nd 6.7-8.7 (m, 9). An ~nalytical sample (acetonitrile) ~ ad m.p. 189-190.
. .
Anal. Calcd. for C2~23~0-: C, 84.42; H, 6.79; ~J, 4.10 Found: C, 84.o~; H, 6.79; N, 4.29.
A mixture of 11.67 g of the above product 2nd 60 ml 0~ tri~luoroacetic acid is heated under reflux for 2 hours. The e~cess acid is removed under vacuum, the residue is dissolved in ~e~hylene chloride and the solution is poured into cold, stirred, ~cess aqueous sodium hydroxide solution. The mixture is ~Xtracted several times with methylene chloride, the extracts ~e dr~ed, the solvent is re~o~ed and the residue is crystallized ~r~m ~0 ml of toluene to give 10.89 g of 2-cyclopentanecarbonyl-,3-dihydro-8H-3a,8-methanodibenzo~3,4:6,7]cyClohejpta~1,2~C]~yrrole (9b), I~r spectr~m: . 2.5-3.2 (m, 9); 5.0-6.1 (m, ~ and 6.6-8.
(h, 11). An analytical samD'e (~cetonitrile ) had m.p.l8~-186 .
"
.
:'', ' .
:. ' ....
., ., .
iO779Z9 Anal. Calcd. for C2~H2~N0: C, 84.42; H, 6.79; ~, 4.10.
Found: C, 8~.60; H, 6.93; M, 4.55.
To a cooled slurry of 0.40 g of lithium aluminum hydricle in 30 ~1 of ether is added 1.55 g of 9b and the mixture i5 stirred at roG~ temp2rature for 6 hours. The excess hydride is decomposed by the addition of 0.~ ml of water, follo.~ed by 0.4 ml of 15~ aqueous sodiu~ hydroxide solution and 1.2 ml of water. The ~ixture is f~ltered and the filtra~e is concentrated.
Crystalliz2tion of the residue from isopropyl alcohol gives o.89 g of 2-cyclooentylmethyl-2,~-dinydro-8X-3a,8-methanodibenzo-[3,4:6,7]cyclohepta~1,2-c]pyrrole (8e), identical by infrared and nmr spectroscopy ~lith the product ob~ained in Example 8.
R~du~tion of & as described in Exa~le 8 ~g~ves 2-cyclopenty methyl-2,3,8,12b-tetrahydro-lH-~a,8-mzthanodibenzo~3,4:6,7~cyclo-heptatl,2-c]pyrrole.
When 2-cyclopent2necarbonyl-2,3-dihydro-8H-3~,8-~.ethano-d$benzo~3S4:6,7]cyclohepta[1,2-c]pyrrole (9b) is hydro~enated with palladium-on-carbon catalyst intetr2hydrofur?n, 2-cyclopentane carbonyl-2~3~8~l2b-te~rahydro-lH-~8-methanodibenzo~3~:6~7J
~epta[1,2-c]pyrrole having the cis sterochemistry at the 3a-12b-ring fusion is formed.
Exam~le 10 2-Allyl-2,3,8,12b-tetrahydro-lH-3a,8-~.ethanodibenzo-L~-4~ .?lc~clohepta~l~2-cl~vrrole _ _ . , ' .
~ 30 . ~CHzCH=CH2 ., ,. - 36 -., 1077g2~ , A mixture of 2.19 g of 2,3,8,12b-tetrahydro-lH-3a,8-methanodibenzo~,4:6,7]cyclo~epta~1,2-c~pyrrole (Example ~, 20 ml of ch:Loroform, 20 ml ~f 10~ ~queous potassium carbonate solution and 4 ml of allyl bromide is st.irred v~ gorously under nitrogen at room temperature for 5 hours. A precipitate formed 1s brought into solution by addition of methanol; the layers are separated and the aqueous phase is extracted once with a mixture of methylene chloride and methanol. The solvent is removed from the dried extracts and the residue is heated with 15 ml o~ methanol and 6 g of trimethylamine in a sealed Carius tub~ at 110 for 8 hours; this trea~ment converts any quaternarys~
to the desi~ed tertiary amine. The solvent is removed and the resldue is dissolved in methylene chloride. The solution is washed with aqueous sodium hydroxide solution and dried. Rer..o~æl of the solvent gives 2~allyl-2,3,8,12b-te'ranydro-lH-3a,8-methano-dibenzo[3,4:6,7]cycloh~pta[1,2-c]~yrrole. The hydrochloride, after crystallization from isopropyl alcohol weighed,1.60 g;
m-p- 20a-209 (dec.) Anal. Calcd. for CzlH22ClN: C, 77.88;H,6.85; N, ~.33 Found: C,78.14;X, 7.02; N, 4.47-The free bæse h2s the following nmr s~eetru~: ~
2.7-3.2 (m, 8); 3.7-~.4 (m, 1); 4.6-5.1 (mJ 2) and ~.1-7.9 (m, 10).
Example 11 Ethyl 2,3,8,12b-Tetrahydro-lH-3a,8-methanodibanzo-6 ~ll cyclohePt2r 1 . 2-c~ rrol~-2-butvrate . .
,. . .
~\~
N
CH2CH2CH2C02C2Hg ',:
.
1(~779Z9 A mixture of 2.35 g of 2,3,8,12b-tetrahydro-lH-3a,8-~ethanodîbenzo[3,4:6,7~cycloheota~1,2-c]pyrrole, 25 ml o~
dimethyiformamide, 4 ml of trLe~hylamine and 2.55 g of ethyl
4-bro~lobutyrate is heated at 60-65 bath tempera~ure under nitrogen for 18 hours. The cooled reaction mixture is diluted with water and extracted ~rice with methylene chloride.
The extracts are ~ashed with dilute aqueous sodium hydroxide 601u~ion, dried and concentrated to give 3.07 g of crude ethyl 2,3,8,12b-tetrahydro-lH,3a,8-meth~nodibenzo[3,4:6,7]cyclohepta-1~ [1,2-c]pyrrole-2-butyrate. Nmr spectrum: r 2.7-3.2 (m, 8);
The extracts are ~ashed with dilute aqueous sodium hydroxide 601u~ion, dried and concentrated to give 3.07 g of crude ethyl 2,3,8,12b-tetrahydro-lH,3a,8-meth~nodibenzo[3,4:6,7]cyclohepta-1~ [1,2-c]pyrrole-2-butyrate. Nmr spectrum: r 2.7-3.2 (m, 8);
5.9 (quartet J = 7 Hz, 2); 6.0-805 (m, 14) and 8.8 (t, 7 Hz, 3).
The ~ollow1ng derivatives of 2,3,8,12b-tetra-hydro-lH~3a,8-methanodibenzo[3,4:6,7]cycloh~pta[1,2-c]pyrrole have been prepared æccord'n~ to the procedures outlined in th~
preceed~n~ Examples. For th~ purpose of identifica.tion, thes~
procedures are designated:
(I) Acylation of 2,3,8,12o-tetrahydro-lH-3a,8-; methanodibenzo[3,4:6,7]cyclohep~a[1,2-c]pyrrole ~Jith the appropriate acid chloride follo~ed by reduction (Exæ~ple 6).
tII) Reaction of 9-znt~raldehyde, optionally ~ubstituted in the benzene ring(s), with an appropriate primary æmine, followed by the steps outlined in Example 5.
(III) ~eaction of 9-anthroyl chloride with an appropriately N-substituted propargylamine follo~ed by th~
6teps outline in Exampl~ 1.
(I~) Alkylztion of 2,3,8,12b-tetrahydro-lH-3a,8-methanodibenzot3~4:6~7]cyclohep~2[l~2-c]pyrrole~Examples 10 and 11).
. ~xam~le 12: 2-~thyl-2,3,8,12b-tetrahydro-lH-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole; method I;
nmr spectrum: T 2.5-3.2 (~, 8); 6.o-8.o (~, lo), and 8.8 (t, 3) 3 E~m~19_13: 2-n-Buty1-2 9 3,8,12b-tetrahydro-lH-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole; method I;
nmr spectrum: ~ 2.7-3.2 (m, 8) and 6.1~9.3 (m, 17), .' 10779~5~
Example 14: 2-n-Hexyl-2,3,8,12b-tetrahydro-lH-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1J2 c]pyrrole; method I;
nmr spectr~: ~ 2.7-3.2 (~, 8) and 6.o-g.~ ~m, 21), Example 15: 2-n-Hepty1-2,3,8,12b-tetrahydro-lH-3a,8-methanod~benzo[3,4:6,7]cyclohe~ta~1,2-c]pyrrole; method I;
nmr ~pectrum: ~ 2-6-3-1 (m,8) and 6.o-9.~ (m, 23).
Exam~le 16: 2-n-Octyl-2,3,8,12b-tetrahydro~ ,3a,8-methanodibenzo[3,~:6,7]cycloh~pta[1,2-c]pyrrole; method I;
nmr spec~ru~: T 2.6-3.2 (~, 8) and 6.0-9.3 (m, 25) Exam~lo_17: 2-(2-~hyibuty')-2,3,8,12b-tetrahydro-1H-3a 8-methanod~benzo~3,4:6,73cyclohep~[1,2-c]~rrole; m~thod I;
nmr ~pectrum:T 2.7-3.2 (m, 8~ and 6.1-9.2 (m, 21).
Example 18: 2-pr3pargyl-2~3~8~l2b-tetrahydro-lH-3aJ8 methanodibenzo[3,4:o,7]cyclohepta~1~2-c3pyrrole; ~e~hod IV;
~mr spectru~: ~ 2.5-3.1 (m, 8) and 6.0-7.8 (~ 11). -Exam~le 19: 2-Cyclobutyl~etnyl-2,3,8,12b-tetrahydro-lH-3a,8-m2th~nodibenzo~,4:6,73cyclohepta~1,2-c~pyrrole; method I;
`',,!~ ~ydr~chloride: mp ~ 260 (dec.); Anal. Calcd. for C2~2~Cl~:
C, 78.49; H, 7.45; N, 3.98. Found: C, 78.31; H, 7.31; ~T, 3.9~.
Example 20: 2-(3-~athylenncyclobutylmetnyl)-2,3,8,12b-tetrahydro-lH-3a,8-m~thanodibenZo~3,4:6,7]cyclohept2~1,2-cJpyrrole;
method I; nmr spec~ru~: ~ 2.7-3.3 (m, 8); 5.2-5.5 (m, 2); and ',J~. 6.1-8.0 (m, 15)-~; . .
Exam~le ?1: 2-(1-Cyclopentenylmethyl)-2,3,8,12b-tetra-hydro-1~,3a,8-meth~nodibenzo[3,4:6,7~cyclohepta~1,2-c3pyrrole5 m~t~.od I; nmr s~ectru~: ~ 2.7-3.2 (m, 8); 4.3-~.5 (m, 1) and ` 6.0-8.3 (m, 16). .
`~ . Exam~le ~2: 2-(2-Cyclopent~lethyl)-2,3,8,12b-tetr~hydro-lH-3a,8-methanod~2nzo[3,4:o,7]cyclohepta~1,2-cJpyrrole; method I;
3 hydrochloride: mp 246-2~8 (dec.); Anal. Calcd. for C25~ oClN:
C, 79702; H, 7.96; N, 3.69. Found: C, 78.83; H, 7.87; N, 3.55.
.
107~9~9 Exa~ 2~: 2-(2-Cyclopent-2-enylethyl!-?,3,8,12b-te~ra-hydro-lH-3a,8-~eihanodibenzo~3,4:6,7]cyclohe~?ta~1,2-c~pyrrole;
;:ethod I, nmr s~c-r~ T 2.7-~.1 (m, 8); 4.2-4.4 (m, 2) and
The ~ollow1ng derivatives of 2,3,8,12b-tetra-hydro-lH~3a,8-methanodibenzo[3,4:6,7]cycloh~pta[1,2-c]pyrrole have been prepared æccord'n~ to the procedures outlined in th~
preceed~n~ Examples. For th~ purpose of identifica.tion, thes~
procedures are designated:
(I) Acylation of 2,3,8,12o-tetrahydro-lH-3a,8-; methanodibenzo[3,4:6,7]cyclohep~a[1,2-c]pyrrole ~Jith the appropriate acid chloride follo~ed by reduction (Exæ~ple 6).
tII) Reaction of 9-znt~raldehyde, optionally ~ubstituted in the benzene ring(s), with an appropriate primary æmine, followed by the steps outlined in Example 5.
(III) ~eaction of 9-anthroyl chloride with an appropriately N-substituted propargylamine follo~ed by th~
6teps outline in Exampl~ 1.
(I~) Alkylztion of 2,3,8,12b-tetrahydro-lH-3a,8-methanodibenzot3~4:6~7]cyclohep~2[l~2-c]pyrrole~Examples 10 and 11).
. ~xam~le 12: 2-~thyl-2,3,8,12b-tetrahydro-lH-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole; method I;
nmr spectrum: T 2.5-3.2 (~, 8); 6.o-8.o (~, lo), and 8.8 (t, 3) 3 E~m~19_13: 2-n-Buty1-2 9 3,8,12b-tetrahydro-lH-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole; method I;
nmr spectrum: ~ 2.7-3.2 (m, 8) and 6.1~9.3 (m, 17), .' 10779~5~
Example 14: 2-n-Hexyl-2,3,8,12b-tetrahydro-lH-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1J2 c]pyrrole; method I;
nmr spectr~: ~ 2.7-3.2 (~, 8) and 6.o-g.~ ~m, 21), Example 15: 2-n-Hepty1-2,3,8,12b-tetrahydro-lH-3a,8-methanod~benzo[3,4:6,7]cyclohe~ta~1,2-c]pyrrole; method I;
nmr ~pectrum: ~ 2-6-3-1 (m,8) and 6.o-9.~ (m, 23).
Exam~le 16: 2-n-Octyl-2,3,8,12b-tetrahydro~ ,3a,8-methanodibenzo[3,~:6,7]cycloh~pta[1,2-c]pyrrole; method I;
nmr spec~ru~: T 2.6-3.2 (~, 8) and 6.0-9.3 (m, 25) Exam~lo_17: 2-(2-~hyibuty')-2,3,8,12b-tetrahydro-1H-3a 8-methanod~benzo~3,4:6,73cyclohep~[1,2-c]~rrole; m~thod I;
nmr ~pectrum:T 2.7-3.2 (m, 8~ and 6.1-9.2 (m, 21).
Example 18: 2-pr3pargyl-2~3~8~l2b-tetrahydro-lH-3aJ8 methanodibenzo[3,4:o,7]cyclohepta~1~2-c3pyrrole; ~e~hod IV;
~mr spectru~: ~ 2.5-3.1 (m, 8) and 6.0-7.8 (~ 11). -Exam~le 19: 2-Cyclobutyl~etnyl-2,3,8,12b-tetrahydro-lH-3a,8-m2th~nodibenzo~,4:6,73cyclohepta~1,2-c~pyrrole; method I;
`',,!~ ~ydr~chloride: mp ~ 260 (dec.); Anal. Calcd. for C2~2~Cl~:
C, 78.49; H, 7.45; N, 3.98. Found: C, 78.31; H, 7.31; ~T, 3.9~.
Example 20: 2-(3-~athylenncyclobutylmetnyl)-2,3,8,12b-tetrahydro-lH-3a,8-m~thanodibenZo~3,4:6,7]cyclohept2~1,2-cJpyrrole;
method I; nmr spec~ru~: ~ 2.7-3.3 (m, 8); 5.2-5.5 (m, 2); and ',J~. 6.1-8.0 (m, 15)-~; . .
Exam~le ?1: 2-(1-Cyclopentenylmethyl)-2,3,8,12b-tetra-hydro-1~,3a,8-meth~nodibenzo[3,4:6,7~cyclohepta~1,2-c3pyrrole5 m~t~.od I; nmr s~ectru~: ~ 2.7-3.2 (m, 8); 4.3-~.5 (m, 1) and ` 6.0-8.3 (m, 16). .
`~ . Exam~le ~2: 2-(2-Cyclopent~lethyl)-2,3,8,12b-tetr~hydro-lH-3a,8-methanod~2nzo[3,4:o,7]cyclohepta~1,2-cJpyrrole; method I;
3 hydrochloride: mp 246-2~8 (dec.); Anal. Calcd. for C25~ oClN:
C, 79702; H, 7.96; N, 3.69. Found: C, 78.83; H, 7.87; N, 3.55.
.
107~9~9 Exa~ 2~: 2-(2-Cyclopent-2-enylethyl!-?,3,8,12b-te~ra-hydro-lH-3a,8-~eihanodibenzo~3,4:6,7]cyclohe~?ta~1,2-c~pyrrole;
;:ethod I, nmr s~c-r~ T 2.7-~.1 (m, 8); 4.2-4.4 (m, 2) and
6.o-g.o (m, 17)-EX2m~1Q 2~1: 2~ Cyclopentylpropyl~-2~3,8,12b-tetra-hydro-lH-~a,8-;~L.anodibQn~o~3,~:6,7]cyclohepta~ 1,2-cJpyrrole;
metnod I; hydro~r.'o~id~: -il3 . 242-24.~ (dec.):
A~al . C~lcd for '28. 32Cl.~: C, 79.20; H, 8.19; M, ~5.56 ~ound: C, 79.83; H, 8.33; N, 3.51.
. . ~
Exar!lple 25: 2~yclohQxyl~thyl-2,3,8,12b-tetrahydro-lH-3a,8-methanodibenzo[3,~:6,7~cyclohep.a~1,2-c~pyrrole; method I, III. Hydrochlori de: mp 248-253 (dec.):
Anal. Calcd. for C25x30Cl~: C, 79-02; H, 7-96; N~ 3-69-Found: C, 78.69; H, 7.91; N, 3.79.
ExamPle 26: 2-(l~yclohexenylm~thyl)-2,3,8,12b-tetrahydro-lH~3a,8-me-hanod~benzo~,4:6,7~cyclohepta[1,2-c~pyrrole;
method I; nmr spectrum: ~ 2.7-3.2 (mJ 8); 4.0 ( m, 1~ and 5.5-8.6 ( m, 18).
Exam~le 27: 2-(~yclohexenylmethyl)-2,3,8,12b-tetrahydro-lH-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c~pyrrol~;
method I; nmr spectr~m: ~ 2.6-3.1 (m, 8~; 4.~i (m, 2) and 6.o-s.o (m, 17)-~ : 2-(1,~-C yclohexadienylmethyl)-2,3,8,12h-- tetrahydro-lH-3a,8-methanodibenzo[3,4:6,7]cyclohep-a[1 2-c]pyrrole;
me~hod I; nmr s~ectru:n: T 2.6-3.1 (m, 8); 4.1-4.5 (m, 3) and 6.0-7.8 (m, 14)-Exam~le 29: 2-(2~yclohexylethyl)-2,3,8,12h-tetr2hydro-lH-3a,8-methanodibenzo[3,4:6,7]Cycloh~pta~1,2-c]pyrrole; ~ethod I;
hydrochloride: mp. 234-2~8 (dec.);
30Anal. Calcd. for C2eH32ClN: C, 79.26; H, 8.18; N, 3.56 Found: C, 78.77; X, 8.26; ~r, 3.40.
; ' ~0779Z9 Exam~le 30: 2-(3~ yclohexylpropyl)-2,3,8,12b-tetr2hydro~
lX-3a,~-methanodibenzo~3,4:6,7]cyclohepta~1,2-c~pyrrole; method I;
n~r Eipectrum: T 2.5-3.1 (m, 8) and 6.0-9.5 (m, 2~).
Exam~le ~1: 2-(4~ yclohexylbutyl)-2,3,8,12b-tetrahydro-1~-3a,8-metheno~;benzo~3,4:o,7].ycloh~ta[1,2 c]pyrrole; rethod I;
nmr spectrum: ~ 2.7-~.2 (~, 8~; and 6.1-9.7 (m, 27).
Exa~le 32: 2 ~ ycloheptylmethyl-2,3,8,120-t~trahydro-lH-3a,8-methanod;Den~o~3,4:6,73cyclo~2pta[1~2-c]pyrrole; method I;
hydrochloride: mp. 254-256 (dec.) Anal. Calcd for Cz9-~32ClM: C, 79.26; H, 8.19; ;i, ~.56 Found: C, 79.00; H, 7.86; N, 3.81.
, . , ; The nmr spectru~ oD the free base, obtæined æs an oil, showed bands at ~ 2.~-3.2 (m, 8) ~nd 6.0-9.2 (m, 23).
Exam~le ~3: 2-(~ yclohep~enylmethyl)-2,3,8,12h-~etra-i hydro-lH-3a,8-~th~odibenzo~3,4:6,7]cycloheptz~1 2-c]pyrrole;
method I; nmr spectrum: T 2.7-3.1 (m, 8); 4.0-4.5 (m, 2) and 6.0-9.~ (m, 19);
Exa~le ~: 2 ~ yclooc~ylmethyl-2,3,8,12b-tetrahydro-., ~ lH-~a,8-methanodibenzo[3,4:6,7]cyclohepta~1 2-c]pyrrole; method I;
~ . ..
n~r spectrum: T 2.7-3.3 (~, 8) and 6.1-9.2 (m, 25).
~xa~e 3~: 2-(2-Exo-bicyclo~2.2.1~hep~ylm~hyl)-2,3,8, ,. ~2b-tetrz.hydro-1U-~a~8-methanodibenzo~3~4 6~7]cyclohepta~1~2-c~-pyrrole; method I; nmr spectr~m: T 2.6-3.1 (m, 8) and 6.0-9.2 (m, 21)-; ~xam~le ~6: 2-(2 ~ ndo-bicyclo~2.2.1~heptylmethyl)-2,3,8,12b-te~rzh~dro-lH,3a,8-methanodibenzo~3,4:6,7~cyclohepta-- tl,2-c]pyrrole; method I; nmr spectrum: T 2.6-3.1 tm, 8) and ~ 6 . o - s .3 (m, 21)-i Exam~le ~7: 2-(2 ~ xo-bicyclo[2.2.1~hept-5-enylmethyl)-.. . .
30 2,3,8,12b-~etrzhydro-lH-3a,8-methanodibenzo~3,4:6,7]cyclohepta-tl,2-c]pyrrole; method I; nrr spectrum: T, 2.6-~,2 (m, 8);
3.8-~.1 (m, 2) and 6.o-8.9 (m, 17).
.:
, ~077925 EY~a~le ~8 2-(2~-ndo-bicyclo~2~2~l]hQp~-s-e 2,3,8,12h-tetra~dro-1~-3a,8-methanodibenzo[3,4:6,7]cyclohepta-tl,2-c~pyrrole; method Ii nmr s?ec~r~: ~ 2.6-3.3 ~m, 8); 3.8-".
(~, 2) and 6.1-9.6 (~, 17).
Exam~le 39: 2-(2-Phenylethyl)-2,3,8,12b-tetrahydro-lH-3a,8-methanodibenzo[3,~:6,7~cyclohepta~1,2-c]pyrrole; method I;
hydrochloride: mp 2~8-250 (dec.);
Anzl. Calcd. for C2~H2~Cl~ CJ 80.43; H~ 6.76; N~ 3.61.
Found: C, 80.71; ~, 6.82; N, 3.59.
The nmr spectrum of the ~ree base, obtained as an oil, ~howed bands at T 2.6-~.2 ~m, 8) and 6.0-7.9 (mJ 12).
Exam~le 40: 2-(2-Phenoxyethy1)-2,~,8,12b-tetrahydro-lH-3a,8-methanodibenzo[3,4:6,7~cyclohepta~1,2-c]pyrrole; methoa I;
nmr spectr~: T 2.6-3.3 (m, 13) and 5.7-8.3 (m, 12).
Exam~le 41: 2-(2-Methox~ethyl)-2,3,8,12b-tetrahydro- r' lH,3a,8-meth2nodibenzo[3,4:6J7]cyclohepta~1,2-C]pyrrole; method I, nmr spectrum: T 2.7-3.1 (m, 8) and 6.1-7.9 (m, 15).
xam~le h2: 2-(2-Furylmethyl)-2,3,ô,12b-tetr~hydro-lH-3a,8-methænodibenzo[3j4:6,7~cyclohepta[1,2-c~pyrro e; ~ethod I;
hmx spectrum: ~ 2.6-3.2 (m, 9); 3.6-3.9 (m, 2) and 6.o-8.o (m, 10) - ExamPle 43: 5- and 11-Chloro-2-methy1-2,3,8,12b-tetra-hydro~ a,8-methanodibenzo[3,4:6,7]cyclohepta~1,2-c~pyrrole;
method II~ nmLr spectrum: T 2.6-3.2 (~, 7) and 5.9-7.8 (m, 11) Exam~le h,4: 5- and 11-Chloro-2~cyclohexyl~ethyl-2,3,8,12b-tetrahydro-lH-3a,8-methanodibenz~[~5,4:6,7~cyclohepta-~1,2-c3pyrrole; meth~d II; nmr spectrum: T 2.5-3.~ (m, 7) and 6.o-s .~ (m,'21).
.
_ 42 -... .
Dle ~5 2-Cyclohe~lr~ethyl-2~3~8~12b-tetrahydro-lH-3a~8-methano-dlbenzo~ ,l~:6,7~cyclo~1eDtarl,2-c,7pyFrolc COCl ~ CH2C CH
~ O-N O
0 C~12 F~ NCH2r\~
, ~))C) ~
, . ' N
`; ~ ' ' ' .
~ CK~ O
A solution of 12.66 g of 9-anthroyl chloride i~
~ ml of tetrahydrofurzn is added dropwise to a stirred `~ mixture of 8.~9 g of N-propargylcyclohexylmethylamine a~d 9 ~ of magnesium oxide in 80 ml of tetrahydrofuran.
. After s~irrin~ at room temperature o~erni~ht, the mlxture is filtered and the filtrate is concentrated to d~yness.
The residue is taken ùp in methylene chloride and washed, . 30 .
. _ 43 _ .
''' ~779~9 in turn, with dilute sulfuric acid, water, and dilute sodiunl hydroxide solution, and dried. Removal of the solvent gives 14.7 9 of N-cyclohexylmethyl-N-propargyl-9-anthramide as an oil. It is dissolved in 100 ml of p-xylene and the mixture is heated under reflux for three hours. The solvent is removed, and the residue is heated under reflux with ~0 ml of tetrahydrofuran and 6~ ml of 15% aqueous sodium hydroxide solution for one hour. The mixture is concentrated to a small volume, diluted with water and filtered. The solid is washed with dilute alkali and water, dried, and crystallized from toluene to give 6.68 9 of 2-cyclohexylmethyl-3,5-dihydro-5,9b-, o-benzenobenz ~e~isoindol-1(2H)-one; nmr spectrum:
,....
2.3-3.4 (m, 9), 4.8 (d, J = 6Hz, 1) 5.9 (d, J = 2Hz, 2), 6.6 (d, J = 6.5 Hz, 2) and 8.0-9.2 (m, 11).
The above product (2.94 9) is treated with 1.41 9 of bromine in methylene chloride at room temperature.
The resulting crude 12b,13-dibromo-2-cyclohexyl-methyl-2,3,8,12b-tetrahydro-lH-3a,8-methanodibenzo ~3,4: 6,7 cyclohepta ~1,2-c~ pyrrol-l-one is heated under reflux with 9 9 of tributyltin hydride and 25 ml of anhydrous benzene for 3 days. The benzene is removed and the residue is concentrated further using short-path dis-tillation (1 micron, 125 bath temperature). Crystal-lization of the residue from isopropyl alchol gives 2.39 9 of 2-cyclohexylmethyl-2,3,8,12b-tetrahydro-lH-3a,C-methanodibenzo ~3,4: 6,7~ cyclohepta ~1,2-c,7pyrrol-1-one;
nmr spectrum: ~ 2.2-3.3 (m, 8); 5.9-6.2 (m,2); 6.6-7.0 (m, 4); 8.1 (m, 2) and 8.1-9.7 (m, 11).
:
, ~77929 The above product is he~ed under reflux with 70 ml 0~ dlborane in tetrah~drofuran overnight. The excess cliborane is destroyed.~Jith 15 ml of conc. hydrochloric acid; the mixture is concen~rated, and the residue is heated under reflux with 15 ml Or conc. hydrochloric acid and 20 ml of meth2nol for ~ days. Af~er removal of the methanol the residue is made basic and extr~cted . with methylene chloride. Removal of the solvent from - the dried e~tracts~ives 2.06 g Or 2~cycloheY.ylmethyl-3~8~ tetrahydro-lH_~a~-methanodibenzo/~4:b.~7-. cyclohepta[l,2-c]pyrrole as an oil. An ether solution c~ the product is treated with hydrogen chloride,and , the pre~ pitate is crystallized from 9~J e~hanol to give , 1.90 ~ ol the hydrochloride~ mp 218-220~-(dec).
Anal. Calcd for C2sH30ClN: C, 79,02; H, 7.96; N, 3.69.
. ,~ . .
Found: C, 78.62; H, 7.47; N, 3.66.
urther puri~lcat~on o~ the hydrochlorlde was achleved by drying it ~or several hours at about 110~ and 0.2 ~lcron ~ressure to ~ive the product Or Example 25, mp. 248-253 ~dec. ) .
ExamPle 46: 2-Cyclopropyl-2,3,8,12b-tetrahydro-lH-3a,-8-methanodlbenzo~3,4:6,7]cyclohepta~1,2-c]pyrrole; method II;
nmr spectrum: T 2.5-3.1 (m, 8); 6.o - 8.4 (m, 9) and 9.4-9.8 (m, 4).
ExamPle 47: 2-Cyclobuty1-2,3,8,12b-tetrahydro-lH-~ 3a,8-methanodlbenzot3,4:6,7]cyclohepta[1,2-c]pyrrole; method II;
;. nmr spectrum: T 2.7-3.2 (m, 8) and 6.1-8.5 (m, 15).
;. xamPle 48: 2-Cyclopentyl-2,3,8,12b-tetrahydro-IH- 3o 3a,8-methanodibenzot3,4:6,7]cyclohepta[1,2-c]pyrrole; method II;
nmr spectrum: T 2.6-3.2 (m, 8) and 6.1-8.8 ~m, 17).
. _ 4~ _ . .
: .
1~77929 ExamPle 49: 2-Isopropyl-2,3,8,12b-tetrahYdro-lH-3a>8-methanodibenzo[3~4:6~7]cyclohepta~l~2-c]pyrrole; method II;
nmr spectrum: T 2.7-3.2 (m, 8); 6.1-7.9 (m, 9); 8.8 (d, 6).
Exam~le 50: 2-(1-Cyclopentylethyl)-2,3,8,12b-tetra-hydro-lH-3a,8-methanodlbenzo[3,4:6,7]cycloheptatl,2-c]pyrrole;
method II; nmr spectrum: T 2.7-3.1 (m, 8) and 6.1-9.1 (m, 21).
Example 51: 2-(2-Methylcyclopentylmethyl)-2,3,8,12b-tetrahydro-lH-3a,8-methanodlbenzo[3,4:6,7]cyclohepta~1,2-c]--- pyrrole; method II; nmr ~pectrum: ~ 2.6-3.3 (m, 8) and 6.1-9.3 (m, 21). Thls compound is a mlxture of two lsomers ln whlch the methyl group attached to the cyclopentane ring ~8 cls and trans.
ExamPle 52: 2-(3-Methylcyclopentylmethyl)-2,3,8,12b-tetrahydro-lH-3a,~-methanodlbenzo[3,4:6,73cyclohepta[1,2-cJ-p~rrole; method II; nmr spectrum: T 2.6-3.3 (m, 8) and 6.0-9.5 (m, 21). Thls compound ls a mlxture o~ two lsomers ln whlch the methyl group attached to the cyclopentane rlng ls cis and trans.
ExamPle 53: 2-(2-Adamantylmethyl)-2,3,8,12b-tetra-hydro-lH-3a,8-methanod~benzot3,4:6,7]cyclohepta~1,2-c]pgrrole;
method I; nmr spectrum: ~ 2.6-3.0 (~ 8) and 6.o-8.5 (m, 25).
Example 54: 2-(2-Thienylmethyl)-2,3,8,12b-tetra-hydro-lH-3a,~-methanodlbenzo~3,4:6,7]cyclohepta~1,2 c3pyrrole;
method I; nmr spectrum: T 2.7-3.3 (m, 8) and 5.9-8.0 (m 10).
Exam~le 55: 2-(trans-2-Phenylcycloprop~lmethy])-2, 3,8,12b-tetrahydro-lH-3a,8-methanodibenzo[3,4:6,7~cyclohepta-tl,2-c]PYrrole; method I; nmr spectrum: r 2.7-3.2 (m, 13) and 6.0-9.3 (m, 14).
,`' ' i .. , ~077g~
.
Example 56: 2-Tertiarybutyl-2,3,8,12b-tetrahydro-lH-3a,8-methanodibenzo f3,4: 6,7~ cyclohepta ~1,2-c~ pyrrole, ' method II; nmr spectrum: ~ 2.6-3.0 (m, 8); 6.0-7.4 (m, 8);
~; 8.7 (s, 9).
Example 57:
:; Nitro-2-methyl-2,3,8,12b-tetrahydro-lH-3a,8-methanodibenzo-~3,4: 6,7_7cyclohepta ~1,2- ~ pyrrole HydrQ hloride ' To a solution of 1.5 9 (5.06 mmoles) of 2-methyl-2,3,8,12b-tetrahydro-lH-3a,8-methanodibenzo 3,4: 6,7 cyclo-- 10 hepta ~1,2-~ pyrrole hydrochloride in 25 ml of anhydrous hydrofluoric acid cooled at -78 was added 562 mg (5.06 mmoles) r~ of potassium nitrate. The reaction mixture was allowed to ~s,;~ warm to room temperature and the hydrofluoric acid was evaporated under a stream of nitrogen. The residue was si., dissolved in methylene chloride, and the solution washed with .i IN aqueous sodium hydroxide, with water, and dried over ~ , ,-` potassium carbonate. The solvent was removed under vacuum, ; the residue was dissolved in ether and insolubles were removed i:, by filtration. The ethereal filtrate was treated with dry ~0 hydrogen chloride to give 1.0 9 of nitro-2-methyl-2,3,8,12b-tetrahydro-lH-3a,8-methanodibenzo~3,4:6,7~cyclohepta~'1,2-c~
i:
pyrrole hydrochloride as a colorless solid, m.p. 202-207 ,',, ~; (slight decomp.).
". Mass spectrum:
Calcd. for ClgH18N2 2 MW 306.174 ~....
:. Found : MW 306.137 .~, NMR spectrum of the free base: ~ 2.2-4.2 (m, ll)i `~ 6.9-7.5 (m, 4); 7.8-8.3 (m, 3).
.::
. Other compounds within the scope of this invention which can be ~ade or described hereabove include compounds :..
of the general formula . - 47 _ .....
.
. .
:1077929 . .
,, '~'' -havlng a slngle sub~tltuent on one Or t~ebenzene rlngs such as the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12-acetyl derivatlves, the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12 t-butyl derlvatlves, the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12-c metho~y derlvatlve~, the 4-, 5-, 6-, 7-, 9-, 10-, 11-and 12-rluoro derlvatives, the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12-chloro derlvatlves, the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12-trlfluoromethyl derlvatlves, the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12-2,2,2-trirluoroethyl derlvatives, the : 4-, 5-, 6-, 7-, 9-, 10-, 11-, 12-methylthlo derlvatlves, the 4-, 5-, 6-, 7-, 9-, 10-, 11-, 12-trlfluoromethyl -sulfonyl derlvatives, the 4-, 5-, 6-, 7-, 9-, 10-, 11- and ~ 12-methyl sulronyl derlvatlves, the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12-carboxyl derivatlves, the 4-, 5-, 6- J 7-, 9-, 10-, 11- and 12-methoxycarbonyl derlvatlves, the 4-, 5-, 6-, 7-, 9-, 10-, 11-, and 12-ethoxycarbonyl derlvatives, the 4-, 5-, `~ 6-, 7-, 9-, 10-, 11- and 12-carbamoyl derlvatlves, the 4-, 5-, . .
6-, 7 , 9-, 10-, 11- and 12 sul~amyl derivatlves, the 4-, 5-, 6-, 7-, 9-, 10-, 11-, and 12-N-methyl sulfamyl derlvatlves, the 4-, 5-, 6-, 7-, 9-, 10-, 11-, and 12-N,N-dlmethylsulfamyl .j derlvatlves, the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12-methyl -:; 3 ~ulronyl derlvatlves, the 4-, 5-, 6-, 7-, 9-, 10-, 11-, and .~ . .
:. ' ... . .
' - .
.
:1077~Z~
12-hydrazino carbonyl derlvatiYe~, the 4-, 5-, 6-, 7-, 9-, lO-, 11- and 12-hydroxylamlnocarbonyl derivatlves, the 4-, 5-, 6-,
metnod I; hydro~r.'o~id~: -il3 . 242-24.~ (dec.):
A~al . C~lcd for '28. 32Cl.~: C, 79.20; H, 8.19; M, ~5.56 ~ound: C, 79.83; H, 8.33; N, 3.51.
. . ~
Exar!lple 25: 2~yclohQxyl~thyl-2,3,8,12b-tetrahydro-lH-3a,8-methanodibenzo[3,~:6,7~cyclohep.a~1,2-c~pyrrole; method I, III. Hydrochlori de: mp 248-253 (dec.):
Anal. Calcd. for C25x30Cl~: C, 79-02; H, 7-96; N~ 3-69-Found: C, 78.69; H, 7.91; N, 3.79.
ExamPle 26: 2-(l~yclohexenylm~thyl)-2,3,8,12b-tetrahydro-lH~3a,8-me-hanod~benzo~,4:6,7~cyclohepta[1,2-c~pyrrole;
method I; nmr spectrum: ~ 2.7-3.2 (mJ 8); 4.0 ( m, 1~ and 5.5-8.6 ( m, 18).
Exam~le 27: 2-(~yclohexenylmethyl)-2,3,8,12b-tetrahydro-lH-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c~pyrrol~;
method I; nmr spectr~m: ~ 2.6-3.1 (m, 8~; 4.~i (m, 2) and 6.o-s.o (m, 17)-~ : 2-(1,~-C yclohexadienylmethyl)-2,3,8,12h-- tetrahydro-lH-3a,8-methanodibenzo[3,4:6,7]cyclohep-a[1 2-c]pyrrole;
me~hod I; nmr s~ectru:n: T 2.6-3.1 (m, 8); 4.1-4.5 (m, 3) and 6.0-7.8 (m, 14)-Exam~le 29: 2-(2~yclohexylethyl)-2,3,8,12h-tetr2hydro-lH-3a,8-methanodibenzo[3,4:6,7]Cycloh~pta~1,2-c]pyrrole; ~ethod I;
hydrochloride: mp. 234-2~8 (dec.);
30Anal. Calcd. for C2eH32ClN: C, 79.26; H, 8.18; N, 3.56 Found: C, 78.77; X, 8.26; ~r, 3.40.
; ' ~0779Z9 Exam~le 30: 2-(3~ yclohexylpropyl)-2,3,8,12b-tetr2hydro~
lX-3a,~-methanodibenzo~3,4:6,7]cyclohepta~1,2-c~pyrrole; method I;
n~r Eipectrum: T 2.5-3.1 (m, 8) and 6.0-9.5 (m, 2~).
Exam~le ~1: 2-(4~ yclohexylbutyl)-2,3,8,12b-tetrahydro-1~-3a,8-metheno~;benzo~3,4:o,7].ycloh~ta[1,2 c]pyrrole; rethod I;
nmr spectrum: ~ 2.7-~.2 (~, 8~; and 6.1-9.7 (m, 27).
Exa~le 32: 2 ~ ycloheptylmethyl-2,3,8,120-t~trahydro-lH-3a,8-methanod;Den~o~3,4:6,73cyclo~2pta[1~2-c]pyrrole; method I;
hydrochloride: mp. 254-256 (dec.) Anal. Calcd for Cz9-~32ClM: C, 79.26; H, 8.19; ;i, ~.56 Found: C, 79.00; H, 7.86; N, 3.81.
, . , ; The nmr spectru~ oD the free base, obtæined æs an oil, showed bands at ~ 2.~-3.2 (m, 8) ~nd 6.0-9.2 (m, 23).
Exam~le ~3: 2-(~ yclohep~enylmethyl)-2,3,8,12h-~etra-i hydro-lH-3a,8-~th~odibenzo~3,4:6,7]cycloheptz~1 2-c]pyrrole;
method I; nmr spectrum: T 2.7-3.1 (m, 8); 4.0-4.5 (m, 2) and 6.0-9.~ (m, 19);
Exa~le ~: 2 ~ yclooc~ylmethyl-2,3,8,12b-tetrahydro-., ~ lH-~a,8-methanodibenzo[3,4:6,7]cyclohepta~1 2-c]pyrrole; method I;
~ . ..
n~r spectrum: T 2.7-3.3 (~, 8) and 6.1-9.2 (m, 25).
~xa~e 3~: 2-(2-Exo-bicyclo~2.2.1~hep~ylm~hyl)-2,3,8, ,. ~2b-tetrz.hydro-1U-~a~8-methanodibenzo~3~4 6~7]cyclohepta~1~2-c~-pyrrole; method I; nmr spectr~m: T 2.6-3.1 (m, 8) and 6.0-9.2 (m, 21)-; ~xam~le ~6: 2-(2 ~ ndo-bicyclo~2.2.1~heptylmethyl)-2,3,8,12b-te~rzh~dro-lH,3a,8-methanodibenzo~3,4:6,7~cyclohepta-- tl,2-c]pyrrole; method I; nmr spectrum: T 2.6-3.1 tm, 8) and ~ 6 . o - s .3 (m, 21)-i Exam~le ~7: 2-(2 ~ xo-bicyclo[2.2.1~hept-5-enylmethyl)-.. . .
30 2,3,8,12b-~etrzhydro-lH-3a,8-methanodibenzo~3,4:6,7]cyclohepta-tl,2-c]pyrrole; method I; nrr spectrum: T, 2.6-~,2 (m, 8);
3.8-~.1 (m, 2) and 6.o-8.9 (m, 17).
.:
, ~077925 EY~a~le ~8 2-(2~-ndo-bicyclo~2~2~l]hQp~-s-e 2,3,8,12h-tetra~dro-1~-3a,8-methanodibenzo[3,4:6,7]cyclohepta-tl,2-c~pyrrole; method Ii nmr s?ec~r~: ~ 2.6-3.3 ~m, 8); 3.8-".
(~, 2) and 6.1-9.6 (~, 17).
Exam~le 39: 2-(2-Phenylethyl)-2,3,8,12b-tetrahydro-lH-3a,8-methanodibenzo[3,~:6,7~cyclohepta~1,2-c]pyrrole; method I;
hydrochloride: mp 2~8-250 (dec.);
Anzl. Calcd. for C2~H2~Cl~ CJ 80.43; H~ 6.76; N~ 3.61.
Found: C, 80.71; ~, 6.82; N, 3.59.
The nmr spectrum of the ~ree base, obtained as an oil, ~howed bands at T 2.6-~.2 ~m, 8) and 6.0-7.9 (mJ 12).
Exam~le 40: 2-(2-Phenoxyethy1)-2,~,8,12b-tetrahydro-lH-3a,8-methanodibenzo[3,4:6,7~cyclohepta~1,2-c]pyrrole; methoa I;
nmr spectr~: T 2.6-3.3 (m, 13) and 5.7-8.3 (m, 12).
Exam~le 41: 2-(2-Methox~ethyl)-2,3,8,12b-tetrahydro- r' lH,3a,8-meth2nodibenzo[3,4:6J7]cyclohepta~1,2-C]pyrrole; method I, nmr spectrum: T 2.7-3.1 (m, 8) and 6.1-7.9 (m, 15).
xam~le h2: 2-(2-Furylmethyl)-2,3,ô,12b-tetr~hydro-lH-3a,8-methænodibenzo[3j4:6,7~cyclohepta[1,2-c~pyrro e; ~ethod I;
hmx spectrum: ~ 2.6-3.2 (m, 9); 3.6-3.9 (m, 2) and 6.o-8.o (m, 10) - ExamPle 43: 5- and 11-Chloro-2-methy1-2,3,8,12b-tetra-hydro~ a,8-methanodibenzo[3,4:6,7]cyclohepta~1,2-c~pyrrole;
method II~ nmLr spectrum: T 2.6-3.2 (~, 7) and 5.9-7.8 (m, 11) Exam~le h,4: 5- and 11-Chloro-2~cyclohexyl~ethyl-2,3,8,12b-tetrahydro-lH-3a,8-methanodibenz~[~5,4:6,7~cyclohepta-~1,2-c3pyrrole; meth~d II; nmr spectrum: T 2.5-3.~ (m, 7) and 6.o-s .~ (m,'21).
.
_ 42 -... .
Dle ~5 2-Cyclohe~lr~ethyl-2~3~8~12b-tetrahydro-lH-3a~8-methano-dlbenzo~ ,l~:6,7~cyclo~1eDtarl,2-c,7pyFrolc COCl ~ CH2C CH
~ O-N O
0 C~12 F~ NCH2r\~
, ~))C) ~
, . ' N
`; ~ ' ' ' .
~ CK~ O
A solution of 12.66 g of 9-anthroyl chloride i~
~ ml of tetrahydrofurzn is added dropwise to a stirred `~ mixture of 8.~9 g of N-propargylcyclohexylmethylamine a~d 9 ~ of magnesium oxide in 80 ml of tetrahydrofuran.
. After s~irrin~ at room temperature o~erni~ht, the mlxture is filtered and the filtrate is concentrated to d~yness.
The residue is taken ùp in methylene chloride and washed, . 30 .
. _ 43 _ .
''' ~779~9 in turn, with dilute sulfuric acid, water, and dilute sodiunl hydroxide solution, and dried. Removal of the solvent gives 14.7 9 of N-cyclohexylmethyl-N-propargyl-9-anthramide as an oil. It is dissolved in 100 ml of p-xylene and the mixture is heated under reflux for three hours. The solvent is removed, and the residue is heated under reflux with ~0 ml of tetrahydrofuran and 6~ ml of 15% aqueous sodium hydroxide solution for one hour. The mixture is concentrated to a small volume, diluted with water and filtered. The solid is washed with dilute alkali and water, dried, and crystallized from toluene to give 6.68 9 of 2-cyclohexylmethyl-3,5-dihydro-5,9b-, o-benzenobenz ~e~isoindol-1(2H)-one; nmr spectrum:
,....
2.3-3.4 (m, 9), 4.8 (d, J = 6Hz, 1) 5.9 (d, J = 2Hz, 2), 6.6 (d, J = 6.5 Hz, 2) and 8.0-9.2 (m, 11).
The above product (2.94 9) is treated with 1.41 9 of bromine in methylene chloride at room temperature.
The resulting crude 12b,13-dibromo-2-cyclohexyl-methyl-2,3,8,12b-tetrahydro-lH-3a,8-methanodibenzo ~3,4: 6,7 cyclohepta ~1,2-c~ pyrrol-l-one is heated under reflux with 9 9 of tributyltin hydride and 25 ml of anhydrous benzene for 3 days. The benzene is removed and the residue is concentrated further using short-path dis-tillation (1 micron, 125 bath temperature). Crystal-lization of the residue from isopropyl alchol gives 2.39 9 of 2-cyclohexylmethyl-2,3,8,12b-tetrahydro-lH-3a,C-methanodibenzo ~3,4: 6,7~ cyclohepta ~1,2-c,7pyrrol-1-one;
nmr spectrum: ~ 2.2-3.3 (m, 8); 5.9-6.2 (m,2); 6.6-7.0 (m, 4); 8.1 (m, 2) and 8.1-9.7 (m, 11).
:
, ~77929 The above product is he~ed under reflux with 70 ml 0~ dlborane in tetrah~drofuran overnight. The excess cliborane is destroyed.~Jith 15 ml of conc. hydrochloric acid; the mixture is concen~rated, and the residue is heated under reflux with 15 ml Or conc. hydrochloric acid and 20 ml of meth2nol for ~ days. Af~er removal of the methanol the residue is made basic and extr~cted . with methylene chloride. Removal of the solvent from - the dried e~tracts~ives 2.06 g Or 2~cycloheY.ylmethyl-3~8~ tetrahydro-lH_~a~-methanodibenzo/~4:b.~7-. cyclohepta[l,2-c]pyrrole as an oil. An ether solution c~ the product is treated with hydrogen chloride,and , the pre~ pitate is crystallized from 9~J e~hanol to give , 1.90 ~ ol the hydrochloride~ mp 218-220~-(dec).
Anal. Calcd for C2sH30ClN: C, 79,02; H, 7.96; N, 3.69.
. ,~ . .
Found: C, 78.62; H, 7.47; N, 3.66.
urther puri~lcat~on o~ the hydrochlorlde was achleved by drying it ~or several hours at about 110~ and 0.2 ~lcron ~ressure to ~ive the product Or Example 25, mp. 248-253 ~dec. ) .
ExamPle 46: 2-Cyclopropyl-2,3,8,12b-tetrahydro-lH-3a,-8-methanodlbenzo~3,4:6,7]cyclohepta~1,2-c]pyrrole; method II;
nmr spectrum: T 2.5-3.1 (m, 8); 6.o - 8.4 (m, 9) and 9.4-9.8 (m, 4).
ExamPle 47: 2-Cyclobuty1-2,3,8,12b-tetrahydro-lH-~ 3a,8-methanodlbenzot3,4:6,7]cyclohepta[1,2-c]pyrrole; method II;
;. nmr spectrum: T 2.7-3.2 (m, 8) and 6.1-8.5 (m, 15).
;. xamPle 48: 2-Cyclopentyl-2,3,8,12b-tetrahydro-IH- 3o 3a,8-methanodibenzot3,4:6,7]cyclohepta[1,2-c]pyrrole; method II;
nmr spectrum: T 2.6-3.2 (m, 8) and 6.1-8.8 ~m, 17).
. _ 4~ _ . .
: .
1~77929 ExamPle 49: 2-Isopropyl-2,3,8,12b-tetrahYdro-lH-3a>8-methanodibenzo[3~4:6~7]cyclohepta~l~2-c]pyrrole; method II;
nmr spectrum: T 2.7-3.2 (m, 8); 6.1-7.9 (m, 9); 8.8 (d, 6).
Exam~le 50: 2-(1-Cyclopentylethyl)-2,3,8,12b-tetra-hydro-lH-3a,8-methanodlbenzo[3,4:6,7]cycloheptatl,2-c]pyrrole;
method II; nmr spectrum: T 2.7-3.1 (m, 8) and 6.1-9.1 (m, 21).
Example 51: 2-(2-Methylcyclopentylmethyl)-2,3,8,12b-tetrahydro-lH-3a,8-methanodlbenzo[3,4:6,7]cyclohepta~1,2-c]--- pyrrole; method II; nmr ~pectrum: ~ 2.6-3.3 (m, 8) and 6.1-9.3 (m, 21). Thls compound is a mlxture of two lsomers ln whlch the methyl group attached to the cyclopentane ring ~8 cls and trans.
ExamPle 52: 2-(3-Methylcyclopentylmethyl)-2,3,8,12b-tetrahydro-lH-3a,~-methanodlbenzo[3,4:6,73cyclohepta[1,2-cJ-p~rrole; method II; nmr spectrum: T 2.6-3.3 (m, 8) and 6.0-9.5 (m, 21). Thls compound ls a mlxture o~ two lsomers ln whlch the methyl group attached to the cyclopentane rlng ls cis and trans.
ExamPle 53: 2-(2-Adamantylmethyl)-2,3,8,12b-tetra-hydro-lH-3a,8-methanod~benzot3,4:6,7]cyclohepta~1,2-c]pgrrole;
method I; nmr spectrum: ~ 2.6-3.0 (~ 8) and 6.o-8.5 (m, 25).
Example 54: 2-(2-Thienylmethyl)-2,3,8,12b-tetra-hydro-lH-3a,~-methanodlbenzo~3,4:6,7]cyclohepta~1,2 c3pyrrole;
method I; nmr spectrum: T 2.7-3.3 (m, 8) and 5.9-8.0 (m 10).
Exam~le 55: 2-(trans-2-Phenylcycloprop~lmethy])-2, 3,8,12b-tetrahydro-lH-3a,8-methanodibenzo[3,4:6,7~cyclohepta-tl,2-c]PYrrole; method I; nmr spectrum: r 2.7-3.2 (m, 13) and 6.0-9.3 (m, 14).
,`' ' i .. , ~077g~
.
Example 56: 2-Tertiarybutyl-2,3,8,12b-tetrahydro-lH-3a,8-methanodibenzo f3,4: 6,7~ cyclohepta ~1,2-c~ pyrrole, ' method II; nmr spectrum: ~ 2.6-3.0 (m, 8); 6.0-7.4 (m, 8);
~; 8.7 (s, 9).
Example 57:
:; Nitro-2-methyl-2,3,8,12b-tetrahydro-lH-3a,8-methanodibenzo-~3,4: 6,7_7cyclohepta ~1,2- ~ pyrrole HydrQ hloride ' To a solution of 1.5 9 (5.06 mmoles) of 2-methyl-2,3,8,12b-tetrahydro-lH-3a,8-methanodibenzo 3,4: 6,7 cyclo-- 10 hepta ~1,2-~ pyrrole hydrochloride in 25 ml of anhydrous hydrofluoric acid cooled at -78 was added 562 mg (5.06 mmoles) r~ of potassium nitrate. The reaction mixture was allowed to ~s,;~ warm to room temperature and the hydrofluoric acid was evaporated under a stream of nitrogen. The residue was si., dissolved in methylene chloride, and the solution washed with .i IN aqueous sodium hydroxide, with water, and dried over ~ , ,-` potassium carbonate. The solvent was removed under vacuum, ; the residue was dissolved in ether and insolubles were removed i:, by filtration. The ethereal filtrate was treated with dry ~0 hydrogen chloride to give 1.0 9 of nitro-2-methyl-2,3,8,12b-tetrahydro-lH-3a,8-methanodibenzo~3,4:6,7~cyclohepta~'1,2-c~
i:
pyrrole hydrochloride as a colorless solid, m.p. 202-207 ,',, ~; (slight decomp.).
". Mass spectrum:
Calcd. for ClgH18N2 2 MW 306.174 ~....
:. Found : MW 306.137 .~, NMR spectrum of the free base: ~ 2.2-4.2 (m, ll)i `~ 6.9-7.5 (m, 4); 7.8-8.3 (m, 3).
.::
. Other compounds within the scope of this invention which can be ~ade or described hereabove include compounds :..
of the general formula . - 47 _ .....
.
. .
:1077929 . .
,, '~'' -havlng a slngle sub~tltuent on one Or t~ebenzene rlngs such as the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12-acetyl derivatlves, the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12 t-butyl derlvatlves, the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12-c metho~y derlvatlve~, the 4-, 5-, 6-, 7-, 9-, 10-, 11-and 12-rluoro derlvatives, the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12-chloro derlvatlves, the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12-trlfluoromethyl derlvatlves, the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12-2,2,2-trirluoroethyl derlvatives, the : 4-, 5-, 6-, 7-, 9-, 10-, 11-, 12-methylthlo derlvatlves, the 4-, 5-, 6-, 7-, 9-, 10-, 11-, 12-trlfluoromethyl -sulfonyl derlvatives, the 4-, 5-, 6-, 7-, 9-, 10-, 11- and ~ 12-methyl sulronyl derlvatlves, the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12-carboxyl derivatlves, the 4-, 5-, 6- J 7-, 9-, 10-, 11- and 12-methoxycarbonyl derlvatlves, the 4-, 5-, 6-, 7-, 9-, 10-, 11-, and 12-ethoxycarbonyl derlvatives, the 4-, 5-, `~ 6-, 7-, 9-, 10-, 11- and 12-carbamoyl derlvatlves, the 4-, 5-, . .
6-, 7 , 9-, 10-, 11- and 12 sul~amyl derivatlves, the 4-, 5-, 6-, 7-, 9-, 10-, 11-, and 12-N-methyl sulfamyl derlvatlves, the 4-, 5-, 6-, 7-, 9-, 10-, 11-, and 12-N,N-dlmethylsulfamyl .j derlvatlves, the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12-methyl -:; 3 ~ulronyl derlvatlves, the 4-, 5-, 6-, 7-, 9-, 10-, 11-, and .~ . .
:. ' ... . .
' - .
.
:1077~Z~
12-hydrazino carbonyl derlvatiYe~, the 4-, 5-, 6-, 7-, 9-, lO-, 11- and 12-hydroxylamlnocarbonyl derivatlves, the 4-, 5-, 6-,
7-, 9-, 10-, 11- and 12-acetyl derivatlve~, the 4-, 5-, 6-, 7-, 9-, 10-, 11-, and 12-propionyl derivat~es, the 4-, 5-, 6-, 7-, 9-, 10-, 11- and 12-cyclopentylcarbonyl derlvatives, and the 4-, 5-, 6-, 7-, 9-, lO-, 11- and 12-cyclohexylcarbonyl derlvatives.
Compounds of Structure I ~rherein R is not hydro~en, show activit~- in the mammalian central nervous system as cllnically userul tranquilizers. They can be employed in pharmaceutical compositions composed of the acti~e ingredient, l.e., the compound(s) of the invention, in combinntion ~Jith nontoxic pharmaceutical carriers and additives. In any fo~mulation of the pharmaceutically active agent, the acti~e in~redient will ordinarily be present in an amount from about O.5~ t, 95~ based on total weight of the composition.
Formulat~ons include in~ectables and oral dosage forms such as tablets, hard and soft gelatln cap-sules, suspen~lons, sy~ups, elixirs ~n~ the like.
Additives that çan be employed ln such formulations include solvents ~nd dlluç~ts, ~ub~ic~nts, bi~ding agents, disintegrants, Preservat~ves, eolorants, flavors and other additives whiçh are common ~nd well known to the art and which form no part of this inve~tion.
. The çompounds can be administered as tranquilizing . . . .. . . , _ ~ .. . ............ .
~ agents according t.o the int.~entio.n by any means that effects .
contact of the active ingredient compound with the site of actlon in the body of a warm-blooded animal. For example, administration can be parenterally, i.e., subcutaneously, . ' ~
.
intravenously, intramuscularly or intraperitoneally.
Alternatively or concurrently, administration can be by the oral route.
The dosage administered will be dependent upon the age, health and weight of the recipient, the type and severity of illness, kind of concurrent treatment, if any, frequency of treatment and the nature of the effect desired. Generally a daily dosage of active ingredient compound will be from about 0.01 to 200 milligrams per kilogram of body weight. Ordinarily, from 0.05 to 100 and preferably 0.1 to 50 milligrams per kilogram per day in one or more applications per day is effective to obtain the desired results. For the more potent compounds of the invention, e.g., trans-2-cyclopentylmethyl-2,3,~,12b-tetrahydro-lH-3a,8-methanodibenzo~3,4:6,7J cyclohepta~ ,2-pyrrole (Example 7), the daily dosage ranges are from about 0.01 to 100 mg/kg, preferably 0.05 to SO mg/kg, and more : ,;
preferably 0.1 to 25 mg/kg.
~` The pharmaceutical carrier can be a solid or a ~i~ sterile liquid such as water, or an oil, e.g., petroleum oil, ., ;~ animal oil, or vegtable oils such as peanut oil, soy-bean oil, mineral oil, sesame oil, and the llke. In . general, water, saline, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene `' glycol or polyethylene glycols are preferred liquid ;~ carriers, particularly ~or injectable solutions.
x~ Sterile injectable solutions such as saline will ordin-arily contain from about 0.5 to 25% and preferably about ~ 1 to 10% by weight of the active ingredient.
;~ 30 Liquid oral administration can be in a sus-.. . .
:'."
.
~ ~,7g29 penslon, syrup or elixir, in ~hlch ~he actlve ineredient ordinarily ~Jill constitute from about 0.5 to 10% and preferably about 1 to 5$ by ~eight. The pharmaceutical carrier in such composition can be an agueous vehicle ~uch as an aromatic ~rater, a syrup, a pharmaceutical mucllage, or a hydroalcoholic elixlr. Addltional in-formation concerning pharmaceutical carriers, diluents and additives can be found in the well-~nown reference text: ~lartln, "Remingtonls Pharmaceutical Sciences."
The following illustrate the preparation o~
pharmaceutical compositions of the in~ention.
EX~PLE A
A large number of unit capsules are prepared by f lling standard two-piece hard gelatin capsules each ;withr50 mg of po~dered active ingredient; 300 mg of lactose, 32 mg Or talc and 8 mg of magnesium stearate.
EXA~IPLE B
A mixture of the act~ve ingredient in soybean ` 20 oll is prepared and in~ected by means of a positive dis-placement pump into gelatin to form so~t gelatin capsules containing 35 mg of the active ingredient. The capsules are washed in petroleum ether and dried.
: EXAMPLE ~
A large number of tablets are prepared by con-: ~entional procedures so that the dosage unit is 300 mg of active ingredient, 7 mg of ethyl cellulose, 0.2 mg of colloidal silicon dioxide, 7 mg of magnesium stearate, 11 mg of microcrystalline cellulose, 11 mg of cornstarch and 98.8 e o~ lactose. Appropriate coatin~s may be applied to lncrease palatability or delay absorptlon.
10779~9 EXA~PLE D
A parenteral composition sultable for admin- -lstration by ln~ection is prepared by stlrring 1.5% by wei~ht o~ the active ingredient in 10% by volume propylene glycol and water. The solution is sterillzed by ~iltra- -tion.
EXA~P~E E
.
An aqueous suspension is prepared ~or oral administration so that each 5 ml contains 50 mg of finely divided active ingrçdie~t, 500 r~ of acacia, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., 5 mg o~ sodium saccharin and 0.025 ml of vanilla tincture.
EXAMPLE F
A parenteral compositlon suitable for admin-istration by in~ection is prepared by d,ssolving 1~ by weight of the active lngredient as the maleate salt ln ~odlum chloride inJection U.S.P. and adJ~st~ng the pH
of the solution to between 6 and 7. The solution is ; sterilized by ~lltration.
,........................ The gener~l tra~quili~er a~tivi~y Or the compounds . ls evidenced by tests conducted in remale white mice in ~; which exploratory loss, ptosls, grip and li~t reflexes, ; catatonia, muscle tone, and plnna twitch reflex were measured. Tests conducted with mice are predictive of hurnan tranqulllzer response.
Groups o~ five Carworth CFlS fer~ale rnice, 16-20 g each, were fa~ted 16-22 hours before use. The rnice were put in opaque plastic "shoe-bo~" cages 15-30 min.
before in~ection, and then treated orally with 4, 12, .
' - , .
- ` 10779Z9 36, 108 and 324 mg/kg of the compound to be tested as a 13 mg~ml solution in 1% aqueous distilled ~later solution of methylcellulose (Methocel~). Each dose was gi~en in a standard ~olume Or 0.45 ml. Observat~ons were m~de at O. ~, 2 and 24 hours after dosing. ~D50 values were calculated ~orelch parameter includin~ death (LD50).
The EDso al~d LDso values are the doses at which 50% of the animals ~ould be expected to re~pond.
Exploratory Act~vity - The mouse 1~ placed on a stalnless steel wire mesh screen (8" x 12", ~ mesh per lnch, 1/4" mesh openings) "shoe-box" lid (1" high) and ls observed for normal activities, such as nose movements, head movements with apparent visual examina-tlon of the Qrea, and/or walklng around on the screen.
Ab~ence of or mar~ed depression o~ these activities ror 5 seconds constitutes loss of exploratory activity.
~ osis - The mouse is picked up by the tail
Compounds of Structure I ~rherein R is not hydro~en, show activit~- in the mammalian central nervous system as cllnically userul tranquilizers. They can be employed in pharmaceutical compositions composed of the acti~e ingredient, l.e., the compound(s) of the invention, in combinntion ~Jith nontoxic pharmaceutical carriers and additives. In any fo~mulation of the pharmaceutically active agent, the acti~e in~redient will ordinarily be present in an amount from about O.5~ t, 95~ based on total weight of the composition.
Formulat~ons include in~ectables and oral dosage forms such as tablets, hard and soft gelatln cap-sules, suspen~lons, sy~ups, elixirs ~n~ the like.
Additives that çan be employed ln such formulations include solvents ~nd dlluç~ts, ~ub~ic~nts, bi~ding agents, disintegrants, Preservat~ves, eolorants, flavors and other additives whiçh are common ~nd well known to the art and which form no part of this inve~tion.
. The çompounds can be administered as tranquilizing . . . .. . . , _ ~ .. . ............ .
~ agents according t.o the int.~entio.n by any means that effects .
contact of the active ingredient compound with the site of actlon in the body of a warm-blooded animal. For example, administration can be parenterally, i.e., subcutaneously, . ' ~
.
intravenously, intramuscularly or intraperitoneally.
Alternatively or concurrently, administration can be by the oral route.
The dosage administered will be dependent upon the age, health and weight of the recipient, the type and severity of illness, kind of concurrent treatment, if any, frequency of treatment and the nature of the effect desired. Generally a daily dosage of active ingredient compound will be from about 0.01 to 200 milligrams per kilogram of body weight. Ordinarily, from 0.05 to 100 and preferably 0.1 to 50 milligrams per kilogram per day in one or more applications per day is effective to obtain the desired results. For the more potent compounds of the invention, e.g., trans-2-cyclopentylmethyl-2,3,~,12b-tetrahydro-lH-3a,8-methanodibenzo~3,4:6,7J cyclohepta~ ,2-pyrrole (Example 7), the daily dosage ranges are from about 0.01 to 100 mg/kg, preferably 0.05 to SO mg/kg, and more : ,;
preferably 0.1 to 25 mg/kg.
~` The pharmaceutical carrier can be a solid or a ~i~ sterile liquid such as water, or an oil, e.g., petroleum oil, ., ;~ animal oil, or vegtable oils such as peanut oil, soy-bean oil, mineral oil, sesame oil, and the llke. In . general, water, saline, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene `' glycol or polyethylene glycols are preferred liquid ;~ carriers, particularly ~or injectable solutions.
x~ Sterile injectable solutions such as saline will ordin-arily contain from about 0.5 to 25% and preferably about ~ 1 to 10% by weight of the active ingredient.
;~ 30 Liquid oral administration can be in a sus-.. . .
:'."
.
~ ~,7g29 penslon, syrup or elixir, in ~hlch ~he actlve ineredient ordinarily ~Jill constitute from about 0.5 to 10% and preferably about 1 to 5$ by ~eight. The pharmaceutical carrier in such composition can be an agueous vehicle ~uch as an aromatic ~rater, a syrup, a pharmaceutical mucllage, or a hydroalcoholic elixlr. Addltional in-formation concerning pharmaceutical carriers, diluents and additives can be found in the well-~nown reference text: ~lartln, "Remingtonls Pharmaceutical Sciences."
The following illustrate the preparation o~
pharmaceutical compositions of the in~ention.
EX~PLE A
A large number of unit capsules are prepared by f lling standard two-piece hard gelatin capsules each ;withr50 mg of po~dered active ingredient; 300 mg of lactose, 32 mg Or talc and 8 mg of magnesium stearate.
EXA~IPLE B
A mixture of the act~ve ingredient in soybean ` 20 oll is prepared and in~ected by means of a positive dis-placement pump into gelatin to form so~t gelatin capsules containing 35 mg of the active ingredient. The capsules are washed in petroleum ether and dried.
: EXAMPLE ~
A large number of tablets are prepared by con-: ~entional procedures so that the dosage unit is 300 mg of active ingredient, 7 mg of ethyl cellulose, 0.2 mg of colloidal silicon dioxide, 7 mg of magnesium stearate, 11 mg of microcrystalline cellulose, 11 mg of cornstarch and 98.8 e o~ lactose. Appropriate coatin~s may be applied to lncrease palatability or delay absorptlon.
10779~9 EXA~PLE D
A parenteral composition sultable for admin- -lstration by ln~ection is prepared by stlrring 1.5% by wei~ht o~ the active ingredient in 10% by volume propylene glycol and water. The solution is sterillzed by ~iltra- -tion.
EXA~P~E E
.
An aqueous suspension is prepared ~or oral administration so that each 5 ml contains 50 mg of finely divided active ingrçdie~t, 500 r~ of acacia, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., 5 mg o~ sodium saccharin and 0.025 ml of vanilla tincture.
EXAMPLE F
A parenteral compositlon suitable for admin-istration by in~ection is prepared by d,ssolving 1~ by weight of the active lngredient as the maleate salt ln ~odlum chloride inJection U.S.P. and adJ~st~ng the pH
of the solution to between 6 and 7. The solution is ; sterilized by ~lltration.
,........................ The gener~l tra~quili~er a~tivi~y Or the compounds . ls evidenced by tests conducted in remale white mice in ~; which exploratory loss, ptosls, grip and li~t reflexes, ; catatonia, muscle tone, and plnna twitch reflex were measured. Tests conducted with mice are predictive of hurnan tranqulllzer response.
Groups o~ five Carworth CFlS fer~ale rnice, 16-20 g each, were fa~ted 16-22 hours before use. The rnice were put in opaque plastic "shoe-bo~" cages 15-30 min.
before in~ection, and then treated orally with 4, 12, .
' - , .
- ` 10779Z9 36, 108 and 324 mg/kg of the compound to be tested as a 13 mg~ml solution in 1% aqueous distilled ~later solution of methylcellulose (Methocel~). Each dose was gi~en in a standard ~olume Or 0.45 ml. Observat~ons were m~de at O. ~, 2 and 24 hours after dosing. ~D50 values were calculated ~orelch parameter includin~ death (LD50).
The EDso al~d LDso values are the doses at which 50% of the animals ~ould be expected to re~pond.
Exploratory Act~vity - The mouse 1~ placed on a stalnless steel wire mesh screen (8" x 12", ~ mesh per lnch, 1/4" mesh openings) "shoe-box" lid (1" high) and ls observed for normal activities, such as nose movements, head movements with apparent visual examina-tlon of the Qrea, and/or walklng around on the screen.
Ab~ence of or mar~ed depression o~ these activities ror 5 seconds constitutes loss of exploratory activity.
~ osis - The mouse is picked up by the tail
8!, and placed on the screen with lts head ~acing the observer.
Bilateral eyel~d closure of 50~ or more two seconds after ` placement is consldered ptosis.
Catatonla - m e mouse is placed wlth lts ~ront - paws on the edge o~ a stainless steel "shoe-box" cover, 1" high, covered with adhesive tape. Fa lure to remove both paws ~rom the cover's edge wlthin 5 seconds consti-tutes catatonia.
Muscle Tone - The observer gently strokes the abdominal musculature of the mouse with thumb and fore-~inger. Flaccldity (or rarely, tenseness) is recorded.
Grip and Lift Reflexes - The mouse is gently swuna by the tail toward a horizontal 12 gauge wlre .;
iQ779Z9 tautly stretched 25 cm abo~e the bench, After the mouse grasps the wire ~l~th lts forepa~Js, lts posterior end is held directly below the wire, A normal mouse grasps the ~ire with its forepaws and immed~ately lifts its hind limbs to the ~ire, Failure to grasp the wire with the forepa~ls in both trials constitutes loss of the grip reflex; failure to lift the hind limbs to grasp the wire with at least ~ne hind paw ~lithin 5 seconds consti-tutes loss of the lift reflex~
1~ The ratio of grip to lift response is signif-lcant since the loss of lift reflex is much more pro-nounced in most compounds exhibiting tranquilizing activity.
- Pinna Twitch Re~lex - The mouse is placed on .
the bar 10-20 cm hor~zontally and 9 cm vertically from a Galton lhistle ad~usted for 13 kc (5 mm on the wh~stle - -scale) and is sub~ected to several short bursts of sound.
I~ the mouse does not t~tch its ears or flatten them against its head the pinna rerlex is lost.
An ef~ective tranquilizer should induce little or no tremor response. Most of the compounds, as shown ln Table I, induce little tremor response in the tested mice Tremors include fine or coarse and intermittent or con-tinuous ~remors.
Mou_e Spontaneous IIotor Act~v.lt:r (Activity Caec) ~enty-four per dose, 16-20 g or 18-22 g, ~emale CFlS mice, fasted 16-22 hours, are intubated (in pairs) with drug ~t doses such as 0, 1, 3, 9, 27 and 81 m~g in 10 ~/kg of aqueous 1~ methylcellulo~c.
m e m~ce are then put in separate "shoe-box" ca~es , 54 -..
' `'` 1~77~Zg (12 " x 7. 5 " x 5. 3 " pla~tic with a o, 33 n mesh ~talnles~ ~teel l~d), and 20 minutes a~ter intubatlon the anlmals in pair~
are moved to covered Woodard Photoelec~ric Activi~y chambers (central light 60urce type measurement ~loor areA = 96 in2).
Ten mlnutes later (30 mlnutes after dosing) a 5-minute count ls taken. Counting chamber characteristlcs are balanced out by counting 2 pairs of mice from each dose level in each of 6 different counting chamberæ. Half o~ each test is run ln the a.m. and the other half i8 run ln the p.m. to mlnlmize "biologlcal clock" varlatlons, - Since actl~lty counts do not distrlbute normally and thelr square roots do, Irwin, S.: Rev. Canacl. Biol. 20, 239-50 (1961), raw counts are thu~ tran~formed for stati~tical treatment (Student's t test). The means of the ~quare roots . ,, then are ~quared and an ED50 for ~timulation or depres~ion (or both) i9 determined graphically.
With the above-listed responses as criteria, the compounds of the invention exhlbit potent tranquilizing ..: .
activity as sho~n in Table I. The ED50 values, 1. e., the dose ,~ 20 which caused the re~pon~e ln 50% of the mice, are tabulated.
.~, ffl e re~ults obtained in the tests for two well known commercial ,:
tranqulllzers, Chlorpromazine and Dlazepam, are included for comparison.
Several compounds of the lnventlon, e~pccially those of Examples 7 and 25, exhiblt potent antl-anxiety or minor tranquilizer activlty in additlon to their m~or tranquillzer activity. Potentlal as antl-anxiety agents was as6e6~ed by means of the potency o~ the~e compounds in the rat approach-avoldance te~t~ Antl-anxiety agent~ ~uch as Diazepam are actlve in thls test, but maJor tranqullizers such QS Chlor-promazine are not actlve at non-~edating doses.
`~'''';
,.
:
`` 1077~
Approach-Avo~dance Test Method - 18 hr. water-deprlved Holzman male white rat~, 150-175 g each~ were used. The appara-tus conslsts o~ two int~rconnected chambers~ the ~irst in ~hich the animal i~ placed, and a second whlch cont~ins the stimulus ~nd ~ water bottle. The ~cond ls fitted with an electrifiable floor. On the ~lrst day, the rat~ are placed in the first chamber. They are allowed three mlnu~es to find the water bottle in the second chamber and to drink water ~or at least two seconds. After three successrul trial~ on the rirst day - 1~ the anlmals are given one predrug trial on the second day~
Then follows a second predrug trlal durtng ~hlch the ~loor o~
the second chamber i~ electrifled 1.5 ~econds a~ter the rat has commenced drinking water~ m e animals are randomized, dosed orally, and reexposed to the test sltuation at 1, 2, or 4 hours after the 3hock tr~al. Solvent-treated rat~ usually do not reenter the second chamber after the shock trial.
The results of thls te~t are summarized ln Table II.
The ED50 values, i.e., the dose which caused the respon~e in 50~ of the rats are tabulated. The re~ult~ obtained in the ; 20 test of a well known commercial tranquillz~r, Diazep~m, are lncluded ~or comparison.
Compounds of the Structure I ~herein R is not hydro~en, show acti~lty in the mammallan central nervou~ system as useful analge~lcs. The analge~ic actlvlty of these compounds was evidenced by tesks conducted in female whlte mlce in which preventlon of the well-known writhing re~ponse caused by intraperltoneal in~ec-tion o~ phenyl-p-benzoquinone (phenylquinone) ~as demonstrated.
mi8 mou~e test i3 predlcti~e o~ analgesic re~ponse in humRns.
~. Slegmund, R. Cadmus and G. Lee, Proc. Soc. Exp. Blol. Med., ` ~, 729 (1957 ~.
'' - 5~ -10779~9 Group~ of flve Carworth CFlS female mlce, 18-21 g each, were fa~ted 17-21 hour~ and were intubated with analgeslc compound a~ antagonist to phenylquinone at oral doses of 8, 40 and 200 or of 0,33, 1, 3, 9, 27 and 81 mg/kg in 0.20 ml 1~
methylcellulose (Methocel~). Thlrty minutes later the mice werle challenged with phenylquinone, 1.1 ~g/kg intraperitoneally (dis~olved ln pure ethanol and diluted to 5% ethanol with dis-tilled water at 40C). At 37 minutes to 47 minute~ after the analge3ic compound, the mice were ob~erved for appearance of the wrlthing ~yndrome. The number of mice whlch did not writhe at all during th~ 10 mlnute~ observatloh wa3 recorded as a quantal lndex of analgesla. ED50 values were obtained gr~ph-lcally from the data.
Wlth blockade o~ phenylqulnono-lnduced writhing the criterlon, many Or the compounds o~ the invention are analgesic. The ED50 value~, i.e., the dose~ which blocked phenylquinone-induced wrlthing ln 50% of the mice, are al80 tabulated ln Table I.
:
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Bilateral eyel~d closure of 50~ or more two seconds after ` placement is consldered ptosis.
Catatonla - m e mouse is placed wlth lts ~ront - paws on the edge o~ a stainless steel "shoe-box" cover, 1" high, covered with adhesive tape. Fa lure to remove both paws ~rom the cover's edge wlthin 5 seconds consti-tutes catatonia.
Muscle Tone - The observer gently strokes the abdominal musculature of the mouse with thumb and fore-~inger. Flaccldity (or rarely, tenseness) is recorded.
Grip and Lift Reflexes - The mouse is gently swuna by the tail toward a horizontal 12 gauge wlre .;
iQ779Z9 tautly stretched 25 cm abo~e the bench, After the mouse grasps the wire ~l~th lts forepa~Js, lts posterior end is held directly below the wire, A normal mouse grasps the ~ire with its forepaws and immed~ately lifts its hind limbs to the ~ire, Failure to grasp the wire with the forepa~ls in both trials constitutes loss of the grip reflex; failure to lift the hind limbs to grasp the wire with at least ~ne hind paw ~lithin 5 seconds consti-tutes loss of the lift reflex~
1~ The ratio of grip to lift response is signif-lcant since the loss of lift reflex is much more pro-nounced in most compounds exhibiting tranquilizing activity.
- Pinna Twitch Re~lex - The mouse is placed on .
the bar 10-20 cm hor~zontally and 9 cm vertically from a Galton lhistle ad~usted for 13 kc (5 mm on the wh~stle - -scale) and is sub~ected to several short bursts of sound.
I~ the mouse does not t~tch its ears or flatten them against its head the pinna rerlex is lost.
An ef~ective tranquilizer should induce little or no tremor response. Most of the compounds, as shown ln Table I, induce little tremor response in the tested mice Tremors include fine or coarse and intermittent or con-tinuous ~remors.
Mou_e Spontaneous IIotor Act~v.lt:r (Activity Caec) ~enty-four per dose, 16-20 g or 18-22 g, ~emale CFlS mice, fasted 16-22 hours, are intubated (in pairs) with drug ~t doses such as 0, 1, 3, 9, 27 and 81 m~g in 10 ~/kg of aqueous 1~ methylcellulo~c.
m e m~ce are then put in separate "shoe-box" ca~es , 54 -..
' `'` 1~77~Zg (12 " x 7. 5 " x 5. 3 " pla~tic with a o, 33 n mesh ~talnles~ ~teel l~d), and 20 minutes a~ter intubatlon the anlmals in pair~
are moved to covered Woodard Photoelec~ric Activi~y chambers (central light 60urce type measurement ~loor areA = 96 in2).
Ten mlnutes later (30 mlnutes after dosing) a 5-minute count ls taken. Counting chamber characteristlcs are balanced out by counting 2 pairs of mice from each dose level in each of 6 different counting chamberæ. Half o~ each test is run ln the a.m. and the other half i8 run ln the p.m. to mlnlmize "biologlcal clock" varlatlons, - Since actl~lty counts do not distrlbute normally and thelr square roots do, Irwin, S.: Rev. Canacl. Biol. 20, 239-50 (1961), raw counts are thu~ tran~formed for stati~tical treatment (Student's t test). The means of the ~quare roots . ,, then are ~quared and an ED50 for ~timulation or depres~ion (or both) i9 determined graphically.
With the above-listed responses as criteria, the compounds of the invention exhlbit potent tranquilizing ..: .
activity as sho~n in Table I. The ED50 values, 1. e., the dose ,~ 20 which caused the re~pon~e ln 50% of the mice, are tabulated.
.~, ffl e re~ults obtained in the tests for two well known commercial ,:
tranqulllzers, Chlorpromazine and Dlazepam, are included for comparison.
Several compounds of the lnventlon, e~pccially those of Examples 7 and 25, exhiblt potent antl-anxiety or minor tranquilizer activlty in additlon to their m~or tranquillzer activity. Potentlal as antl-anxiety agents was as6e6~ed by means of the potency o~ the~e compounds in the rat approach-avoldance te~t~ Antl-anxiety agent~ ~uch as Diazepam are actlve in thls test, but maJor tranqullizers such QS Chlor-promazine are not actlve at non-~edating doses.
`~'''';
,.
:
`` 1077~
Approach-Avo~dance Test Method - 18 hr. water-deprlved Holzman male white rat~, 150-175 g each~ were used. The appara-tus conslsts o~ two int~rconnected chambers~ the ~irst in ~hich the animal i~ placed, and a second whlch cont~ins the stimulus ~nd ~ water bottle. The ~cond ls fitted with an electrifiable floor. On the ~lrst day, the rat~ are placed in the first chamber. They are allowed three mlnu~es to find the water bottle in the second chamber and to drink water ~or at least two seconds. After three successrul trial~ on the rirst day - 1~ the anlmals are given one predrug trial on the second day~
Then follows a second predrug trlal durtng ~hlch the ~loor o~
the second chamber i~ electrifled 1.5 ~econds a~ter the rat has commenced drinking water~ m e animals are randomized, dosed orally, and reexposed to the test sltuation at 1, 2, or 4 hours after the 3hock tr~al. Solvent-treated rat~ usually do not reenter the second chamber after the shock trial.
The results of thls te~t are summarized ln Table II.
The ED50 values, i.e., the dose which caused the respon~e in 50~ of the rats are tabulated. The re~ult~ obtained in the ; 20 test of a well known commercial tranquillz~r, Diazep~m, are lncluded ~or comparison.
Compounds of the Structure I ~herein R is not hydro~en, show acti~lty in the mammallan central nervou~ system as useful analge~lcs. The analge~ic actlvlty of these compounds was evidenced by tesks conducted in female whlte mlce in which preventlon of the well-known writhing re~ponse caused by intraperltoneal in~ec-tion o~ phenyl-p-benzoquinone (phenylquinone) ~as demonstrated.
mi8 mou~e test i3 predlcti~e o~ analgesic re~ponse in humRns.
~. Slegmund, R. Cadmus and G. Lee, Proc. Soc. Exp. Blol. Med., ` ~, 729 (1957 ~.
'' - 5~ -10779~9 Group~ of flve Carworth CFlS female mlce, 18-21 g each, were fa~ted 17-21 hour~ and were intubated with analgeslc compound a~ antagonist to phenylquinone at oral doses of 8, 40 and 200 or of 0,33, 1, 3, 9, 27 and 81 mg/kg in 0.20 ml 1~
methylcellulose (Methocel~). Thlrty minutes later the mice werle challenged with phenylquinone, 1.1 ~g/kg intraperitoneally (dis~olved ln pure ethanol and diluted to 5% ethanol with dis-tilled water at 40C). At 37 minutes to 47 minute~ after the analge3ic compound, the mice were ob~erved for appearance of the wrlthing ~yndrome. The number of mice whlch did not writhe at all during th~ 10 mlnute~ observatloh wa3 recorded as a quantal lndex of analgesla. ED50 values were obtained gr~ph-lcally from the data.
Wlth blockade o~ phenylqulnono-lnduced writhing the criterlon, many Or the compounds o~ the invention are analgesic. The ED50 value~, i.e., the dose~ which blocked phenylquinone-induced wrlthing ln 50% of the mice, are al80 tabulated ln Table I.
:
'.' _~
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': ~ ~ Q~ ~ ~ 0 td ~. O E~ ~ ~ 0 E~ S h : :- rl I 1:) Ei I O
~rl ~a~ I
,' ~ ~ ^o :~, ^o O
o C ~
.. ~: a~ ~ o a~ ~ o P- I ~ S I ~I ~
'' OP::~ o:r:~ P
; o 1~ 0 ~
': P, O ~ :>. O - Z
~t o ~,=r ._~, N p~ ~ N ~ d td ;' I ~J I
o m ~d O
~: h N ~ h N N
h ~ 0 ~-' ' . :
. .
Claims (62)
1. A process for preparing compounds of the formula:
wherein R1, R2 are H, chlorine or nitro, and where R is H, alkyl of up to 10 carbon atoms, alkenyl of 3-7 carbon atoms attached to N by a saturated carbon atom, cycloalkyl of 3-5 carbon atoms, propargyl, 2-furylmethyl, 2-thienylmethyl, -(CH2)qOR3, -(CH2)3CO2 (lower alkyl) and -CH(R4)(CH2)pR5 of up to 14 carbons, where q is 2-6;
p is 0-5;
R3 is lower alkyl, phenyl or lower alkylphenyl;
R4 is H or n-lower alkyl;
R5 is a hydrocarbyl group containing at least one ring of 3-9 carbon atoms attached to alkylene by a ring carbon atom, with the proviso that when p is O, the carbon atom attached to -CH(R4)- is not a quaternary carbon atom; and, when R is lower alkyl or cycloalkylmethyl of 5-10 carbon atoms, the nitrogen atom can be additionally substi-tuted with oxygen to form a tertiary amine oxide, said compounds being prepared by a process selected from the group consisting of (A) contacting a compound of the formula:
where R, R1 and R2 are as defined above, with diborane dissolved in an ether solvent at a temperature of 0-100°C, (B) contacting a compound of the formula:
where R, R1 and R2 are defined above, with a reducing agent at a temperature of 0-60°C, said reducing agent being selected from the group consisting of (a) sodium cyanoborohydride and (b) hydrogen in the presence of a catalyst selected from the group consisting of palladium, platinum and rhodium.
wherein R1, R2 are H, chlorine or nitro, and where R is H, alkyl of up to 10 carbon atoms, alkenyl of 3-7 carbon atoms attached to N by a saturated carbon atom, cycloalkyl of 3-5 carbon atoms, propargyl, 2-furylmethyl, 2-thienylmethyl, -(CH2)qOR3, -(CH2)3CO2 (lower alkyl) and -CH(R4)(CH2)pR5 of up to 14 carbons, where q is 2-6;
p is 0-5;
R3 is lower alkyl, phenyl or lower alkylphenyl;
R4 is H or n-lower alkyl;
R5 is a hydrocarbyl group containing at least one ring of 3-9 carbon atoms attached to alkylene by a ring carbon atom, with the proviso that when p is O, the carbon atom attached to -CH(R4)- is not a quaternary carbon atom; and, when R is lower alkyl or cycloalkylmethyl of 5-10 carbon atoms, the nitrogen atom can be additionally substi-tuted with oxygen to form a tertiary amine oxide, said compounds being prepared by a process selected from the group consisting of (A) contacting a compound of the formula:
where R, R1 and R2 are as defined above, with diborane dissolved in an ether solvent at a temperature of 0-100°C, (B) contacting a compound of the formula:
where R, R1 and R2 are defined above, with a reducing agent at a temperature of 0-60°C, said reducing agent being selected from the group consisting of (a) sodium cyanoborohydride and (b) hydrogen in the presence of a catalyst selected from the group consisting of palladium, platinum and rhodium.
2. The process of claim 1 wherein R1 and R2 are each hydrogen.
3. The process of claim 2 wherein R is alkyl of 1-10 carbons, .alpha.-furylmethyl -(CH2)q-0-(lower alkyl), -(CH2)q-0-phenyl, or -CH(R4)(CH2)pR5;
q is 2-6;
p is 0-3;
R4 is H or CH3;
R5 is cycloalkyl of 3 to 8 carbon atoms;
cycloalkenyl of 3 to 8 carbon atoms;
methylenecycloalkyl of 4 to 9 carbon atoms;
polycycloalkyl of 7 to 9 carbon atoms or polycycloalkenyl of 7 to 9 carbon atoms and phenyl.
q is 2-6;
p is 0-3;
R4 is H or CH3;
R5 is cycloalkyl of 3 to 8 carbon atoms;
cycloalkenyl of 3 to 8 carbon atoms;
methylenecycloalkyl of 4 to 9 carbon atoms;
polycycloalkyl of 7 to 9 carbon atoms or polycycloalkenyl of 7 to 9 carbon atoms and phenyl.
4. The process of claim 3 wherein R is n-alkyl of 2-8 carbon atoms.
5. The process of claim 4 whereln R is n-butyl.
6. The process of claim 4 wherein R is n-hexyl.
7. The process of claim 4 wherein R is n-heptyl.
8. The process of claim 4 wherein R is n-octyl.
9. The process of claim 3 wherein R is -CH(R4)(CH2)pR5, R4 is H or methyl and R5 is cycloalkyl of 3-8 carbons;
cycloalkenyl of 3-8 carbons;
methylenecycloalkyl of 4-9 carbons;
polycycloalkyl of 7-9 carbons;
polycycloalkenyl of 7-9 carbons; or phenyl.
cycloalkenyl of 3-8 carbons;
methylenecycloalkyl of 4-9 carbons;
polycycloalkyl of 7-9 carbons;
polycycloalkenyl of 7-9 carbons; or phenyl.
10. The process of claim 9 wherein R is cycloalkylmethyl of 5-10 carbon atoms.
11. The process of claim 10 wherein R is cyclopentylmethyl.
12. The process of claim 10 wherein R is cyclohexylmethyl.
13. The process of claim 10 wherein R is cycloheptylmethyl.
14. The process of claim 9 wherein R is benzyl.
15. The process of clalm 9 wherein R is cycloalkenylmethyl of 5-8 carbon atoms.
16. The process of claim 15 wherein R is 1-cyclopentenylmethyl.
17. The process of claim 15 wherein R is 3-cyclohexenylmethyl.
18. The process of claim 9 wherein R is 2-exo-bi-cyclo[2.2.1] heptylmethyl.
19. The process of claim 9 wherein R is 2-exo-bi-cyclo[2.2.1] hept-5-enylmethyl.
20. The process of claim 9 wherein R is 3-methylenecyclobutylmethyl.
21. The process of claim 3 for the preparation of (-) trans-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8 methanodibenzo[3,4:6,7] cyclohepta[1,2-c]pyrrole, a compound of the formula of claim 3 in which R is cyclopentylmethyl.
22. The process of claim 3 followed by the step of converting the compound to a pharmaceutically acceptable addition salt thereof.
23. The process of claim 22 wherein the salt is the hydrochloride.
24. The process of claim 23 wherein R is cyclopentylmethyl.
25. The process of claim 23 wherein R is cyclohexylmethyl.
26. The process of claim 1 which is prccess (A).
27. The process of claim 1 which is process (B).
28. The process of claim 27 wherein R1 and R2 are each hydrogen and R is alkenyl of 3-7 carbons attached to N
by a saturated carbon atom.
by a saturated carbon atom.
29. The process of claim 28 wherein R is allyl.
30. The process of claim 28 followed by the step of converting the compound to a pharmaceutically acceptable addition salt thereof.
31. The process of claim 30 wherein the salt is the hydrochloride.
32. A compound of the formula:
wherein R1, R2 are H, chlorine or nitro, and where R is H, alkyl of up to 10 carbon atoms, alkenyl of 3-7 carbon atoms attached to N by a saturated carbon atom, cycloalkyl of 3-5 carbon atoms, propargyl, 2-furylmethyl, 2-thienylmethyl, -(CH2)qOR3, -(CH2)3CO2 (lower alkyl) and -CH(R4)(CH2)pR5 of up to 14 carbons, where q is 2-6;
p is 0-5;
R3 is lower alkyl, phenyl or lower alkylphenyl;
R4 is H or n-lower alkyl;
R5 is a hydrocarbyl group containing at least one ring of 3-9 carbon atoms attached to alkylene by a ring carbon atom, with the proviso that when p is O, the carbon atom attached to -CH(R4)- is not a quaternary carbon atom; and, when R is lower alkyl or cycloalkylmethyl of 5-10 carbon atoms, the nitrogen atom can be additionally substi-tuted with oxygen to form a tertiary amine oxide, when prepared by the process of claim 1.
wherein R1, R2 are H, chlorine or nitro, and where R is H, alkyl of up to 10 carbon atoms, alkenyl of 3-7 carbon atoms attached to N by a saturated carbon atom, cycloalkyl of 3-5 carbon atoms, propargyl, 2-furylmethyl, 2-thienylmethyl, -(CH2)qOR3, -(CH2)3CO2 (lower alkyl) and -CH(R4)(CH2)pR5 of up to 14 carbons, where q is 2-6;
p is 0-5;
R3 is lower alkyl, phenyl or lower alkylphenyl;
R4 is H or n-lower alkyl;
R5 is a hydrocarbyl group containing at least one ring of 3-9 carbon atoms attached to alkylene by a ring carbon atom, with the proviso that when p is O, the carbon atom attached to -CH(R4)- is not a quaternary carbon atom; and, when R is lower alkyl or cycloalkylmethyl of 5-10 carbon atoms, the nitrogen atom can be additionally substi-tuted with oxygen to form a tertiary amine oxide, when prepared by the process of claim 1.
33. The compound of claim 32 wherein R1 and R2 are each hydrogen, when prepared by the process of claim 2.
34. The compound of claim 32 wherein R1 and R2 are each hydrogen and R is alkyl of 1-10 carbon atoms, .alpha.-furyl-methyl -(CH2)q-O-(lower alkyl), -(CH2)q-O-phenyl, or -CH(R4)(CH2)pR5, where q is 2-6;
p is 0-3;
R4 is H or CH3;
R5 is cycloalkyl of 3 to 8 carbon atoms;
cycloalkenyl of 3 to 8 carbon atoms;
methylenecycloalkyl of 4 to 9 carbon atoms;
polycycloalkyl of 7 to 9 carbon atoms or polycycloalkenyl of 7 to 9 carbon atoms and phenyl, when prepared by the process of claim 3.
p is 0-3;
R4 is H or CH3;
R5 is cycloalkyl of 3 to 8 carbon atoms;
cycloalkenyl of 3 to 8 carbon atoms;
methylenecycloalkyl of 4 to 9 carbon atoms;
polycycloalkyl of 7 to 9 carbon atoms or polycycloalkenyl of 7 to 9 carbon atoms and phenyl, when prepared by the process of claim 3.
35. The compound of claim 32 wherein R1 and R2 are each hydrogen and R is n-alkyl of 2-8 carbon atoms, when prepared by the process of claim 4.
36. The compound of claim 32 wherein R1 and R2 are each hydrogen and R is n-butyl, when prepared by the process of claim 5.
37. The compound of claim 32 wherein R1 and R2 are each hydrogen and R is n-hexyl, when prepared by the process of claim 6.
38. The compound of claim 32 wherein R1 and R2 are each hydrogen and R is n-heptyl, when prepared by the process of claim 7.
39. The compound of claim 32 wherein R1 and R2 are each hydrogen and R is n-octyl, when prepared by the process of claim 8.
40. The compound of claim 32 wherein R1 and R2 are each hydrogen and R is -CH(R4)(CH2)pR5, R4 is H or methyl and R5 is cycloalkyl of 3-8 carbons;
cycloalkenyl of 3-8 carbons;
methylenecycloalkyl of 4-9 carbons;
polycycloalkyl of 7-9 carbons;
polycycloalkenyl of 7-9 carbons; or phenyl, when prepared by the process of claim 9.
cycloalkenyl of 3-8 carbons;
methylenecycloalkyl of 4-9 carbons;
polycycloalkyl of 7-9 carbons;
polycycloalkenyl of 7-9 carbons; or phenyl, when prepared by the process of claim 9.
41. The compound of claim 32 wherein R1 and R2 are each hydrogen and R is cycloalkymethyl of 5-10 carbon atoms, when prepared by the process of claim 10.
42. The compound of claim 32 wherein R1 and R2 are each hydrogen and R is cyclopentylmethyl, when prepared by the process of claim 11.
43. The compound of claim 32 wherein R1 and R2 are each hydrogen and R is cyclohexylmethyl, when prepared by the process of claim 12.
44. The compound of claim 32 wherein R1 and R2 are each hydrogen and R is cycloheptylmethyl, when prepared by the process of claim 13.
45. The compound of claim 32 wherein R1 and R2 are each hydrogen and R is benzyl, when prepared by the process of claim 14.
46. The compound of claim 32 wherein R1 and R are each hydrogen and R is cycloalkenylmethyl of 5-8 carbon atoms, when prepared by the process of claim 15.
47. The compound of claim 32 wherein R1 and R are each hydrogen and R is 1-cyclopentenylmethyl, when prepared by the process of claim 16.
48. The compound of claim 32 wherein R1 and R2 are each hydrogen and R is 3-cyclohexenylmethyl, when prepared by the process of claim 17.
49. The compound of claim 32 wherein R1 and R2 are each hydrogen and R is 2-exo-bi-cyclo [2.2.1]heptylmethyl, when prepared by the process of claim 18.
50. The compound of claim 32 wherein R1 and R2 are each hydrogen and R is 2-exo-bi-cyclo [2.2.1]hept-5-enylmethyl, when prepared by the process of claim 19.
51. The compound of claim 32 wherein R1 and R2 are each hydrogen and R is 3-methylenecyclobutylmethyl, when pre-pared by the process of claim 20.
52. (-) trans-2-cyclopentylmethyl-2,3,8,12b-tetra-hydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta [1,2-c]pyrrole, the compound of claim 32 wherein R1 and R2 are each hydrogen and R is cyclopentylmethyl, when prepared by the process of claim 21.
53. A pharmaceutically acceptable addition salt of the compound of claim 32 wherein R1 and R2 are each hydrogen and R is alkyl of 1-10 carbons, 2-furylmethyl -(CH2)q-0-(lower alkyl), -(CH2)q-0-phenyl, or -CH(R4)(CH2)pR5, where q is 2-6;
p is 0-3;
R4 is H or CH3, R5 is cycloalkyl of 3 to 8 carbon atoms;
cycloalkenyl of 3 to 8 carbon atoms;
methylenecycloalkyl of 4 to 9 carbon atoms;
polycycloalkyl of 7 to 9 carbon atoms or polycycloalkenyl of 7 to 9 carbon atoms and phenyl, when prepared by the process of claim 22.
p is 0-3;
R4 is H or CH3, R5 is cycloalkyl of 3 to 8 carbon atoms;
cycloalkenyl of 3 to 8 carbon atoms;
methylenecycloalkyl of 4 to 9 carbon atoms;
polycycloalkyl of 7 to 9 carbon atoms or polycycloalkenyl of 7 to 9 carbon atoms and phenyl, when prepared by the process of claim 22.
54. The hydrochloride salt of the compound of claim 32 wherein R1 and R2 are each hydrogen and R is alkyl of 1-10 carbons, 2-furylmethyl -(CH2)q-O-(lower alkyl), -(CH2)q-O-phenyl, or -CH(R4)(CH2)pR5, where q is 2-6;
p is 0-3;
R4 is H or CH3;
R5 is cycloalkyl of 3 to 8 carbon atoms;
cycloalkenyl of 3 to 8 carbon atoms;
methylenecycloalkyl of 4 to 9 carbon atoms;
polycycloalkyl of 7 to 9 carbon atoms or polycycloalkenyl of 7 to 9 carbon atoms and phenyl, when prepared by the process of claim 23.
p is 0-3;
R4 is H or CH3;
R5 is cycloalkyl of 3 to 8 carbon atoms;
cycloalkenyl of 3 to 8 carbon atoms;
methylenecycloalkyl of 4 to 9 carbon atoms;
polycycloalkyl of 7 to 9 carbon atoms or polycycloalkenyl of 7 to 9 carbon atoms and phenyl, when prepared by the process of claim 23.
55. The hydrochloride salt of the compound of claim 32 wherein R1 and R2 are each hydrogen and R is cyclopentyl-methyl, when prepared by the process of claim 24.
56. The hydrochloride salt of the compound of claim 32 wherein R1 and R2 are each hydrogen and R is cyclohexyl-methyl, when prepared by the process of claim 25.
57. The compound of claim 32, when prepared by the process of claim 26.
58. The compound of claim 32, when prepared by the process of claim 27.
59. The compound of claim 32 wherein R1 and R2 are each hydrogen and R is alkenyl of 3-7 carbon atoms attached to N by a saturated carbon atom, when prepared by the process of claim 28.
60. The compound of claim 32 wherein R1 and R2 are each hydrogen and R is allyl, when prepared by the process of claim 29.
61. A pharmaceutically acceptable addition salt of the compound of claim 32 wherein R1 and R2 are each hydrogen and R is alkenyl of 3-7 carbon atoms attached to N by a satu-rated carbon atom, when prepared by the process of claim 30.
62. The hydrochloride salt of the compound of claim 32 wherein R1 and R2 are each hydrogen and R is alkenyl of 3-7 carbon atoms attached to N by a saturated carbon atom, when prepared by the process of claim 31.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US44868674A | 1974-03-06 | 1974-03-06 | |
| US54500175A | 1975-01-30 | 1975-01-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1077929A true CA1077929A (en) | 1980-05-20 |
Family
ID=27035443
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA221,222A Expired CA1077929A (en) | 1974-03-06 | 1975-03-04 | Methanodibenzocycloheptapyrroles |
Country Status (22)
| Country | Link |
|---|---|
| JP (1) | JPS5136451A (en) |
| AR (1) | AR210074A1 (en) |
| AT (1) | AT346839B (en) |
| AU (1) | AU503121B2 (en) |
| CA (1) | CA1077929A (en) |
| CH (1) | CH615664A5 (en) |
| DD (1) | DD118425A5 (en) |
| DE (1) | DE2509617A1 (en) |
| DK (1) | DK89475A (en) |
| ES (1) | ES435329A1 (en) |
| FI (1) | FI62663C (en) |
| FR (1) | FR2262981B1 (en) |
| GB (1) | GB1470900A (en) |
| HU (1) | HU173838B (en) |
| IE (1) | IE40728B1 (en) |
| IL (1) | IL46755A (en) |
| LU (1) | LU71970A1 (en) |
| NL (1) | NL7502667A (en) |
| NO (1) | NO145882C (en) |
| SE (1) | SE405475B (en) |
| SU (1) | SU659088A3 (en) |
| YU (1) | YU52675A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3069086D1 (en) * | 1979-12-10 | 1984-10-04 | Ciba Geigy Ag | AZATETRACYCLIC CARBONITRILES |
| JPH0676285B2 (en) * | 1985-11-01 | 1994-09-28 | 三井東圧化学株式会社 | Benzylamine derivative, its production method and its use |
| CN114957090B (en) * | 2021-12-31 | 2023-09-19 | 淮阴师范学院 | Process for the preparation of fused isoindole derivatives |
-
1975
- 1975-02-11 SE SE7501519A patent/SE405475B/en unknown
- 1975-02-28 AU AU78701/75A patent/AU503121B2/en not_active Expired
- 1975-03-04 CA CA221,222A patent/CA1077929A/en not_active Expired
- 1975-03-04 IE IE450/75A patent/IE40728B1/en unknown
- 1975-03-04 CH CH272775A patent/CH615664A5/en not_active IP Right Cessation
- 1975-03-05 AT AT170275A patent/AT346839B/en not_active IP Right Cessation
- 1975-03-05 ES ES435329A patent/ES435329A1/en not_active Expired
- 1975-03-05 DK DK89475*#A patent/DK89475A/da unknown
- 1975-03-05 IL IL46755A patent/IL46755A/en unknown
- 1975-03-05 AR AR257851A patent/AR210074A1/en active
- 1975-03-05 LU LU71970A patent/LU71970A1/xx unknown
- 1975-03-05 YU YU00526/75A patent/YU52675A/en unknown
- 1975-03-05 SU SU752111450A patent/SU659088A3/en active
- 1975-03-05 NO NO750731A patent/NO145882C/en unknown
- 1975-03-05 DD DD184576A patent/DD118425A5/xx unknown
- 1975-03-05 DE DE19752509617 patent/DE2509617A1/en not_active Withdrawn
- 1975-03-05 GB GB918575A patent/GB1470900A/en not_active Expired
- 1975-03-05 FR FR7506878A patent/FR2262981B1/fr not_active Expired
- 1975-03-06 HU HU75DU233A patent/HU173838B/en unknown
- 1975-03-06 NL NL7502667A patent/NL7502667A/en unknown
- 1975-03-06 FI FI750645A patent/FI62663C/en not_active IP Right Cessation
- 1975-03-06 JP JP50027555A patent/JPS5136451A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| DD118425A5 (en) | 1976-03-05 |
| FR2262981A1 (en) | 1975-10-03 |
| NL7502667A (en) | 1975-09-09 |
| IL46755A (en) | 1978-12-17 |
| AT346839B (en) | 1978-11-27 |
| FI750645A (en) | 1975-09-07 |
| FR2262981B1 (en) | 1980-01-11 |
| NO750731L (en) | 1975-09-09 |
| SE405475B (en) | 1978-12-11 |
| SU659088A3 (en) | 1979-04-25 |
| NO145882C (en) | 1982-06-16 |
| ATA170275A (en) | 1978-04-15 |
| YU52675A (en) | 1982-10-31 |
| FI62663B (en) | 1982-10-29 |
| NO145882B (en) | 1982-03-08 |
| AU7870175A (en) | 1976-09-02 |
| CH615664A5 (en) | 1980-02-15 |
| AU503121B2 (en) | 1979-08-23 |
| IE40728L (en) | 1975-09-06 |
| DK89475A (en) | 1975-09-07 |
| ES435329A1 (en) | 1977-04-01 |
| IE40728B1 (en) | 1979-08-01 |
| GB1470900A (en) | 1977-04-21 |
| HU173838B (en) | 1979-08-28 |
| IL46755A0 (en) | 1975-07-28 |
| DE2509617A1 (en) | 1975-09-11 |
| SE7501519L (en) | 1975-09-08 |
| FI62663C (en) | 1983-02-10 |
| AR210074A1 (en) | 1977-06-30 |
| LU71970A1 (en) | 1975-08-20 |
| JPS5136451A (en) | 1976-03-27 |
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