CA1042444A - Preparation of tetrahydrocarbazoles - Google Patents
Preparation of tetrahydrocarbazolesInfo
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- CA1042444A CA1042444A CA000208148A CA208148A CA1042444A CA 1042444 A CA1042444 A CA 1042444A CA 000208148 A CA000208148 A CA 000208148A CA 208148 A CA208148 A CA 208148A CA 1042444 A CA1042444 A CA 1042444A
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- hydroxy
- tetrahydrocarbazole
- dimethylamino
- acid
- hydrogen
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Abstract
ABSTRACT OF THE DISCLOSURE
There are disclosed novel 3-A-9-R-Q-1,2,3,4-tetrahydrocarbazoles where in Q is 7 hydroxy, A is dimethylamino and R is hydrogen or methyl; or Q is 7-hydroxy, A is 1-pyrrolidyl and R is hydrogen; or Q is 7-acetoxy, A is dimethylamino and R is hydrogen, said compounds having one or more of positive inotropic, antiarrhythmic and bronchodilating activities and methods and compositions for the use thereof in treating cardiac disorders in mammals.
There are disclosed novel 3-A-9-R-Q-1,2,3,4-tetrahydrocarbazoles where in Q is 7 hydroxy, A is dimethylamino and R is hydrogen or methyl; or Q is 7-hydroxy, A is 1-pyrrolidyl and R is hydrogen; or Q is 7-acetoxy, A is dimethylamino and R is hydrogen, said compounds having one or more of positive inotropic, antiarrhythmic and bronchodilating activities and methods and compositions for the use thereof in treating cardiac disorders in mammals.
Description
~V4244~ ~
Thls inventlon relates to tetrahydrocarbazoles and pharmaceutlcal composltlons suitable for treating the failing heart ln mammals affllcted wlth congestive heart failure.
Congestive heart failure in mammals results from heart dlsease or other causes, for exarnple, hypertension, valvular affection, arteriosclerosis, etc. In the treatment of the failing heart in mammals afflicted with congestlve heart failure, a cardiotonic drug is admlnlstered. Such a drug stlmulates the cardlac muscle to greater contractile force~ l.e., provldes a positive inotropic effect, thus restoring essentially normal tonicity of the congestive heart. The mammal afflicted with congestive heart failure must be maintained on cardiotonic drug therapy at dose levels of the drug which are effective to continually provide a positive inotropic ef~ect. A well known class of drugs having cardiotonic activity which are commonly used in the treatment of the digitalis type.
The compounds of the present invention are 3-A-9-R-Q-1,2,3,4-tetrahydrocarbazoles having in the free base form the structural Formula ~ ~ ~ A
where Q is 7-hydroxy~ A is dimethylamino and R is hydrogen or methyl; or Q is 7-hydroxy, A is l-pyrrolidyl and R is hydrogen;
or Q is 7-acetoxy, A is dimethylamino and R is hydrogen and acid-addition salts thereof. The compounds can be used for treating the failing heart in mammals afflicted with congestlve heart failure by administration to said mammal in an amount effective to provide a positive inotropic effect. One can treat cardiac arrhythmia in a mammal afflicted with or susceptible to cardiac arrhythmia by administering to said mammal a 3-(dimethylamino)-7-hydroxy-1,233,4-tetrahydrocarbazole or a pharmaceutically acceptable acid-addition salt thereof in an amount effective to provide normal -1- ~
.. . .
, . . . . . ................. ~ , -- -- -- . -- .
10~;~4~4 rhythm of the heart beat of said mammal.
"The compounds of Formula I where Q is 7-hydroxy are prepared by cleavlng the corresponding benzyl, lower-alkyl or lower-alkenyl ethers, that is by cleaving R' from the 7-R'O
substltuent of a correspondlng 3-A-9- R-7-(OR')-1,2,3,4-tetra hydrocarbazole (Ia) where R' is benzyl, lower-alkyl, or lower-alkenyl.
When R' is benzyl, benzyl may be unsubstituted or substituted on phenyl by one or more of the same or different substituents such as lower-alkyl, lower-alkoxy, halo, nitro, etc.
The terms lower-alkyl, lower-alkenyl and lower-alkoxy mean such groups having from one to six carbon atoms arranged in stralght or branched chalns such as methyl~ ethyl, isopropyl, tertiary butyl, n-hexyl for lower-alkyl, allyl, methallyl, hex-5-enyl for alkenyl; and methoxy, ethoxy, isopropoxy for lower-alkoxy.
The term halo means bromo, chloro, fluoro and lodo.
Cleavage of the benzyl, lower-alkenyl, and lower-alkyl ethers~is effected using known procedures, i.e., by treatment with an acidic or basic reagent.
Acidic reagents which may be used are hydrogen bromide or hydrogen iodide in acetic acid or water, alone or in combinatlon with red phosphorus, potassium iodide in 95% phosphoric acid, pyridine hydrochloride, boron tribromide, concentrated hydrochloric acid in acetlc acid, trifluoroacetic acid, anhydrous aluminum chloride or bromide, etc. Reaction time and temperature are lnter~
dependent and wlll vary with the nature of the particular ether to be cleaved and the acidic reagent employed. Thus reaction tempera-ture may range from 0C. to 200C. and reaction time form one half hour to forty-eight hours. Cleavage of a benzyl, lower-alkenyl or lower-alkoxy ether is conveniently effected by heating the ether at reflux with hydrogen bromide or hydrogen iodide in water or acetic acid solution for about four to eight hours. When pyrldine . .
--. : . , ~
104;~444 hydrochlorlde ls employed higher temperatures, e.~., about 200C.
may be requlred to effect cleavage. In the case of allyl or methallyl ethers, cleavage ls effectecl on treatment with boron tribromide in ethylene dlchloride at 0C. and allowing the reaction solution to rise to room temperature.
Basic reagents which may be employed are sodium and potassium hydroxide, methylmagnesium lodlde, sodium or sodlum amalgam ln an alcohol, e.g., butyl or ethyl alcohol (for benzyl ethers), sodium or sodium and potassium ln liquid ammonia, and the lithium salt of diphenylphosphine (for methyl, benzyl and allyl ethers). As in the case of cleavage with acidic reagents, the reaction time and temperature are interdependent and will vary with the particular reagent employed and the particular type of ether to be cleaved. Cleavage of methyl, allyl and benzyl ethers with the lithium salt of diphenylphosphlne is conveniently carrled out in aqueous tetrahydrofuran at reflux for about two to four hours.
In the case of potassium and/or sodlum in llquid ammonia cleavage of the ethers ls effected at the boiling point of ammonia. In the case of hydroxide, temperatures of about 200C. may be required to effect cleavage of the ethers.
Benzyl ethers can also be cleaved by standard catlytic hydrogenation procedures using a suitable catalyst, e.g., Raney nickel, palladium on charcoal, platinum, copper-chromium oxide, etc. and inert solvents such as acetic acid, ethyl alcohol, etc.
For example, the hydrogenation can be effected at room tempera-ture in an lnert solvent such as ethyl or methyl alcohol under neutral or acidic conditions in the presence of palladium on charcoal at atmospheric or elevated pressure. Although room temperature is preferred, ~emperature ranging from about 0C.
to 100C. may also be employed and will depend on the nature o~
the benzyl substituent, the catalyst employed and other reaction conditions. The hydrogenation is pre~erably stopped when a stoichiometric amount of hydrogen has reacted." -10424~4 The compound of ~ormula I, where Q is acetoxy can be obtained by esterlflcatlon of the correspondlng hydroxy compound.
The 7-acetoxy compound (I) can be prepared from the corresponding 7-hydroxy compound by conventional esterification procedures, e.g. by esterification in a suitable solvent with an appropriate acylating agent, e.g., acetic anhydride or acetyl chloride, preferably in the presence of at least an equivalent of an appropriate acid acceptor, e.g., pyridlne or sodium hydroxide.
The 3-A-9-R-7-(OR')-1,2,3,4-tetrahydrocarbazole starting materials can be prepared by the Fischer indole synthesis in which an appropriate l-R-1-[3-(OR')-phenylhydrazine] (III), where R is H or methyl and R' is benzyl, lower-alkyl, or lower-alkenyl as defined hereinabove, is reacted with the appropriate 4 A-cyclo-hexanone, where A has the meaning given above. The reaction is carried out in an acidic medium, at room or elevated temperatures, for about one-half to twenty four hours. Acids which may be employed are inorganic acids such as hydrochloric acid, mineral acids such as sulfuric acid, and organic acids such as acetic or methanesulfonic acid, as well as Lewis acids. The reaction is conveniently carried out in ethyl alcohol in the presence of at least two moles of hydrochloric acid per mole of hydrazine or in acetic acid at room or elevated temperature.
The phenylhydrazine III is prepared by well known procedures from the corresponding anilines. Said anilines are known compounds or are readily prepared by etherification of 3-aminophenol, using conventional methods for etherification of phenols, to convert it to a corresponding 3-(OR')-aniline, where R' has the meaning given above.
By virtue of possessing an asymmetric carbon atom, that is, the carbon atom at the 3-position of the 1,2,3,4-tetrahydrocarba~ole ring, each of the compounds of Formula I
can exist as optical isomers, that is, in two stereoisomeric forms (enantiomers), whose molecular structures are mirror ~04Z9~4~
lmages Or each other. Therefore, within the purview of this invention are the dextrorot~tory isomers and levorotatory isomers, hereinafter the d- and l-isomers, and the d,l-mixtures thereof, hereinafter racemic mixtures, of the compounds of Formula I. The racemlc mixture of any particular cornpound of Formula I, obtained directly by the synthetlc procedures described hereinbelow, is separated into the d-isomer and l-isomer, using standard resolu-tion procedures. Thus the racemic mixture is converted to a mixture of two diastereomeric acid-addition salts by reaction, using standard procedures, with a suitable optically active acid, e.g., d-tartaric acid, l-malic acid, l-mandelic acid, d-camphor-10-sulfonic acid, dibenzoyl l-tartaric acid and the like and the resulting two diastereomeric salts in the mixture, which are no longer identical or mirror images and there~ore possess different physical properties, are separated by conventional physical procedures such as crystallization. The two separated diastereomeric salts so obtained can then be converted by stand~red procedures, e.g., by treatment with base, to the corresponding d-isomer and l-isomer.
The compounds of Formula I are useful both in the free base form and in the form of acid-addition salts, and both forms are within the purview of the invention. The acid-addition salts are simply a more convenient form for use, and in practice, use of the salt form inherently amounts to use of the base ~orm.
When the compounds of the invention represented by Formula I are to be utilized for pharmaceutical purposes, the acids which can be used to prepare the acid-addition salts include preferably those which produce, when combined with the free base, medicinally acceptable salts, that is, salts whose anions are relatively innocuous to the animal organism in medicinal doses of the salts so that the beneficial properties inherent in the free base are not vitiated by side effects ascribable to the anions. Appropriate medicinally acceptable salts within the scope of the invention are ~4Z~44 those derived from mlneral acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid, pho~phoric acid, sulfamic acid and sulfuric acid; and, organic aclds such as cyaclohexanesulfamic acid, methanesulfonic acid, ethanesulfonic acid, beneæenesulfonic acid, p-toluenesulfonic acid, naponic acld (1,4-naphthalenedisulfonic acid), quinic acid, and the like, giving the hydrochloride, hydrobromide, hydriodide, nitrate, phosphate, sulfamate, sulfate, cyclohexanesulfamate, methane-sulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, naponate and quinate respectively.
The acid-addition salts of the bases of Formula I
are obtained by dissolving either or both of the base and the acid separately ln water or an organic solvent and mlxin~
the two solutions or by dissolving both the base and the acld together in water or an organic solvent. The resulting acid-addition salt is isolated by filtration lf it is insoluble in the reaction medlum or by concentration of the solution or dilution of the solution with a solvent in which the acid-addition salt is insoluble or only sparingly soluble, or by evaporation of the reaction medium to leave the acid-addition salt as a residue.
Although medicinally acceptable salts of basic compounds I are preferred for pharmaceutical purposes, all acid-addition salts thereof are within the scope of the invention. All acid-addition salts are useful as sources of the free base form even lf the particular salt per se ls desired only as an intermediate pro-duct as for example when the salt is formed only for purposes of purifica~lon or identification, or when it is used as an inter-medlate in preparing a medicinally acceptable salt by ion exchange procedures.
The compounds of Formula ~, when tested in one or more of the standard biological test procedures more fully described hereinbelow, were found to possess useful cardiotonic activity, i.e., positive inotropic activity, thus indicating their utilitY
~ , ' . , 1~34~4~4 a~ cardiotonlc agents in the treatment Or con~es~lve heart ~allure.
The ef~lcacy o~ the~e compounds was ~ud~ed, ~n vltro, on the basls of per cent lncrea~e in contractlle ~orce ln lsolated CRt atrla and paplllary musole and/or, ln vlvo, on the basls Or per oent lnoreas2 ln cardlac ¢ontractlle force ln the intaot ane~thetlzed dog.
The ln vltro te~t procedures used are de~crlbed ~B ~ollows:
Cardlotonic Te~t Procedure I- Male cats wei~hlng rrom .
0.8 to 1.5 kg. were anesthetl-~ed wlth ~-chloralose (80 mg.~kg. i.
p.). The chest wa~ opened, the heart exclsed and the two atrla dlssected. A ~llk suture was tled to each o~ two opposlte 31des of the rlght atrium. One slde of the atrium was tled to a gla8s rod and then mounted ln a 50 ml. or~an bath fllled with T~ro~'s solution. The aecond suture wa8 attached to a force dlsplacement transducer and the ten~lon on the atrium was ad~ùsted to 1.5 +
0.5 ~rams. The transducer wa~ then connected to a ~rass pol~raph and rate o~ atrlal contraction was recorded contlnuously. The left atrlum was treated simllarly using sllver wlre instead o~
~llk sutures. The sil~er wlre al~o ~erved a~ a stimulatlng~
electrode. Both atria were mounted ln the same bath. The ri~ht atrium was beating spontaneously due to the presence of the sinoatrlal node, whlle the left atrium was stimulated electrlcally at a rate of 3 beatæ/sec. by suprathreshold rectangular pulses o~
5 mllllsecond duration. The Tyrode's ~olution bathin~ the atr~a was of the ~ollowlng compositlon (ln mM): NaCl 136.87, XCl 5.36~ -NaH2P04 0.41, CaCl2 1.80, MgCl26H20 1.05, NaHC03 ll.90, glucose 5.55 and EDTA 0.04. The solution was equlllbrated with a ga~
mlxture con~isting ~ 95% ~2 and 5% C02. The preparatlon was left to equilibrate ~or one hour before a~ny dru~ was added, The bathlng ~luid was changed 3 to 4 times durin~ the equili~ratlon tlme. At the end of equillbratlon perlod, the drug dl~solve~ ln a vehlcle or the vehlcle alone was added to the ti~sue ~ath an~
the full response recorded. The vehlcle u~ed wa8 Tyrode'~ ~olution to which, ir requlred, suf~lclent acld WQB added to cause solution .
- -: :
1~)424~4 of the drug. When the response reached a maximum it was abollshed by 3 washes at 10 mln. intervals or until pre-drug values Or force of contractlon were reached. Generally, a dose response study of at least 3 doses was done in the same preparation.
Cardiotonic Test Procedure IB - Male cats o.8 to 1.5 k~.
were anesthetized with ~ -chloralose (80 mg./kg. i.p.). The chest was opened and the heart excised. The heart was dipped and shaken in Tyrode's solution for the removal of blood from the cavities.
The right ventricle was then sllt open and the small and thin (about 1 mm. ln diameter and 4 to 7 mm. in length) papillary muscles were dissected out. A silver wire was attached to each of the two ends of the papillary muscle. The ventricular end was attached to a platinum electrode and mounted in a tissue bath containing Tyrode's solution described above. The silver wire on the valvular end of the muscle was attached to a force displacement transducer for the measurement of the force and rate of muscle contraction. The muscle was stimulated at a rate of 3 beats/sec. by suprathreshold rectangular pulses of 5 mill~second duration. The rest of the procedure was continued as descrlbed above.
Cardiotonic Test Procedure II - The in vivo test pro-cedure used is described as follows: Mongrel dogs of both sexes and varying in weight from 9 to 15 kg. were anesthet~ed with 30 mg./kg. pentobarbital sodium administered intravenously. The trachea was exposed and cannulated. The tracheal cannula was then attached to a Harvard respiratory pump using room air. The right femaoral artery and vein were cannulated. The arterial cannula was attached to a Statham P23A pressure transducer connected to a Grass polygraph for the continuous recording of arterial blood pressure. The venous cannula was used for the intravenous administration of drugs. Pin electrodes were attached to the right forelimb and left hindlimb. The electrodes were then connected to a Grass polygraph for the continuous recording of the standard limb lead II electrocardiogram. A ventro-dorsal incision at the thlrd -~04~44 lnter-costal ~pace was made, the ribs laterally retracted and the perlcardlum slit open to expose the myocardlum. The base of the aorta was dissected and a flow probe was ritted around it. The flow probe was attached to a square wave electromagnetic ~lowmeter (Carolina Medical Electronics). The flowmeter was then connected to a Grass polygraph for the continuous recording of aortic blood flow. Thls flow was used as an lndex of cardiac output (actual cardiac output i9 aortic blood flow + coronary blood flow).
Cardlac contractlle force was measured by suturlng a Walton-Brodie strain gauge to the wall of the right ventricle. At theend of the surgical procedure, the animal was left to rest and equilibrate for one hour with continuous recording of blood pressure, EKG, cardiac contractile force and ascorbic blood ~low.
After the equilibration period, the vehicle or the drug di~solved in the vehicle was administered by intravenous infuslon (i.v.lng.), intravenous bolus (i.v. bol.) or intraduodenally (i.d.) and the response of all the parameters measured to drug administration was recorded continuously for different periods of times depending on the route of drug administration. When the route of administra-tion was i.v. inf., the drug was administered until a peak effectwas reached and infusion was then maintained for ten minutes. The above-dehcribed test systems were standardized using dopamine.
The compounds of Formula I, when tested in vitro in the cardiotonic test procedures IA and IB described hereinbefore, were effective in producing a significant per cent increase (at least 30%) from controls in right atrial and/or papillary muscle force in the dose range of from 3 ~/cc to 100 ~g/cc. Results obtained in test procedures IA and IB for speciflc compounds of Formula I, identified by their hereinbelow designated example numbers (Ex.), are given in Table I where the per cent changes from control in - right atrial rate, right atrial force and papillary muscle force (positive unless otherwise indicated) is listed under RAR, RAF and PMF respectively, and C is the concentration in lug/cc at which the - _g_ '":~ ~ ' ' ' , i~34Z4~4 compound was tested. The concentration for each compound was calculated on the basis of the hydrochlorlde salt exoept for the compound of Example 2, the dose for which was calculated on the basls of the free base. The per cent change given for each com-pound is the average of values obtained in from two to six tests for a particular dose.
Table I
. C RAR RAF I PMF _ Ex. lE3 3 3 37 100 26 _58 84_ Ex. lC3o 11 22 65 .
Ex. lD100 12 ~0 40 .
Ex. 2 3 9 10 40 . . .
Ex. 43o 31 25 55 The compounds of Formula I, when tested in vivo in cardiotonic test procedure II, were effective in producing a significant per cent increase (at least 30%) over controls in myocardial contractile force when administered by i.v. infusion in a dose range of from 0.1 to 0.3 mg./kg. per minute; by i.v.
bolus in a dose range of from 3 to 10 mg./kg., and i.d. at 30 mg./kg. Results ~or specific compounds of Formula I, identifled by their hereinbelow designated example numbers (Ex.), are given in Table 2 ln which positive ~+) and negative (-) per cent changes from control ln myocardial contractile force, heart rate, systolic blood pressure and diastolic blood pressure are listed under CF, HR, SBP and DBP respectively, D is the dose in mg./kg. (per minute in the case of i.v. inf.) and Route is the route of administration.
The dose for each compound was calculated on the basis of the ': . ,, . , :' 1~)4Z~44 hydrochlorlde salt except for the compound o~ Example 2 the dose ~or which was calculated on the basis o~ the free base. The per cent changes given for each compound are an average of values obtained in ~rom two to six dogs for a particular dose excepk as otherwise indlcated. Where the duratlon o~ activity of a particular compound was determined, the duration in minutes is listed in Table II under DUR.
Table II
. .
_ _ D ~ Route CF HR SBP DBP DUR
Ex. lEO.lOa) i.v. inf. +5o +7 +17 +10 0.30b) i.v. inf. +173 +26 +24 +3 116 i.d. +65 +20 +15 -25 ;~ 240 . . . ~ _ Ex. 2 3 i.v. bol. ~47 -19 +18 +12 . _10 i.v. bol. +59 +14 +10 ~-12 Ex. 3B 0.30 i.v. inf. +59 -14 +28 +6 .
a) average of three values obtained in the same dog.
b) at peak lnotropic ef~ect, cardiac output and coronary blood flow were increased 36% on the average.
The efficacy of 3-(dimethylamino)-7-hydroxy-1,2,3,4-tetrahydrocarbazole also was ~udged, in vivo, on the basis of percent increase in myocardial contractile force when administered orally (p.o.) to the intact unanesthetized dog. The test procedure is described as follows:
Cardiotonic Test Procedure III- Mongrel dogs of either sex with body weights ranging from 9.2 to 15.2 kg. were anesthetized with sodium pentobarbital 30 mg./kg. i.v. An endotracheal tùbe was inserted and artiflcial respiration was instituted with a Harvard constant-volume, positive pressure pump using room air . The dog was placed on its right side, a ventro~dorsal inclsion in the 4th intercostal space was made and an opening was made in the peri~
cardium and a Walton-Brodie strain gauge was sutured to the wall -11~
.
lV42444 Or the right ventrlcle. The wires ~rom the strain gauge were run under the skln and out a ~mall stab wound ln the mlddle Or the back. After placlng a large gauge blunted needle attached to rubber tublng between the rlbs, they were rirmly tled together wlth heavy twlne and the wound sutured. The lungs were then hyperventllated ror re-expansion and the alr from the thoraclc cavity allowed to escape through the needle wlth tublng lmmersed ln sterlle sallne. After the re-establlshment of thoraclc vacuum the needle was removed and the anlmal allowed to breath spontane-ously. An lnclslon was made ln the skln over the left femoralartery and the artery was cannulated.
~ The other end of the cannula was attached to a 30 lnch plece of rubber tublng. The "U" shaped curve in the polyethylene tublng was fastened wlth sutures to the fascia and the rubber tublng was run under the skin and through a small stab wound ln the middle o~ the back a few inches ~rom that used ~or the straln gauge wires. The tublng was fllled with heparlnized sallne and tied off at the exlt site in the back. The wounds were then sutured. The animal was wrapped with bandage so that the chest wound, the wires from the strain gauge, and the tublng from the ~emoral artery were covered. An intramuscular in~ection of 250,OQ~u penlcillin G (Longicll Forti~led) was administered and the anlmal returned to its cage. A meal of horse meat and water was lert in the cage for an evening mealO The next day when the an mal was awake it was placed in a sling, the strain gauge wlres were attached to a relay box whlch feeds into a Grass polygraph and the tubing ~rom the femoral artery was attached to a Statham P23A pres-sure transducer ror the measurement of arterial blood pressure.
Plate electrodeQ were attached to the right forelimb J r~ght hlndlimb and le~t hindllmb and Lead II electrocardlogram was monitored. The blood pressure, cardlac rorce and electrocardlo gram were recorded ~imultaneously on a multl-channel ~rass polygraph Drugs were admlnistered orally ln "000" gelatin capsules. The ~ -12- ~
. .
e~fectlveness of the lmplanted strain gauge wa~ te~ted by the admlnlntratlon of 20 or 40 mg./kg. o:~ dopamine. A one hour equlllbrium perlod wlth contlnuous r,cordlng o~ cardlac contractile force, blood pre~ure and heart rate 19 always allowed be~ore adminl~tration of the dopamine.
When tested in vlvo ln the unanesthetlzed dog ln cardiotonlc test procedure III descrlbed hereinabove, 3-(dlmethylamino)-7-hydroxy-1,2,3,4-tetrahydrocarba~ole hydroahlo-ride was e~rective ln producing a 35 and 90 per cent increase over controls in cardiac contractlle force when administered orally at doses o~ 30 and 60 mg./kg. respectlvely with little change in heart rate or blood pressure. The duration o~
activity at these dose levels was greater than ~our hours and eight hours re~pectlvely.
When te3ted in vivo ln the anesthetlzed dog with ouabaln lnduced arrhy~hmla, 3-(dimethylamino)-7-hydroxy-1,2,3,4-tetrahydrocarbazole was found to posse3~ antlarrhythmic activlty and i8 therefore lndlcated for use as an antiarryhthmic agent in reversing and preventing cardiac arrhythmia. The test procedure used ls described as ~ollow~:
Antlarrhythmic Test Procedure - Anesthetized dogs, prepared as described in cardiotonic te3t procedure II herein-above, were used in thi~ procedure. Cardlac arrhythmia was induced ln a control group of dogs by the intravenous injectlon of ouabain ln an lnitial dose of 50 mg./kg. ~ollowed thir~y minu~es later by a dose o~ 5 mg./kg. every ten mlnute~ until cardiac arrhythmla appeared. A continuous trend o~ ~rrhythmia was observed ~or a minimum of ten minutes before ouabain administratlon was termlnated. The arrhythmia3 were atrial and/or ventrlcular ln origln. These include atrial tachycard~a wlth dif~erent degree~
of A-~ block and ventricular extoplc beats from slngle or multiple foci. ~he dog~ were then allowed to recover from the arrhythmias and th~ complete reversal of Lead II electrocardiogram from ~1~--. . .- . ~ .- , : , -:~4Z444 ouabain toxic pattern to a very characterl~tic ouabain therapeutlc pattern was recorded. Cardiac arrhythmia in a ~econd ~roup o~
dogs wa~ flrst lnduced a~ descrlbed above and after establlshment of a contlnuous trend of arrhythmias the drug dissoived in a uehlcle was intravenously lnfu~ed.
When te~ted ln the antiarrhythmio test procedure descrlbed hereinabove, 3-(dimethyamlno) -7-hy~roxy-1,2,3,4-tetrahydrocarbazole hydrochloride was e~fectlve ln reversing cardlao arrhythmla to normal slnus rhythm in five out of seven dogs in from three to flfteen minutes when inrused ln a do~e of 0.3 mg./k~. per milute compared to a recovery ~ime of thlrty to forty mlnutes ln the control group, and, ln addition to the reversal o~ the arrhythmias, caused a marked improvement in cardiac contractile force (48%
lncrease) over the origlnal lncrease (58%) caused by ouabaln.
In utilizlng the compounds of Formula 1 ~or treatin~
the failing heart in mammals a~llcted wlth con~estive heart fallure, and 3-(dimethylamlno)-7-hydroxy-1,2,3,4-tetrahy~ro¢arbazole for treating cardiac arrhythmia ln mammals, the dose to be admin-istered and the frequency o~ admlnlstration wil~ be dependent on the potency and duration of actlvity o~ the compound to be admin-istered as well as on the well as on the route G f' administration.
While all the compounds o~ Formula I are u~e~ul a3 cardiontonlc a~ents ~or oral and in~ra~enous admlnistration9 the longer the duration of posltive inotropic effect of any parti¢ular compound, the more pre~erred is such a compound ~or u~e by oral administration.
On the ba~is o~ the tes~ results obtalned in the cardiotonic and antiarrhythmic test procedures described herein-a~ove and the well known ~act that the cardlac activity o~ ~ drug in intact dogs iB correlated with ldentical cardial actlvit~ in humans, the compounds o~ Formula I ~re indicated for use in treating the failing heart ln humans afflicted witll conge~tlve heart failure and 3-(dimethylamlno)-7-hydroxy-1,2,3,4-te~rshy~ro-carbazole i~ indlcated ~or use ln reversing cardiao arrhythmia ~nd maintaining normal heart beat in hum~n~. Dose~ o~ the compound~
-14~
10~2~4~
of Formula I contemplated ror use ln treating the ~ailing heart in congestive heart failure are about 0.1 mg. or greater per minut~ per person for intravenous inf'usion, about 3 mg. or greater per person for intravenous bolus, and about 30 mg. or greater per-person orally. Doses of 3-(dimethylamino)-7-hydroxy-1,2,3,4-tetra-hydrocarbazole contemplated ~or use ln treating cardiac arrhythm~a are about 0.3 mg. or greater per person when admlnistered orally or intravenously.
The actual determinatlon of the numerical biological data deflnitive for a particular compound is readlly determined by technlclans versed in pharmacological test procedures, without the need for any extensive experimentation.
when tested in the standard biological test procedure de-scribed below, 3-(dimethylamino)-7-hydroxy-1,2,3,4-tetrahydrocarb-azole was ~ound to possess bronchodilating activity thus tndicating the use of this compound as a bronchodilator. The efficacy o~ thls compound as a bronchodilator was ~udged in vivo on the basis o~
per cent inhibition of histamine-induced bronchoconstriction in the intact'anesthetized'dog. The test'procedure used is descrived as follows:
Bronchodllation Test Procedure-Mongrel dogs (9 tQ 13 kg.~ of elther sex were anesthetized with pentobarbital sodium (30mg./kg., i.v.) ~ollowed 30 minutes later by morphine sulphate (3 mg./kg., l.m.). Each openchest dog was maintained by artificial respiration u~lng a constant volume pump attached to the tracheal cannula. A non-rebreathing plastic valve was attached to the tracheal cannula'so that expiratory air returned to room air. A
Statham P23B pressure transducer was attached to the side arm o~
the tracheal cannula and the lntratracheal pressure recorded on a Grass Model 7 polygraph. The right ~emoral vein was cannulated for in~ections. Bronchoconstriction was induced with histamine diphosphate. Doses ranged ~rom 25 to 50 ~g/kg. i.v., but were kept constant during each experiment. The degree of bronchocon-striction was determined by measuring the area of ~he lntratracheal ~042444 pressure recordings above the baseline for a flve minute periodafter the hi~tamlne ln~ection. A planimeter was used to measure this area. Solutlons Or the test con~pound were prepared in dlstilled water. These solutions were then tested for broncho-dllator actlvity by mixing a graded dose of the te~t compound with the constant dose of histamine ln a syringe and ln~ecting the mlxture into the femoral vein of the dog. In~ectlons of solutlons of a constant dose of histamlne alone were repeated at thirty and slxty mlnutes following the lnltial in~ectlon and hourly thereafter.
The degree of bronchoconstrlctlon was determined, as describe~
above, after admlnlstratlon of the test compound and each subse-quent adminlstration of histamlne. Bronchodilatlon was expressed as per cent lnhlbition of the control histamine-induced broncho-constrlctions.
When tested in twenty dogs ln the bronchodilator test procedure, 3-(dlmekhylamlno)-7-hydroxy-1,2,3-4-tetrahydrocarbazole hydrochlorlde was found to effect a 15 to 81 per cent inhlbition ln bronchoconstrlction for a perlod of at least flve hours when admlnlætered intravenously ln the dose range of from 1 to 10 mg./kg.
The acute toxiclty of 3-(dlmethylamlno)-7-hydroxy-1,2,3,4-tetrahydrocarbazole was determlned as follows:
Groups of ten young adult, male Charles River CD alblno rats weighing in the range of 100 to 120 grams were used. Rats for oral study were fasted four hours before medicatlon. The animals were medicated once either intravenously as a solution in distilled water via the tail or orally as a suspension in gum tragacanth by stomach tube. An addltional group of ten rats was similarly medicated orally wlth gum tragacanth alone and used a~
con~rols, whlle another group of ten unmedlcated rats were used as controls for the l.v. study. All survlvors were observed ~or seven days after medication.
When tested in the above acute toxicity test procedure, 3-(dimethylamlno)~7-hydroxy-1,2,3,4-tetrahydrocarbazole hydro-.. . . . . . . .
1~42444 chlorlde was determlned to have a 7-day LD50 f 138 mg./kg~ and 5250 mg./kg. when adminstered lntravenously and orally respectlvely.
The compounds of this invention can be admlnlstered orally in composltion form in the form in the form of pllls, tablets, capsules, e.g., in admlxture wi~h talc 3 starch, milk sugar or other inert, i.e., non-toxic or pharmacologlcally acceptable pharmaceutical carrier, or in the form of aqueous solutions, suspensions, encapsu~ated suspension, gels, elixirs, aqueous alcoholic solutions, e.g., in admixture with sugar or other sweetening agents, flavorings, colorants, thickeners and other conventional pharmaceutical excipients. When inJected subcutan-eously, intramuscularly or intravenously, they can be administered, e.g., as an aqueous or peanut oil solution or suspension using excipients and carriers conventional for this mode of administra-tion. The best route of administration and the best dosage will be apparent from the laboratory tests for activity and toxiclty of the selected compound conventionally undertaken as part of the development phase of a pharmaceutical.
The molecular structures of the compounds of the inven-tion were assigned on the basis of the method of their prepara-tion and study of their NMR and IR spectra, and confirmed by the correspondence between calculated and found values for the elemental analyses of representative ex-amples.
The invention is illustrated by the following examples without, however, being limited thereto.
Example I
(A) A solution of 15.8 g. of 4-dimethylamlnocyclohexanone hydrochloride and 20.3g, of 3-benzyloxyphenylhydrazine hydrochloride (m.p. 165-168C.), prepared in a conventional manner from 3-benzyloxyaniline by nitrosation with sodium nitrite and reduction with stannous chloride, in 225 ml. of absolute ethyl alcohol was heated under reflux for three hours~ cooled to room temperature, and diluted .
. ...
1~4~449~
with 50 ml. of water. After standing ~or three hour~ the result-ing crystals were collected by flltration and washed with ethyl alcohol to give, after recrystallization ~rom ethyl alcohol, 6.1g.
or hydrochloride, m.p. 237-239C.
(B) A solutlon of 3-(dlmethylamlno)-7-(benzyloxy)-1,2j 3,4-tetrahydrocarbazole (201g.) and 228g. of dibenzoyl l-tartarlc acid hydrate in 8.58 liter~ of methyl alcohol were stirred at room temperature ~or forty-five hours. The resulting crystals were filtered (flltrate A), washed wlth 1~0 ml. of methyl alcohol three times, then ether and dried to give, after recrystalliza~ion from methyl alcohol (5 1 ) 98g. of 1-3-(dimethylamlno)-7-(benz~loxy)-1,2,3,4-tetrahydrocarbazole dlbenzoyl l-bitartrate, m.p. 163C.
(dec.~, [ ~] ~ =-102.3 (1% ln acetic acid), whioh was converted to the free base by treatment wi~h ammonlum hydroxide to givè, on extractlon wlth chloroform and recrystallizatlon from isopropyl acetate, 43.5g. o~ 1-3-(dimethylamino)-7-(benzyloxy)-1,293,4-tetrahydrocarbazole, m.p. 128-130~C. Filtrate A (above) was concentrated to 400 ml. and made alkaline with ammonium hydroxide and extracted with chloroform. The chloroform extract was washed once wlth water~ dried and evaporated to dryness and the resultlng 170g. of residue wa~ crystallized from 360 ml. of lsopropyl acetate to give 130g. o~ the racemic starting material. The filtrate, on standlng, yielded 20g. of d 3-(dimethylamino)-7-benzyloxy)-1,2,3,4-tetrahydrocarbazole, m.p. 128-129C., C ~ ] ~ =
~74.3 (1% in CHC13).
(C) To a solution of 20.5g. of d-3-(dimethylamlno)-7-(benzyloxy)-1,2,3,4-tetrahydrocarbazole in 300 ml. of aqueouR
ethyl alcohol (1:1) containing 5.5 ml. o~ concentrated hydro-chlorlc acid was added 2.5g. of 10% palladium on charcoal andthe mixture was sub~ected to a hydrogen atmosphere at about 60 psig until hydrogen uptake ceased. The mixture was ~iltered, the filtrate was evaporated to dryness and the residue was crystallized - : :
~ 42444 from ethyl alcohol to glve 14g. of d-3-~dimethylamlno~-7-h~drox~-1,2L~4-tetrahydrocarba~ole hydrochloride~ m.p. 300-303C. ~dec.), ] ~1.1(1% in H2O).
(D) In a llke manner 42~. o~ 1~3-tdlmethylamlno)-7-(benzyloxy)-1,2,3,4-tetrahydrocarbazole was converted to 31~. o~
(dimethylamino~-7-hydroxy-1,2~3,4-tetrahydrocarbazole h,ydro-chloride, m.p. 303-305C. (dec.), [Cy~ ~ ~-70.4 (1% in H203.
(E) To a solution of 12g. of 3-(dimethylamino)-7-(benzyloxy)-1,2,3,4-tetrahydrocarbazole hydrochloride in 200 ml.
o~ aqueous e~hyl alcohol (1:1) wa~ added 2g. o~ 10% palladium on charcoal and the mixture was sub~ected to a hydrogen atmosphere at about 60psig untll hydrogen uptake ceased. The mixture wac filtered and the filtrate was evaporated to dryne~s to glve 9.7g.
o~ 3-(dimethylamino~-7-hydroxy-1,2,3,4-tetrahydrocarbazole hydrochloride, m.p. 286-288C.
Alternative Procedure I:
By substitutlng 3-methoxyphenylhydrazine hydrochloride ~or 3-benzyloxyphenylhydrazine hydrochloride in (A) above there is obtained hydrochloride which on heating at reflux ~or eight hous in 30%
hydrogen bromlde in acetic acid or in aqueous tetrahydro~uran with the lithium salt of dlphenylphosphine ~ollowed ln each ca~e by lsolatlon, conversion to ~he hydrochloride salt and purification using standard techniques yields 3-tdimeth~lamlno~ 7-hgdrox~-1?2,3~4-tetrahydrocarbazole hydrochlorlde corre~ponding to th@
compound of Example I(E) above.
Alternatlve_Procedure lI:
By subs~ltutlng 3-allyloxyphenylhydrazlne hydrochloride ~or 3-benzyloxyphenylhydrazine hydrochloride in (A) above there is obtained 3-(dimethylamlno ? -7-all~lox~ 2,3,4-tetrahydrooar~
bazole hydrochlorlde which on mixing with boron tribromide in ethylene dichloride at O~C. and allowing the mixture to warm to room temperature followed by lsolatlon, ~onversion to the hydro--, -. .. . . ~ . . .
: ' - -, : . , ` - ~ ` . . , ~42~49~
chlorlde salt and purl~lcatlon u~ing standard teohniques yleld~
3-(dlmethylamlno)-7-hydroxy-152,3,4-tetrahydrocarbazole hydro-chlorlde correspondlng to the compound obtained in Example l(E) above.
Exam~le 2 3-(Dlmethylamlno)-7-hydroxg~-1,2,3J4-tetrahydrocarba-zole (9g.) was suspended in i~e water and an equivalent amount of acetic anhydride and ice cold 10% sodium hydroxide were added alternately in several small portions. The solution was made alkaline with 10% sodium hydroxide and the resulting precipltate was collected, washed wlth water and drled to glve 7.~g. o~
3-(dlmethylamino)-7-acetoxy-1,2,~,4-tetrahydrocarbazole, m.p.
201-204C.
Example 3 (A) A solutlon o~ l-methyl-1-(3-benzyloxyphenyl)-hydrazlne hydrochloride (31.0g.), prepared in a conventional manner from N-methyl-3-benzyloxyaniline by nitrosatlon and reductlon with lithium aluminum hydride, and 4-dimethylamino-cyclohexanone hydrochloride (21.5g.) in 200 ml. of absolute ethyl alcohol was heated at re~lux ~or ~orty-five minutes. The mixture was chllled and flltered and the collected solld was washed with 100 ml. of ethyl alcohol-water (1:1) and triturated wlth 100 ml. o~ water and flltered to glve 33.5g. o~ solid material. The aqueous ethyl alcohol reactlon mother llquors were evaporated to dryness to glve 13g. of an oil. The solid materlal (33g.) was slurried in 200 ml. of hot ethyl alcohol and the slurry was cooled and filtered. Slurrylng was repeated in 500 ml. of ethyl alcohol and the resulting solid was drled to give 25g. o~
3-(dimethylamino)-7-(benzyloxy)-9-methyl-1,2,3?4-tetrahydrocarba-zole hydrochlort~~L m.p. 280~C. ~he filtrate ~rom the 500 ml.
ethyl alcohol slurry, on chilllng, deposlted 3.1g. Or 3-(dlmethyl-amlno)-5-tbenzyloxy)-9-methyl-1,2,3,4-~etrahydrocarbazole hydro-chlorlde, m.p. 198-201C.
~42444 ~ -(Dlmeth~lamino)-7-hydroxv-~-m~-nvl-l.2.-.4-tetrahydrocarbazole hydrochlorlde (4.2g.), m.p. 295C. (dec.) (methane sul~onate ~alt, m.p. 227-230C.), was obtained ~rom 3-(dlmethylamino)-7-(benzyloxy)-9-methyl-1,2,3,4-tetrahydro-carbazole hydrochlorlde (18g.) following a procedure simllar to that described in Example IC.
Example 4 (A) Following a procedure simllar to that desoribed in Example lA and using 4-(1-pyrrolidyl)-ayclohexanone ~14.5g.), 3-benzyloxyphenylhydrazine hydrochlorlde (21.8g.), 160 ml. o~
absolute ethyl alcohol and 60 ml. o~ 4.5N ethanolic hydrogen chloride there was obtained 3-(l-pyrrolidinyl)-7-benzyloxy-1,2,3,4-tetrahydrooarbazole hydrochloride, 4g. o~ whlch was hydrogenated, ~ollowing a procedure similar to that described in Example lC to give 1.3g. o~ 3-(l-pyrrolldyl)-7-hydroxy-1,2,3,4-tetrahydrocarbazole hydrochloride, m p. 294-295C.
tmethYl alcohol-water)
Thls inventlon relates to tetrahydrocarbazoles and pharmaceutlcal composltlons suitable for treating the failing heart ln mammals affllcted wlth congestive heart failure.
Congestive heart failure in mammals results from heart dlsease or other causes, for exarnple, hypertension, valvular affection, arteriosclerosis, etc. In the treatment of the failing heart in mammals afflicted with congestlve heart failure, a cardiotonic drug is admlnlstered. Such a drug stlmulates the cardlac muscle to greater contractile force~ l.e., provldes a positive inotropic effect, thus restoring essentially normal tonicity of the congestive heart. The mammal afflicted with congestive heart failure must be maintained on cardiotonic drug therapy at dose levels of the drug which are effective to continually provide a positive inotropic ef~ect. A well known class of drugs having cardiotonic activity which are commonly used in the treatment of the digitalis type.
The compounds of the present invention are 3-A-9-R-Q-1,2,3,4-tetrahydrocarbazoles having in the free base form the structural Formula ~ ~ ~ A
where Q is 7-hydroxy~ A is dimethylamino and R is hydrogen or methyl; or Q is 7-hydroxy, A is l-pyrrolidyl and R is hydrogen;
or Q is 7-acetoxy, A is dimethylamino and R is hydrogen and acid-addition salts thereof. The compounds can be used for treating the failing heart in mammals afflicted with congestlve heart failure by administration to said mammal in an amount effective to provide a positive inotropic effect. One can treat cardiac arrhythmia in a mammal afflicted with or susceptible to cardiac arrhythmia by administering to said mammal a 3-(dimethylamino)-7-hydroxy-1,233,4-tetrahydrocarbazole or a pharmaceutically acceptable acid-addition salt thereof in an amount effective to provide normal -1- ~
.. . .
, . . . . . ................. ~ , -- -- -- . -- .
10~;~4~4 rhythm of the heart beat of said mammal.
"The compounds of Formula I where Q is 7-hydroxy are prepared by cleavlng the corresponding benzyl, lower-alkyl or lower-alkenyl ethers, that is by cleaving R' from the 7-R'O
substltuent of a correspondlng 3-A-9- R-7-(OR')-1,2,3,4-tetra hydrocarbazole (Ia) where R' is benzyl, lower-alkyl, or lower-alkenyl.
When R' is benzyl, benzyl may be unsubstituted or substituted on phenyl by one or more of the same or different substituents such as lower-alkyl, lower-alkoxy, halo, nitro, etc.
The terms lower-alkyl, lower-alkenyl and lower-alkoxy mean such groups having from one to six carbon atoms arranged in stralght or branched chalns such as methyl~ ethyl, isopropyl, tertiary butyl, n-hexyl for lower-alkyl, allyl, methallyl, hex-5-enyl for alkenyl; and methoxy, ethoxy, isopropoxy for lower-alkoxy.
The term halo means bromo, chloro, fluoro and lodo.
Cleavage of the benzyl, lower-alkenyl, and lower-alkyl ethers~is effected using known procedures, i.e., by treatment with an acidic or basic reagent.
Acidic reagents which may be used are hydrogen bromide or hydrogen iodide in acetic acid or water, alone or in combinatlon with red phosphorus, potassium iodide in 95% phosphoric acid, pyridine hydrochloride, boron tribromide, concentrated hydrochloric acid in acetlc acid, trifluoroacetic acid, anhydrous aluminum chloride or bromide, etc. Reaction time and temperature are lnter~
dependent and wlll vary with the nature of the particular ether to be cleaved and the acidic reagent employed. Thus reaction tempera-ture may range from 0C. to 200C. and reaction time form one half hour to forty-eight hours. Cleavage of a benzyl, lower-alkenyl or lower-alkoxy ether is conveniently effected by heating the ether at reflux with hydrogen bromide or hydrogen iodide in water or acetic acid solution for about four to eight hours. When pyrldine . .
--. : . , ~
104;~444 hydrochlorlde ls employed higher temperatures, e.~., about 200C.
may be requlred to effect cleavage. In the case of allyl or methallyl ethers, cleavage ls effectecl on treatment with boron tribromide in ethylene dlchloride at 0C. and allowing the reaction solution to rise to room temperature.
Basic reagents which may be employed are sodium and potassium hydroxide, methylmagnesium lodlde, sodium or sodlum amalgam ln an alcohol, e.g., butyl or ethyl alcohol (for benzyl ethers), sodium or sodium and potassium ln liquid ammonia, and the lithium salt of diphenylphosphine (for methyl, benzyl and allyl ethers). As in the case of cleavage with acidic reagents, the reaction time and temperature are interdependent and will vary with the particular reagent employed and the particular type of ether to be cleaved. Cleavage of methyl, allyl and benzyl ethers with the lithium salt of diphenylphosphlne is conveniently carrled out in aqueous tetrahydrofuran at reflux for about two to four hours.
In the case of potassium and/or sodlum in llquid ammonia cleavage of the ethers ls effected at the boiling point of ammonia. In the case of hydroxide, temperatures of about 200C. may be required to effect cleavage of the ethers.
Benzyl ethers can also be cleaved by standard catlytic hydrogenation procedures using a suitable catalyst, e.g., Raney nickel, palladium on charcoal, platinum, copper-chromium oxide, etc. and inert solvents such as acetic acid, ethyl alcohol, etc.
For example, the hydrogenation can be effected at room tempera-ture in an lnert solvent such as ethyl or methyl alcohol under neutral or acidic conditions in the presence of palladium on charcoal at atmospheric or elevated pressure. Although room temperature is preferred, ~emperature ranging from about 0C.
to 100C. may also be employed and will depend on the nature o~
the benzyl substituent, the catalyst employed and other reaction conditions. The hydrogenation is pre~erably stopped when a stoichiometric amount of hydrogen has reacted." -10424~4 The compound of ~ormula I, where Q is acetoxy can be obtained by esterlflcatlon of the correspondlng hydroxy compound.
The 7-acetoxy compound (I) can be prepared from the corresponding 7-hydroxy compound by conventional esterification procedures, e.g. by esterification in a suitable solvent with an appropriate acylating agent, e.g., acetic anhydride or acetyl chloride, preferably in the presence of at least an equivalent of an appropriate acid acceptor, e.g., pyridlne or sodium hydroxide.
The 3-A-9-R-7-(OR')-1,2,3,4-tetrahydrocarbazole starting materials can be prepared by the Fischer indole synthesis in which an appropriate l-R-1-[3-(OR')-phenylhydrazine] (III), where R is H or methyl and R' is benzyl, lower-alkyl, or lower-alkenyl as defined hereinabove, is reacted with the appropriate 4 A-cyclo-hexanone, where A has the meaning given above. The reaction is carried out in an acidic medium, at room or elevated temperatures, for about one-half to twenty four hours. Acids which may be employed are inorganic acids such as hydrochloric acid, mineral acids such as sulfuric acid, and organic acids such as acetic or methanesulfonic acid, as well as Lewis acids. The reaction is conveniently carried out in ethyl alcohol in the presence of at least two moles of hydrochloric acid per mole of hydrazine or in acetic acid at room or elevated temperature.
The phenylhydrazine III is prepared by well known procedures from the corresponding anilines. Said anilines are known compounds or are readily prepared by etherification of 3-aminophenol, using conventional methods for etherification of phenols, to convert it to a corresponding 3-(OR')-aniline, where R' has the meaning given above.
By virtue of possessing an asymmetric carbon atom, that is, the carbon atom at the 3-position of the 1,2,3,4-tetrahydrocarba~ole ring, each of the compounds of Formula I
can exist as optical isomers, that is, in two stereoisomeric forms (enantiomers), whose molecular structures are mirror ~04Z9~4~
lmages Or each other. Therefore, within the purview of this invention are the dextrorot~tory isomers and levorotatory isomers, hereinafter the d- and l-isomers, and the d,l-mixtures thereof, hereinafter racemic mixtures, of the compounds of Formula I. The racemlc mixture of any particular cornpound of Formula I, obtained directly by the synthetlc procedures described hereinbelow, is separated into the d-isomer and l-isomer, using standard resolu-tion procedures. Thus the racemic mixture is converted to a mixture of two diastereomeric acid-addition salts by reaction, using standard procedures, with a suitable optically active acid, e.g., d-tartaric acid, l-malic acid, l-mandelic acid, d-camphor-10-sulfonic acid, dibenzoyl l-tartaric acid and the like and the resulting two diastereomeric salts in the mixture, which are no longer identical or mirror images and there~ore possess different physical properties, are separated by conventional physical procedures such as crystallization. The two separated diastereomeric salts so obtained can then be converted by stand~red procedures, e.g., by treatment with base, to the corresponding d-isomer and l-isomer.
The compounds of Formula I are useful both in the free base form and in the form of acid-addition salts, and both forms are within the purview of the invention. The acid-addition salts are simply a more convenient form for use, and in practice, use of the salt form inherently amounts to use of the base ~orm.
When the compounds of the invention represented by Formula I are to be utilized for pharmaceutical purposes, the acids which can be used to prepare the acid-addition salts include preferably those which produce, when combined with the free base, medicinally acceptable salts, that is, salts whose anions are relatively innocuous to the animal organism in medicinal doses of the salts so that the beneficial properties inherent in the free base are not vitiated by side effects ascribable to the anions. Appropriate medicinally acceptable salts within the scope of the invention are ~4Z~44 those derived from mlneral acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid, pho~phoric acid, sulfamic acid and sulfuric acid; and, organic aclds such as cyaclohexanesulfamic acid, methanesulfonic acid, ethanesulfonic acid, beneæenesulfonic acid, p-toluenesulfonic acid, naponic acld (1,4-naphthalenedisulfonic acid), quinic acid, and the like, giving the hydrochloride, hydrobromide, hydriodide, nitrate, phosphate, sulfamate, sulfate, cyclohexanesulfamate, methane-sulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, naponate and quinate respectively.
The acid-addition salts of the bases of Formula I
are obtained by dissolving either or both of the base and the acid separately ln water or an organic solvent and mlxin~
the two solutions or by dissolving both the base and the acld together in water or an organic solvent. The resulting acid-addition salt is isolated by filtration lf it is insoluble in the reaction medlum or by concentration of the solution or dilution of the solution with a solvent in which the acid-addition salt is insoluble or only sparingly soluble, or by evaporation of the reaction medium to leave the acid-addition salt as a residue.
Although medicinally acceptable salts of basic compounds I are preferred for pharmaceutical purposes, all acid-addition salts thereof are within the scope of the invention. All acid-addition salts are useful as sources of the free base form even lf the particular salt per se ls desired only as an intermediate pro-duct as for example when the salt is formed only for purposes of purifica~lon or identification, or when it is used as an inter-medlate in preparing a medicinally acceptable salt by ion exchange procedures.
The compounds of Formula ~, when tested in one or more of the standard biological test procedures more fully described hereinbelow, were found to possess useful cardiotonic activity, i.e., positive inotropic activity, thus indicating their utilitY
~ , ' . , 1~34~4~4 a~ cardiotonlc agents in the treatment Or con~es~lve heart ~allure.
The ef~lcacy o~ the~e compounds was ~ud~ed, ~n vltro, on the basls of per cent lncrea~e in contractlle ~orce ln lsolated CRt atrla and paplllary musole and/or, ln vlvo, on the basls Or per oent lnoreas2 ln cardlac ¢ontractlle force ln the intaot ane~thetlzed dog.
The ln vltro te~t procedures used are de~crlbed ~B ~ollows:
Cardlotonic Te~t Procedure I- Male cats wei~hlng rrom .
0.8 to 1.5 kg. were anesthetl-~ed wlth ~-chloralose (80 mg.~kg. i.
p.). The chest wa~ opened, the heart exclsed and the two atrla dlssected. A ~llk suture was tled to each o~ two opposlte 31des of the rlght atrium. One slde of the atrium was tled to a gla8s rod and then mounted ln a 50 ml. or~an bath fllled with T~ro~'s solution. The aecond suture wa8 attached to a force dlsplacement transducer and the ten~lon on the atrium was ad~ùsted to 1.5 +
0.5 ~rams. The transducer wa~ then connected to a ~rass pol~raph and rate o~ atrlal contraction was recorded contlnuously. The left atrlum was treated simllarly using sllver wlre instead o~
~llk sutures. The sil~er wlre al~o ~erved a~ a stimulatlng~
electrode. Both atria were mounted ln the same bath. The ri~ht atrium was beating spontaneously due to the presence of the sinoatrlal node, whlle the left atrium was stimulated electrlcally at a rate of 3 beatæ/sec. by suprathreshold rectangular pulses o~
5 mllllsecond duration. The Tyrode's ~olution bathin~ the atr~a was of the ~ollowlng compositlon (ln mM): NaCl 136.87, XCl 5.36~ -NaH2P04 0.41, CaCl2 1.80, MgCl26H20 1.05, NaHC03 ll.90, glucose 5.55 and EDTA 0.04. The solution was equlllbrated with a ga~
mlxture con~isting ~ 95% ~2 and 5% C02. The preparatlon was left to equilibrate ~or one hour before a~ny dru~ was added, The bathlng ~luid was changed 3 to 4 times durin~ the equili~ratlon tlme. At the end of equillbratlon perlod, the drug dl~solve~ ln a vehlcle or the vehlcle alone was added to the ti~sue ~ath an~
the full response recorded. The vehlcle u~ed wa8 Tyrode'~ ~olution to which, ir requlred, suf~lclent acld WQB added to cause solution .
- -: :
1~)424~4 of the drug. When the response reached a maximum it was abollshed by 3 washes at 10 mln. intervals or until pre-drug values Or force of contractlon were reached. Generally, a dose response study of at least 3 doses was done in the same preparation.
Cardiotonic Test Procedure IB - Male cats o.8 to 1.5 k~.
were anesthetized with ~ -chloralose (80 mg./kg. i.p.). The chest was opened and the heart excised. The heart was dipped and shaken in Tyrode's solution for the removal of blood from the cavities.
The right ventricle was then sllt open and the small and thin (about 1 mm. ln diameter and 4 to 7 mm. in length) papillary muscles were dissected out. A silver wire was attached to each of the two ends of the papillary muscle. The ventricular end was attached to a platinum electrode and mounted in a tissue bath containing Tyrode's solution described above. The silver wire on the valvular end of the muscle was attached to a force displacement transducer for the measurement of the force and rate of muscle contraction. The muscle was stimulated at a rate of 3 beats/sec. by suprathreshold rectangular pulses of 5 mill~second duration. The rest of the procedure was continued as descrlbed above.
Cardiotonic Test Procedure II - The in vivo test pro-cedure used is described as follows: Mongrel dogs of both sexes and varying in weight from 9 to 15 kg. were anesthet~ed with 30 mg./kg. pentobarbital sodium administered intravenously. The trachea was exposed and cannulated. The tracheal cannula was then attached to a Harvard respiratory pump using room air. The right femaoral artery and vein were cannulated. The arterial cannula was attached to a Statham P23A pressure transducer connected to a Grass polygraph for the continuous recording of arterial blood pressure. The venous cannula was used for the intravenous administration of drugs. Pin electrodes were attached to the right forelimb and left hindlimb. The electrodes were then connected to a Grass polygraph for the continuous recording of the standard limb lead II electrocardiogram. A ventro-dorsal incision at the thlrd -~04~44 lnter-costal ~pace was made, the ribs laterally retracted and the perlcardlum slit open to expose the myocardlum. The base of the aorta was dissected and a flow probe was ritted around it. The flow probe was attached to a square wave electromagnetic ~lowmeter (Carolina Medical Electronics). The flowmeter was then connected to a Grass polygraph for the continuous recording of aortic blood flow. Thls flow was used as an lndex of cardiac output (actual cardiac output i9 aortic blood flow + coronary blood flow).
Cardlac contractlle force was measured by suturlng a Walton-Brodie strain gauge to the wall of the right ventricle. At theend of the surgical procedure, the animal was left to rest and equilibrate for one hour with continuous recording of blood pressure, EKG, cardiac contractile force and ascorbic blood ~low.
After the equilibration period, the vehicle or the drug di~solved in the vehicle was administered by intravenous infuslon (i.v.lng.), intravenous bolus (i.v. bol.) or intraduodenally (i.d.) and the response of all the parameters measured to drug administration was recorded continuously for different periods of times depending on the route of drug administration. When the route of administra-tion was i.v. inf., the drug was administered until a peak effectwas reached and infusion was then maintained for ten minutes. The above-dehcribed test systems were standardized using dopamine.
The compounds of Formula I, when tested in vitro in the cardiotonic test procedures IA and IB described hereinbefore, were effective in producing a significant per cent increase (at least 30%) from controls in right atrial and/or papillary muscle force in the dose range of from 3 ~/cc to 100 ~g/cc. Results obtained in test procedures IA and IB for speciflc compounds of Formula I, identified by their hereinbelow designated example numbers (Ex.), are given in Table I where the per cent changes from control in - right atrial rate, right atrial force and papillary muscle force (positive unless otherwise indicated) is listed under RAR, RAF and PMF respectively, and C is the concentration in lug/cc at which the - _g_ '":~ ~ ' ' ' , i~34Z4~4 compound was tested. The concentration for each compound was calculated on the basis of the hydrochlorlde salt exoept for the compound of Example 2, the dose for which was calculated on the basls of the free base. The per cent change given for each com-pound is the average of values obtained in from two to six tests for a particular dose.
Table I
. C RAR RAF I PMF _ Ex. lE3 3 3 37 100 26 _58 84_ Ex. lC3o 11 22 65 .
Ex. lD100 12 ~0 40 .
Ex. 2 3 9 10 40 . . .
Ex. 43o 31 25 55 The compounds of Formula I, when tested in vivo in cardiotonic test procedure II, were effective in producing a significant per cent increase (at least 30%) over controls in myocardial contractile force when administered by i.v. infusion in a dose range of from 0.1 to 0.3 mg./kg. per minute; by i.v.
bolus in a dose range of from 3 to 10 mg./kg., and i.d. at 30 mg./kg. Results ~or specific compounds of Formula I, identifled by their hereinbelow designated example numbers (Ex.), are given in Table 2 ln which positive ~+) and negative (-) per cent changes from control ln myocardial contractile force, heart rate, systolic blood pressure and diastolic blood pressure are listed under CF, HR, SBP and DBP respectively, D is the dose in mg./kg. (per minute in the case of i.v. inf.) and Route is the route of administration.
The dose for each compound was calculated on the basis of the ': . ,, . , :' 1~)4Z~44 hydrochlorlde salt except for the compound o~ Example 2 the dose ~or which was calculated on the basis o~ the free base. The per cent changes given for each compound are an average of values obtained in ~rom two to six dogs for a particular dose excepk as otherwise indlcated. Where the duratlon o~ activity of a particular compound was determined, the duration in minutes is listed in Table II under DUR.
Table II
. .
_ _ D ~ Route CF HR SBP DBP DUR
Ex. lEO.lOa) i.v. inf. +5o +7 +17 +10 0.30b) i.v. inf. +173 +26 +24 +3 116 i.d. +65 +20 +15 -25 ;~ 240 . . . ~ _ Ex. 2 3 i.v. bol. ~47 -19 +18 +12 . _10 i.v. bol. +59 +14 +10 ~-12 Ex. 3B 0.30 i.v. inf. +59 -14 +28 +6 .
a) average of three values obtained in the same dog.
b) at peak lnotropic ef~ect, cardiac output and coronary blood flow were increased 36% on the average.
The efficacy of 3-(dimethylamino)-7-hydroxy-1,2,3,4-tetrahydrocarbazole also was ~udged, in vivo, on the basis of percent increase in myocardial contractile force when administered orally (p.o.) to the intact unanesthetized dog. The test procedure is described as follows:
Cardiotonic Test Procedure III- Mongrel dogs of either sex with body weights ranging from 9.2 to 15.2 kg. were anesthetized with sodium pentobarbital 30 mg./kg. i.v. An endotracheal tùbe was inserted and artiflcial respiration was instituted with a Harvard constant-volume, positive pressure pump using room air . The dog was placed on its right side, a ventro~dorsal inclsion in the 4th intercostal space was made and an opening was made in the peri~
cardium and a Walton-Brodie strain gauge was sutured to the wall -11~
.
lV42444 Or the right ventrlcle. The wires ~rom the strain gauge were run under the skln and out a ~mall stab wound ln the mlddle Or the back. After placlng a large gauge blunted needle attached to rubber tublng between the rlbs, they were rirmly tled together wlth heavy twlne and the wound sutured. The lungs were then hyperventllated ror re-expansion and the alr from the thoraclc cavity allowed to escape through the needle wlth tublng lmmersed ln sterlle sallne. After the re-establlshment of thoraclc vacuum the needle was removed and the anlmal allowed to breath spontane-ously. An lnclslon was made ln the skln over the left femoralartery and the artery was cannulated.
~ The other end of the cannula was attached to a 30 lnch plece of rubber tublng. The "U" shaped curve in the polyethylene tublng was fastened wlth sutures to the fascia and the rubber tublng was run under the skin and through a small stab wound ln the middle o~ the back a few inches ~rom that used ~or the straln gauge wires. The tublng was fllled with heparlnized sallne and tied off at the exlt site in the back. The wounds were then sutured. The animal was wrapped with bandage so that the chest wound, the wires from the strain gauge, and the tublng from the ~emoral artery were covered. An intramuscular in~ection of 250,OQ~u penlcillin G (Longicll Forti~led) was administered and the anlmal returned to its cage. A meal of horse meat and water was lert in the cage for an evening mealO The next day when the an mal was awake it was placed in a sling, the strain gauge wlres were attached to a relay box whlch feeds into a Grass polygraph and the tubing ~rom the femoral artery was attached to a Statham P23A pres-sure transducer ror the measurement of arterial blood pressure.
Plate electrodeQ were attached to the right forelimb J r~ght hlndlimb and le~t hindllmb and Lead II electrocardlogram was monitored. The blood pressure, cardlac rorce and electrocardlo gram were recorded ~imultaneously on a multl-channel ~rass polygraph Drugs were admlnistered orally ln "000" gelatin capsules. The ~ -12- ~
. .
e~fectlveness of the lmplanted strain gauge wa~ te~ted by the admlnlntratlon of 20 or 40 mg./kg. o:~ dopamine. A one hour equlllbrium perlod wlth contlnuous r,cordlng o~ cardlac contractile force, blood pre~ure and heart rate 19 always allowed be~ore adminl~tration of the dopamine.
When tested in vlvo ln the unanesthetlzed dog ln cardiotonlc test procedure III descrlbed hereinabove, 3-(dlmethylamino)-7-hydroxy-1,2,3,4-tetrahydrocarba~ole hydroahlo-ride was e~rective ln producing a 35 and 90 per cent increase over controls in cardiac contractlle force when administered orally at doses o~ 30 and 60 mg./kg. respectlvely with little change in heart rate or blood pressure. The duration o~
activity at these dose levels was greater than ~our hours and eight hours re~pectlvely.
When te3ted in vivo ln the anesthetlzed dog with ouabaln lnduced arrhy~hmla, 3-(dimethylamino)-7-hydroxy-1,2,3,4-tetrahydrocarbazole was found to posse3~ antlarrhythmic activlty and i8 therefore lndlcated for use as an antiarryhthmic agent in reversing and preventing cardiac arrhythmia. The test procedure used ls described as ~ollow~:
Antlarrhythmic Test Procedure - Anesthetized dogs, prepared as described in cardiotonic te3t procedure II herein-above, were used in thi~ procedure. Cardlac arrhythmia was induced ln a control group of dogs by the intravenous injectlon of ouabain ln an lnitial dose of 50 mg./kg. ~ollowed thir~y minu~es later by a dose o~ 5 mg./kg. every ten mlnute~ until cardiac arrhythmla appeared. A continuous trend o~ ~rrhythmia was observed ~or a minimum of ten minutes before ouabain administratlon was termlnated. The arrhythmia3 were atrial and/or ventrlcular ln origln. These include atrial tachycard~a wlth dif~erent degree~
of A-~ block and ventricular extoplc beats from slngle or multiple foci. ~he dog~ were then allowed to recover from the arrhythmias and th~ complete reversal of Lead II electrocardiogram from ~1~--. . .- . ~ .- , : , -:~4Z444 ouabain toxic pattern to a very characterl~tic ouabain therapeutlc pattern was recorded. Cardiac arrhythmia in a ~econd ~roup o~
dogs wa~ flrst lnduced a~ descrlbed above and after establlshment of a contlnuous trend of arrhythmias the drug dissoived in a uehlcle was intravenously lnfu~ed.
When te~ted ln the antiarrhythmio test procedure descrlbed hereinabove, 3-(dimethyamlno) -7-hy~roxy-1,2,3,4-tetrahydrocarbazole hydrochloride was e~fectlve ln reversing cardlao arrhythmla to normal slnus rhythm in five out of seven dogs in from three to flfteen minutes when inrused ln a do~e of 0.3 mg./k~. per milute compared to a recovery ~ime of thlrty to forty mlnutes ln the control group, and, ln addition to the reversal o~ the arrhythmias, caused a marked improvement in cardiac contractile force (48%
lncrease) over the origlnal lncrease (58%) caused by ouabaln.
In utilizlng the compounds of Formula 1 ~or treatin~
the failing heart in mammals a~llcted wlth con~estive heart fallure, and 3-(dimethylamlno)-7-hydroxy-1,2,3,4-tetrahy~ro¢arbazole for treating cardiac arrhythmia ln mammals, the dose to be admin-istered and the frequency o~ admlnlstration wil~ be dependent on the potency and duration of actlvity o~ the compound to be admin-istered as well as on the well as on the route G f' administration.
While all the compounds o~ Formula I are u~e~ul a3 cardiontonlc a~ents ~or oral and in~ra~enous admlnistration9 the longer the duration of posltive inotropic effect of any parti¢ular compound, the more pre~erred is such a compound ~or u~e by oral administration.
On the ba~is o~ the tes~ results obtalned in the cardiotonic and antiarrhythmic test procedures described herein-a~ove and the well known ~act that the cardlac activity o~ ~ drug in intact dogs iB correlated with ldentical cardial actlvit~ in humans, the compounds o~ Formula I ~re indicated for use in treating the failing heart ln humans afflicted witll conge~tlve heart failure and 3-(dimethylamlno)-7-hydroxy-1,2,3,4-te~rshy~ro-carbazole i~ indlcated ~or use ln reversing cardiao arrhythmia ~nd maintaining normal heart beat in hum~n~. Dose~ o~ the compound~
-14~
10~2~4~
of Formula I contemplated ror use ln treating the ~ailing heart in congestive heart failure are about 0.1 mg. or greater per minut~ per person for intravenous inf'usion, about 3 mg. or greater per person for intravenous bolus, and about 30 mg. or greater per-person orally. Doses of 3-(dimethylamino)-7-hydroxy-1,2,3,4-tetra-hydrocarbazole contemplated ~or use ln treating cardiac arrhythm~a are about 0.3 mg. or greater per person when admlnistered orally or intravenously.
The actual determinatlon of the numerical biological data deflnitive for a particular compound is readlly determined by technlclans versed in pharmacological test procedures, without the need for any extensive experimentation.
when tested in the standard biological test procedure de-scribed below, 3-(dimethylamino)-7-hydroxy-1,2,3,4-tetrahydrocarb-azole was ~ound to possess bronchodilating activity thus tndicating the use of this compound as a bronchodilator. The efficacy o~ thls compound as a bronchodilator was ~udged in vivo on the basis o~
per cent inhibition of histamine-induced bronchoconstriction in the intact'anesthetized'dog. The test'procedure used is descrived as follows:
Bronchodllation Test Procedure-Mongrel dogs (9 tQ 13 kg.~ of elther sex were anesthetized with pentobarbital sodium (30mg./kg., i.v.) ~ollowed 30 minutes later by morphine sulphate (3 mg./kg., l.m.). Each openchest dog was maintained by artificial respiration u~lng a constant volume pump attached to the tracheal cannula. A non-rebreathing plastic valve was attached to the tracheal cannula'so that expiratory air returned to room air. A
Statham P23B pressure transducer was attached to the side arm o~
the tracheal cannula and the lntratracheal pressure recorded on a Grass Model 7 polygraph. The right ~emoral vein was cannulated for in~ections. Bronchoconstriction was induced with histamine diphosphate. Doses ranged ~rom 25 to 50 ~g/kg. i.v., but were kept constant during each experiment. The degree of bronchocon-striction was determined by measuring the area of ~he lntratracheal ~042444 pressure recordings above the baseline for a flve minute periodafter the hi~tamlne ln~ection. A planimeter was used to measure this area. Solutlons Or the test con~pound were prepared in dlstilled water. These solutions were then tested for broncho-dllator actlvity by mixing a graded dose of the te~t compound with the constant dose of histamine ln a syringe and ln~ecting the mlxture into the femoral vein of the dog. In~ectlons of solutlons of a constant dose of histamlne alone were repeated at thirty and slxty mlnutes following the lnltial in~ectlon and hourly thereafter.
The degree of bronchoconstrlctlon was determined, as describe~
above, after admlnlstratlon of the test compound and each subse-quent adminlstration of histamlne. Bronchodilatlon was expressed as per cent lnhlbition of the control histamine-induced broncho-constrlctions.
When tested in twenty dogs ln the bronchodilator test procedure, 3-(dlmekhylamlno)-7-hydroxy-1,2,3-4-tetrahydrocarbazole hydrochlorlde was found to effect a 15 to 81 per cent inhlbition ln bronchoconstrlction for a perlod of at least flve hours when admlnlætered intravenously ln the dose range of from 1 to 10 mg./kg.
The acute toxiclty of 3-(dlmethylamlno)-7-hydroxy-1,2,3,4-tetrahydrocarbazole was determlned as follows:
Groups of ten young adult, male Charles River CD alblno rats weighing in the range of 100 to 120 grams were used. Rats for oral study were fasted four hours before medicatlon. The animals were medicated once either intravenously as a solution in distilled water via the tail or orally as a suspension in gum tragacanth by stomach tube. An addltional group of ten rats was similarly medicated orally wlth gum tragacanth alone and used a~
con~rols, whlle another group of ten unmedlcated rats were used as controls for the l.v. study. All survlvors were observed ~or seven days after medication.
When tested in the above acute toxicity test procedure, 3-(dimethylamlno)~7-hydroxy-1,2,3,4-tetrahydrocarbazole hydro-.. . . . . . . .
1~42444 chlorlde was determlned to have a 7-day LD50 f 138 mg./kg~ and 5250 mg./kg. when adminstered lntravenously and orally respectlvely.
The compounds of this invention can be admlnlstered orally in composltion form in the form in the form of pllls, tablets, capsules, e.g., in admlxture wi~h talc 3 starch, milk sugar or other inert, i.e., non-toxic or pharmacologlcally acceptable pharmaceutical carrier, or in the form of aqueous solutions, suspensions, encapsu~ated suspension, gels, elixirs, aqueous alcoholic solutions, e.g., in admixture with sugar or other sweetening agents, flavorings, colorants, thickeners and other conventional pharmaceutical excipients. When inJected subcutan-eously, intramuscularly or intravenously, they can be administered, e.g., as an aqueous or peanut oil solution or suspension using excipients and carriers conventional for this mode of administra-tion. The best route of administration and the best dosage will be apparent from the laboratory tests for activity and toxiclty of the selected compound conventionally undertaken as part of the development phase of a pharmaceutical.
The molecular structures of the compounds of the inven-tion were assigned on the basis of the method of their prepara-tion and study of their NMR and IR spectra, and confirmed by the correspondence between calculated and found values for the elemental analyses of representative ex-amples.
The invention is illustrated by the following examples without, however, being limited thereto.
Example I
(A) A solution of 15.8 g. of 4-dimethylamlnocyclohexanone hydrochloride and 20.3g, of 3-benzyloxyphenylhydrazine hydrochloride (m.p. 165-168C.), prepared in a conventional manner from 3-benzyloxyaniline by nitrosation with sodium nitrite and reduction with stannous chloride, in 225 ml. of absolute ethyl alcohol was heated under reflux for three hours~ cooled to room temperature, and diluted .
. ...
1~4~449~
with 50 ml. of water. After standing ~or three hour~ the result-ing crystals were collected by flltration and washed with ethyl alcohol to give, after recrystallization ~rom ethyl alcohol, 6.1g.
or hydrochloride, m.p. 237-239C.
(B) A solutlon of 3-(dlmethylamlno)-7-(benzyloxy)-1,2j 3,4-tetrahydrocarbazole (201g.) and 228g. of dibenzoyl l-tartarlc acid hydrate in 8.58 liter~ of methyl alcohol were stirred at room temperature ~or forty-five hours. The resulting crystals were filtered (flltrate A), washed wlth 1~0 ml. of methyl alcohol three times, then ether and dried to give, after recrystalliza~ion from methyl alcohol (5 1 ) 98g. of 1-3-(dimethylamlno)-7-(benz~loxy)-1,2,3,4-tetrahydrocarbazole dlbenzoyl l-bitartrate, m.p. 163C.
(dec.~, [ ~] ~ =-102.3 (1% ln acetic acid), whioh was converted to the free base by treatment wi~h ammonlum hydroxide to givè, on extractlon wlth chloroform and recrystallizatlon from isopropyl acetate, 43.5g. o~ 1-3-(dimethylamino)-7-(benzyloxy)-1,293,4-tetrahydrocarbazole, m.p. 128-130~C. Filtrate A (above) was concentrated to 400 ml. and made alkaline with ammonium hydroxide and extracted with chloroform. The chloroform extract was washed once wlth water~ dried and evaporated to dryness and the resultlng 170g. of residue wa~ crystallized from 360 ml. of lsopropyl acetate to give 130g. o~ the racemic starting material. The filtrate, on standlng, yielded 20g. of d 3-(dimethylamino)-7-benzyloxy)-1,2,3,4-tetrahydrocarbazole, m.p. 128-129C., C ~ ] ~ =
~74.3 (1% in CHC13).
(C) To a solution of 20.5g. of d-3-(dimethylamlno)-7-(benzyloxy)-1,2,3,4-tetrahydrocarbazole in 300 ml. of aqueouR
ethyl alcohol (1:1) containing 5.5 ml. o~ concentrated hydro-chlorlc acid was added 2.5g. of 10% palladium on charcoal andthe mixture was sub~ected to a hydrogen atmosphere at about 60 psig until hydrogen uptake ceased. The mixture was ~iltered, the filtrate was evaporated to dryness and the residue was crystallized - : :
~ 42444 from ethyl alcohol to glve 14g. of d-3-~dimethylamlno~-7-h~drox~-1,2L~4-tetrahydrocarba~ole hydrochloride~ m.p. 300-303C. ~dec.), ] ~1.1(1% in H2O).
(D) In a llke manner 42~. o~ 1~3-tdlmethylamlno)-7-(benzyloxy)-1,2,3,4-tetrahydrocarbazole was converted to 31~. o~
(dimethylamino~-7-hydroxy-1,2~3,4-tetrahydrocarbazole h,ydro-chloride, m.p. 303-305C. (dec.), [Cy~ ~ ~-70.4 (1% in H203.
(E) To a solution of 12g. of 3-(dimethylamino)-7-(benzyloxy)-1,2,3,4-tetrahydrocarbazole hydrochloride in 200 ml.
o~ aqueous e~hyl alcohol (1:1) wa~ added 2g. o~ 10% palladium on charcoal and the mixture was sub~ected to a hydrogen atmosphere at about 60psig untll hydrogen uptake ceased. The mixture wac filtered and the filtrate was evaporated to dryne~s to glve 9.7g.
o~ 3-(dimethylamino~-7-hydroxy-1,2,3,4-tetrahydrocarbazole hydrochloride, m.p. 286-288C.
Alternative Procedure I:
By substitutlng 3-methoxyphenylhydrazine hydrochloride ~or 3-benzyloxyphenylhydrazine hydrochloride in (A) above there is obtained hydrochloride which on heating at reflux ~or eight hous in 30%
hydrogen bromlde in acetic acid or in aqueous tetrahydro~uran with the lithium salt of dlphenylphosphine ~ollowed ln each ca~e by lsolatlon, conversion to ~he hydrochloride salt and purification using standard techniques yields 3-tdimeth~lamlno~ 7-hgdrox~-1?2,3~4-tetrahydrocarbazole hydrochlorlde corre~ponding to th@
compound of Example I(E) above.
Alternatlve_Procedure lI:
By subs~ltutlng 3-allyloxyphenylhydrazlne hydrochloride ~or 3-benzyloxyphenylhydrazine hydrochloride in (A) above there is obtained 3-(dimethylamlno ? -7-all~lox~ 2,3,4-tetrahydrooar~
bazole hydrochlorlde which on mixing with boron tribromide in ethylene dichloride at O~C. and allowing the mixture to warm to room temperature followed by lsolatlon, ~onversion to the hydro--, -. .. . . ~ . . .
: ' - -, : . , ` - ~ ` . . , ~42~49~
chlorlde salt and purl~lcatlon u~ing standard teohniques yleld~
3-(dlmethylamlno)-7-hydroxy-152,3,4-tetrahydrocarbazole hydro-chlorlde correspondlng to the compound obtained in Example l(E) above.
Exam~le 2 3-(Dlmethylamlno)-7-hydroxg~-1,2,3J4-tetrahydrocarba-zole (9g.) was suspended in i~e water and an equivalent amount of acetic anhydride and ice cold 10% sodium hydroxide were added alternately in several small portions. The solution was made alkaline with 10% sodium hydroxide and the resulting precipltate was collected, washed wlth water and drled to glve 7.~g. o~
3-(dlmethylamino)-7-acetoxy-1,2,~,4-tetrahydrocarbazole, m.p.
201-204C.
Example 3 (A) A solutlon o~ l-methyl-1-(3-benzyloxyphenyl)-hydrazlne hydrochloride (31.0g.), prepared in a conventional manner from N-methyl-3-benzyloxyaniline by nitrosatlon and reductlon with lithium aluminum hydride, and 4-dimethylamino-cyclohexanone hydrochloride (21.5g.) in 200 ml. of absolute ethyl alcohol was heated at re~lux ~or ~orty-five minutes. The mixture was chllled and flltered and the collected solld was washed with 100 ml. of ethyl alcohol-water (1:1) and triturated wlth 100 ml. o~ water and flltered to glve 33.5g. o~ solid material. The aqueous ethyl alcohol reactlon mother llquors were evaporated to dryness to glve 13g. of an oil. The solid materlal (33g.) was slurried in 200 ml. of hot ethyl alcohol and the slurry was cooled and filtered. Slurrylng was repeated in 500 ml. of ethyl alcohol and the resulting solid was drled to give 25g. o~
3-(dimethylamino)-7-(benzyloxy)-9-methyl-1,2,3?4-tetrahydrocarba-zole hydrochlort~~L m.p. 280~C. ~he filtrate ~rom the 500 ml.
ethyl alcohol slurry, on chilllng, deposlted 3.1g. Or 3-(dlmethyl-amlno)-5-tbenzyloxy)-9-methyl-1,2,3,4-~etrahydrocarbazole hydro-chlorlde, m.p. 198-201C.
~42444 ~ -(Dlmeth~lamino)-7-hydroxv-~-m~-nvl-l.2.-.4-tetrahydrocarbazole hydrochlorlde (4.2g.), m.p. 295C. (dec.) (methane sul~onate ~alt, m.p. 227-230C.), was obtained ~rom 3-(dlmethylamino)-7-(benzyloxy)-9-methyl-1,2,3,4-tetrahydro-carbazole hydrochlorlde (18g.) following a procedure simllar to that described in Example IC.
Example 4 (A) Following a procedure simllar to that desoribed in Example lA and using 4-(1-pyrrolidyl)-ayclohexanone ~14.5g.), 3-benzyloxyphenylhydrazine hydrochlorlde (21.8g.), 160 ml. o~
absolute ethyl alcohol and 60 ml. o~ 4.5N ethanolic hydrogen chloride there was obtained 3-(l-pyrrolidinyl)-7-benzyloxy-1,2,3,4-tetrahydrooarbazole hydrochloride, 4g. o~ whlch was hydrogenated, ~ollowing a procedure similar to that described in Example lC to give 1.3g. o~ 3-(l-pyrrolldyl)-7-hydroxy-1,2,3,4-tetrahydrocarbazole hydrochloride, m p. 294-295C.
tmethYl alcohol-water)
Claims (6)
1. A process for preparing a 3-A-9-R-Q-1,2,3,4-tetrahydro-carbazole having the formula ...I
wherein Q is 7-hydroxy, A is dimethylamino and R is hydrogen or methyl; or Q is 7-hydroxy, A is 1-pyrrolidyl and R is hydrogen;
or Q is 7-acetoxy, A is dimethylamino and R is hydrogen, or an acid-addition salt thereof, characterized by cleaving R' from the 7-OR' substituent of a corresponding 3-A-9-R-7-(OR')-1,2,3,4-tetrahydrocarbazole, where A and R have the meanings given above, R' is benzyl, lower-alkyl or lower-alkenyl, where benzyl is un-substituted or substituted on phenyl by one or more of the same or different lower-alkyl, lower-alkoxy, halo or nitro substituents and lower-alkyl, lower-alkoxy and lower-alkenyloxy have from one to six carbon atoms and if desired to obtain the compound of Formula I where Q is 7-acetoxy, acetylating the 3-(dimethylamino)-7-hydroxy-1,2,3,4-tetrahydrocarbazole so obtained and, if desired, converting a basic compound obtained to an acid-addition salt thereof.
wherein Q is 7-hydroxy, A is dimethylamino and R is hydrogen or methyl; or Q is 7-hydroxy, A is 1-pyrrolidyl and R is hydrogen;
or Q is 7-acetoxy, A is dimethylamino and R is hydrogen, or an acid-addition salt thereof, characterized by cleaving R' from the 7-OR' substituent of a corresponding 3-A-9-R-7-(OR')-1,2,3,4-tetrahydrocarbazole, where A and R have the meanings given above, R' is benzyl, lower-alkyl or lower-alkenyl, where benzyl is un-substituted or substituted on phenyl by one or more of the same or different lower-alkyl, lower-alkoxy, halo or nitro substituents and lower-alkyl, lower-alkoxy and lower-alkenyloxy have from one to six carbon atoms and if desired to obtain the compound of Formula I where Q is 7-acetoxy, acetylating the 3-(dimethylamino)-7-hydroxy-1,2,3,4-tetrahydrocarbazole so obtained and, if desired, converting a basic compound obtained to an acid-addition salt thereof.
2. A process according to claim 1, where 3-(dimethylamino)-7-hydroxy-1,2,3,4-tetrahydrocarbazole is prepared by cleaving the corresponding 7-benzyloxy ether thereof.
3. A process according to claim 1, where 3-(dimethylamino)-7-hydroxy-1,2,3,4-tetrahydrocarbazole is prepared by cleaving the corresponding 7-methoxy ether thereof.
4. A process according to claim 1, where 3-(dimethylamino)-7-hydroxy-1,2,3,4-tetrahydrocarbazole is prepared by cleavlng the corresponding 7-allyloxy ether thereof.
5. A 3-A-9-R-Q-1,2,3,4-tetrahydrocarbazole as defined in claim 1 when prepared by the process according to claim 1 or by an obvious chemical equivalent thereof.
6. 3-(Dimethylamino)-7-hydroxy-1,2,3,4-tetrahydrocarbazole when prepared by the process according to any one of claims 2, 3 and 4, or by an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000208148A CA1042444A (en) | 1974-08-30 | 1974-08-30 | Preparation of tetrahydrocarbazoles |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000208148A CA1042444A (en) | 1974-08-30 | 1974-08-30 | Preparation of tetrahydrocarbazoles |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1042444A true CA1042444A (en) | 1978-11-14 |
Family
ID=4101014
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000208148A Expired CA1042444A (en) | 1974-08-30 | 1974-08-30 | Preparation of tetrahydrocarbazoles |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1042444A (en) |
-
1974
- 1974-08-30 CA CA000208148A patent/CA1042444A/en not_active Expired
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