CA1116598A - 3-indolyl-tertiary butylaminopropanols - Google Patents
3-indolyl-tertiary butylaminopropanolsInfo
- Publication number
- CA1116598A CA1116598A CA000305281A CA305281A CA1116598A CA 1116598 A CA1116598 A CA 1116598A CA 000305281 A CA000305281 A CA 000305281A CA 305281 A CA305281 A CA 305281A CA 1116598 A CA1116598 A CA 1116598A
- Authority
- CA
- Canada
- Prior art keywords
- formula
- indolyl
- amino
- produced
- dimethylethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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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
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
Abstract of the Disclosure 1-Phenoxy-3[(3-indoly)-tert.-butyl]amino-2-propanols and related 1-aryloxy compounds bearing various ring substituents such as alkyl, cyano, amino, carboxanido, trifluoromethyl, and various heterocyclic groups such as 1-pyrrolyl are antihypertensive agents having vasodilator and adrenergic .beta.-receptor blocking action.
Preferred compounds bear an ortho-substituent in the phenoxy group, and most preferably the methyl group.
Preferred compounds bear an ortho-substituent in the phenoxy group, and most preferably the methyl group.
Description
s~
_ield of hc Invelltion The prcsent lnvelltion is concerned witll heterocyclic carboll compounds of the i~tdole series having an amino substituent (Class 260/326.15~, and with drug, bio-af~ecting and body-crcating processes employing these compounds (Class 424/2i4).
Description of the Prior Art I. A substantial body of prior art has developed during the last ten years involving compounds of the 3-aryloxy-2-hydroxypropyl-amine series whicil have ~-adrenergic receptor blocking activity and are useful in the treatment of cardiovascular diseases. These structures are typified by the substance l-isopropylamino-3-(1-naphthoxy)-2-propanol which is currently in mcdical use under tlle non-proprietary name propranolol. Propranolol and a related ~roup of naphthoxypropanolamine~s arc the subject of U.S. ~atent No. 3,337,628 patented ~ugust 22, 1967. A large number of patents have been &ranted since that time on carbocyclic ethers in which other aromatic rings replace thc naphthoxy group o~ propranolol. ~lany of these compounds are in tlle phenoxy series and others are phenoxy compounds ~lth a fused heterocyclic ring.
II. The follol~in~ patents and publications describe 3-indolyl-alkylamino compounds.
Robinson, U.S. 2,908,691 patented October 13, 1959 describcs a group of 3-indolylalky]amines having an aralkyl substituent attached to the amlno nitrogen atom. These substanccs l-ave utility as hypnotic, anti-se~cretory, and anti-emetic agents. The product of Example 7 th~reof ilas been referred to as SC10049 having broncho-dLlator anclllyperg1ycemlc action (Van ~rman, J. Pharmacol. and Exptl. Therap. 133, 90-97 ~1961)).
~lasson, ct al., U.S. 3,946,009 patented ~arch 23, 1976 discloses a group of pyra~inyloxypropanolamines among which the 3-indolyl-tert.-butyl group is mentioned as an amino substituent.
~efer to column 22, line 15. These substances have adrenergic ~-receptor blocking properties.
Jackman, G. B., et al., J. Pharm. Pharmacol., 1965 17, 742-746 entitl~d "Some Tryptamine Derivatives; 1-Aryloxy-3-C~2-indole-3-ethyl)amino]propanols". 3-Indolylethylaminopropanols w~re conceived of as central nervous system agents of the tranquilizer type. The only compound found to possess any activity had the structural formula shown below. It reflected only a fraction of the CNS activity of chlorproma~ine hydrochloride in laboratory tests, and was considered not worthy of detailed biological study.
cH3~J CH2CH2NIICH2CHCH2-O~
C~12C - C~l III. The following patent discloses various heterocyclic 20 al~ylaminopropanols but no indole compounds are disclosed.
~65~3 Augsteln, et al. U.S. 3,852,291 patented December 3, 1974.
Pyrimidinyl alkylamino and imidazolinylalkylamir)o propanols are described which llave adrenergic ~-receptor blocking action.
IV. The following patents describe arylo~ypropanolamino compounds in which the aryloxy group bears a heterocyclic substituent.
McLoughlin, et al. U.S. 3,328,417 patented June 27, 1967 discloses phenoxypropanolamines in which the phenoxy substituent is further substituted by the 2-indolyl group (column 2, line 12?.
Muchowski, et al. U.S. 3,940,407 patented February 24, 1976 discloses a s~ries of phenoxypropanolamine compounds in which the phenoxy substLtuent is further substituted by a 1,2,3-thiadiazole substituent.
Seeman, Il.S. 3,965,095 patented June 22, 1976 dlscloses a series of oxindole ethers in which the etherifying group is attaclled to the phenyl rlng and has an esterlfied aminopropanol configuration.
These substances are antiarrhythmic ancl ~-blocking agents.
Trcxler, Canadian Patent No. 834,751 issued February l7 1970 discloses a series of indole derivatives having a 3-(N-- substituted amino)-2-propanoloxy substituent in the 4-position of the indole ring. The compounds are useful in the therapy of coronary disease, angina, cardiac arrhyt~ia, and hypertension.
Jaeggi, et al., U.S. 3,984,436 patented October 5, 1976 discloses a series of phenoxypropanolamines in which the phenoxy substituent is further substituted by the l-pyrrolyl group. These compouds are blockers of adrenergic ~-receptors.
Summary of the Invention ___ The present invention illcludes a process for the preparation of a compound having ~ormula I or Formula II and the acid addition salts of these substances CH, OH
CH ~ - C- NUCll, Cll CII ~ - O-Ar-X Fo rmu l:l I
C~, 0~1 ~;~ CU,-C-NUCll,CllCU,-~}Ar-Uec F-rmula 11 In the fore~oing structural formulas the symbols Ar, ~, n, and l-let have the following meanings.
Ar iB selected from the group conslsting of phenyl and naphthyl, X refers to optional Ar-attached substituents which are independe,ntly selected from the group con~isting of alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkanoyl, al~enoyl, alkanoyloxy, alkenoyloxy, alkylsulfonyl, ~lXylsulfinyl, alkylthio, alkanoamido, cycloalkyl.
having 3 to 6 ring ~embers and 1 to 3 optional alkyl substieuents, cycloalkylalkyl having 3 to 5 ring ~embers and 1 to 3 optlonal alkyl sub~tituents wherein each of the foregoin~ groups has up to 8 carbon atoms, phenyl, trifluoromethyl, nitro, amino, hydroxyl, halogen, carboxam1do, cyano, and cyanoalkyl having from 2 to 4 carbon atoms, ;,~
B
n is the integer 0, 1, or 2 signifying the number of X groups, and Het is an Ar-attached heterocyclic substituent selected from the group consisting of S l-pyrrolyl,
_ield of hc Invelltion The prcsent lnvelltion is concerned witll heterocyclic carboll compounds of the i~tdole series having an amino substituent (Class 260/326.15~, and with drug, bio-af~ecting and body-crcating processes employing these compounds (Class 424/2i4).
Description of the Prior Art I. A substantial body of prior art has developed during the last ten years involving compounds of the 3-aryloxy-2-hydroxypropyl-amine series whicil have ~-adrenergic receptor blocking activity and are useful in the treatment of cardiovascular diseases. These structures are typified by the substance l-isopropylamino-3-(1-naphthoxy)-2-propanol which is currently in mcdical use under tlle non-proprietary name propranolol. Propranolol and a related ~roup of naphthoxypropanolamine~s arc the subject of U.S. ~atent No. 3,337,628 patented ~ugust 22, 1967. A large number of patents have been &ranted since that time on carbocyclic ethers in which other aromatic rings replace thc naphthoxy group o~ propranolol. ~lany of these compounds are in tlle phenoxy series and others are phenoxy compounds ~lth a fused heterocyclic ring.
II. The follol~in~ patents and publications describe 3-indolyl-alkylamino compounds.
Robinson, U.S. 2,908,691 patented October 13, 1959 describcs a group of 3-indolylalky]amines having an aralkyl substituent attached to the amlno nitrogen atom. These substanccs l-ave utility as hypnotic, anti-se~cretory, and anti-emetic agents. The product of Example 7 th~reof ilas been referred to as SC10049 having broncho-dLlator anclllyperg1ycemlc action (Van ~rman, J. Pharmacol. and Exptl. Therap. 133, 90-97 ~1961)).
~lasson, ct al., U.S. 3,946,009 patented ~arch 23, 1976 discloses a group of pyra~inyloxypropanolamines among which the 3-indolyl-tert.-butyl group is mentioned as an amino substituent.
~efer to column 22, line 15. These substances have adrenergic ~-receptor blocking properties.
Jackman, G. B., et al., J. Pharm. Pharmacol., 1965 17, 742-746 entitl~d "Some Tryptamine Derivatives; 1-Aryloxy-3-C~2-indole-3-ethyl)amino]propanols". 3-Indolylethylaminopropanols w~re conceived of as central nervous system agents of the tranquilizer type. The only compound found to possess any activity had the structural formula shown below. It reflected only a fraction of the CNS activity of chlorproma~ine hydrochloride in laboratory tests, and was considered not worthy of detailed biological study.
cH3~J CH2CH2NIICH2CHCH2-O~
C~12C - C~l III. The following patent discloses various heterocyclic 20 al~ylaminopropanols but no indole compounds are disclosed.
~65~3 Augsteln, et al. U.S. 3,852,291 patented December 3, 1974.
Pyrimidinyl alkylamino and imidazolinylalkylamir)o propanols are described which llave adrenergic ~-receptor blocking action.
IV. The following patents describe arylo~ypropanolamino compounds in which the aryloxy group bears a heterocyclic substituent.
McLoughlin, et al. U.S. 3,328,417 patented June 27, 1967 discloses phenoxypropanolamines in which the phenoxy substituent is further substituted by the 2-indolyl group (column 2, line 12?.
Muchowski, et al. U.S. 3,940,407 patented February 24, 1976 discloses a s~ries of phenoxypropanolamine compounds in which the phenoxy substLtuent is further substituted by a 1,2,3-thiadiazole substituent.
Seeman, Il.S. 3,965,095 patented June 22, 1976 dlscloses a series of oxindole ethers in which the etherifying group is attaclled to the phenyl rlng and has an esterlfied aminopropanol configuration.
These substances are antiarrhythmic ancl ~-blocking agents.
Trcxler, Canadian Patent No. 834,751 issued February l7 1970 discloses a series of indole derivatives having a 3-(N-- substituted amino)-2-propanoloxy substituent in the 4-position of the indole ring. The compounds are useful in the therapy of coronary disease, angina, cardiac arrhyt~ia, and hypertension.
Jaeggi, et al., U.S. 3,984,436 patented October 5, 1976 discloses a series of phenoxypropanolamines in which the phenoxy substituent is further substituted by the l-pyrrolyl group. These compouds are blockers of adrenergic ~-receptors.
Summary of the Invention ___ The present invention illcludes a process for the preparation of a compound having ~ormula I or Formula II and the acid addition salts of these substances CH, OH
CH ~ - C- NUCll, Cll CII ~ - O-Ar-X Fo rmu l:l I
C~, 0~1 ~;~ CU,-C-NUCll,CllCU,-~}Ar-Uec F-rmula 11 In the fore~oing structural formulas the symbols Ar, ~, n, and l-let have the following meanings.
Ar iB selected from the group conslsting of phenyl and naphthyl, X refers to optional Ar-attached substituents which are independe,ntly selected from the group con~isting of alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkanoyl, al~enoyl, alkanoyloxy, alkenoyloxy, alkylsulfonyl, ~lXylsulfinyl, alkylthio, alkanoamido, cycloalkyl.
having 3 to 6 ring ~embers and 1 to 3 optional alkyl substieuents, cycloalkylalkyl having 3 to 5 ring ~embers and 1 to 3 optlonal alkyl sub~tituents wherein each of the foregoin~ groups has up to 8 carbon atoms, phenyl, trifluoromethyl, nitro, amino, hydroxyl, halogen, carboxam1do, cyano, and cyanoalkyl having from 2 to 4 carbon atoms, ;,~
B
n is the integer 0, 1, or 2 signifying the number of X groups, and Het is an Ar-attached heterocyclic substituent selected from the group consisting of S l-pyrrolyl,
2-oxo-1-pyrrolidinyl having a substituent in the 4-position selected from aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, and alkoxycarbonyl, wherein said alkyl and alkoxy groups have 1 to 4 carbon atoms, 4-morpholinyl, 4~thiamorpholinyl,
3-oxo-1-pyrazolidinyl, and 2-imidazolyl, : lS wherein (a) an epoxypropyl ether starting material of the formula Ar'-OCH2CHCH2 wherein Ar' is Ar-X or Ar-Het as deflned above is contacted under reaction conditions with [2-(3-indolyl)-1,1-dimethylethyl]amine wherein said reaction conditions involve either heating neat or in . ~
the presence of a reaction inert organic liquid medium such as a lower alkanol including methanol, ethanol, : butanol, or hexanol, a hydrocarbon such as benzene or toluene, an ether such as tetrahydrofuran, dibutylether, or dimethoxyethane, or ethyleneglycol at a temperature of from about 60-200C. to yield a compound of Formula I
or Formula II, or - 4a -(b) contacting a phenolic compound of tl~e formula ~r'-OH
wherein Ar' is AR-X or Ar-Het as defined above with an intermediate of Formula III or Formula IV
3-Indolyl-CH2-C - N - CH~CHCH2 Formula III
tCH3 ~ CH20S02R
3-Indolyl-CH2-C - N ~ ~ Formula IV
wherein R is a lower alkyl group of 4 or fewer carbon S atoms under reaction conditions and when employing an intermediate of Formula III debenzylating the resulting product by Icnown means such as catalytic hydrogenation or reaction with sodium in liquid ammonia to produce a compound of Formula I or Formula II, and when employing an intermediate of Formula IV recovering and converting the resulting product to a product of Formula I or Formula II by contact thereof with dilute aqueous mineral acid at a temperature from 20-100C., and if desired when the base of Formula I or Formula II i9 obtained converting said base to a pharmaceutically acceptable acid addition salt.
- 4b -5i~
The compounds of the present invention are unique as anti-hypertensive agents in that they combine adrenergic ~-blocking and vasodilator activity. They also have utility as anti-anginal agents, anti-stress agents, antiarrhythmic agents, antithrombogenic agents S and in the treatment of conditions where it is desirable to reduce the oxyg~n demand of the heart such as post-myocardial infarct management. Preferred members have a particularly desirable com-bination of the foregoing actions, and ancillary pharmacological effects, or a lack thereof, which particularly suits them for specific indications from among those listed. Those of Formula I
- wherein Ar is phenyl, n = 1, and X is located in the ortho position are preferred for antihypertensive use. The utility of the compounds of Formulas I and II can be demonstratecl in various animal models including antagonism of isoproterenol in the conscious rat treated orally (adrenergic ~-receptor blocking action), the spontaneous X
i5~
hyperterlslve rat ~antihypertcnsive actioll), the dog hind limb prepara-tion ~vasodilator actlon), ouabain-induced ventric~lar tachycardia in the dog (antiarrllythmic action), in the coronary artery occluded dog (antiarrhytlmlic action), in vitro by measuring platelet aggregation ln platelet-rlch plasma photometrically followlng chal]enge with a thrombogenic agent such as adenosine diphosphate or collagen (anti-thrombogenic action), and in various other animal and laboratory models.
De ailed Description of the Invention The invention includes compounds havirg the foregoing structural formulas and the acid addition sal~s thereof. For medical use, the pharmaceutically acceptable acid addition salts are pre~erred. The pharmaceutically acceptable acid addition salts are tho~e salts in which the anion does not contribute significantly to the toxicity or pharmacological activity of the salt, and as such, they are the pharmacological equivalents of the bases having the foregoing structural formulas. In some instances, the salts have physical properties which make them more desirable for pharmaceutical formulation purposes such as solubility, lack of hygroscopicity, compressibiliey with respect to tablet formation and compatibllity Wittl other ingredi~nts with which the substances may be used for pharmaceutical purposes. Acid addition salts which do not meet the foregoing criterla for pharmaceutical acceptability, for instance as to toxicity, are sometimes useful as intermediates for isolation and purification of the present suhstances nr for other chemical synthetic purposes such ag separation of optical isomers. Such salts are also part of the invention.
6S~?~3 The acld addltlon salts are made by reaction of a base o the foregoing structural formula with the acid pre.erably by contact in solution. They may also be made by metathesis or treatm~nt with an anion exchange resin whereby the anion of one salt of the substance is replaced by another anion under conditions which allows for separation of the undesired species such as by precipitation ~rom solution or extraction into a solvent or elution from or retention on an anion exchange resin. Pharmaceutically acceptable aciæs for the purposes of salt formation include hydro-chloric, hydrobromic, hydroiodic, Gitric, acetic, benzoic, phosphor~c,nitric, mucic, isethionic, me~hanesulfonic, p-toluenesulfonic, glucosaccharic, palmitic, heptanoic, oxalic, cyclamic, and others.
The compounds of the present invention shown by the fore-going structural formula contain an asymmetric carbon atom in the propanolamine side chain and occur as optically active isomers as well as racemic mixtures thereof. The present invention is intended to include each of the optically active and racemic forms. Some of the substances o~ the present invention contain an asymmetric carbon atom in the X or Het substituent, and diastereoisomeric pairs of Iacemates exis~. These forms are also included.
Resolution of racemic mixtures to provide the optically active isomers of the foregoing compounds is carried out, for e~ample, by forming a salt with an optically active acid many of which are known to those s~illed in the art such as optically active tartaric, mandelic, cholic, 0,0-di-p-toluoyl tartaric, and 0,0-dibenzoyl tartaric acids, or other acids conventional]y employed for this purpose. The claims, therefore, will bc ~mder-stood to embrace the products in the forfn of the several racemic i5~3 mixtures as well as in the form oE the optically active isomers where appropriate.
The therayeutic processes of this invention comprise systemic administration of an effective, non-toxic amount of a compound of Formula I or TFormula II or a pharmaceutically acceptable acid addition salt of either to a mammal having a disease state resulting from excessive stimulation of the adrenergic ~-receptors, or to a mammal requiring vasodilation, or to a mammal having hyper-tension. An effective amount is construed to mean a dose which exerts an adrenergic ~-receptor blocking action, a vasodilator effect, or antihypertensive action in the affected animal without undue toxic side effects. ~y systemic administration, it is intended to include both oral and parenteral routes. Examples of parenteral administration are intravenous injection or infusion, and intraperitoneal, intra-muscular or subcutaneous injection. Rectal administration by ointmentor suppository may be employed. Dosage will vary according to the route of administration with from about 0.1 mcg to 100 mg/kg body weight of a compound of Formula I or Formula II or a pharmaceutically acceptable acid addition salt thereof generally providing the desired therapeutic effect. Acute toxicities measured in the mouse treated orally are within the range of about ALD50 250 mg/kg to >2000 mg/kg of body weight, with non-lethal signs of drug effect such as central nervous system stimulation or depression, mydriasis, or lacrimation appearing at from l/2 to l/lO that dose.
The combination of pharmacological properties of the com-pound of Procedure lO, 1-[[2-~3-indolyl)-1,1-dimethylethyl]amino]-3-(2-methylphenoxy)-2-propanol hydrochloride, indicates that it is B
partlcularly d~sirable for antihypertensive use. It has five-fold ~he adrenergic ~-receptor blocking potency o~ propranolol shown by oral ad~inlstration to rats followed by challenge of the animals with isoproterenol administered intravenously. The latter is a well known adrener~ic ~-receptor stil~ulant which causes an increase ln heart rate and a decrease in blood pressure. These effects of isoproterenol are antagonized by adrenergic ~-receptor blocklng agents, and the relative potency values given above were prepared by regression analysis of log dose-response data for the two compounds.
For therapeutic use, dosage size and Erequency will vary with the sub~ect and the route of administration, with from about 0.2 mg. for intravenous administration up to about 100 mg orally being suitable for man.
The substance of Procedure 10 is distinguished from other adrenergic B-receYtor blocking drugs in that it is effective in lowering the blood pressure in the spontaneously hypertensive rat.
Although adrenergic ~-receptor blocking agents have come into widespread usc ln human medicine for the treatment of hypertension, their mechanism of action is unknown and their antihypertensive activity cannot be detected by this animal test in most instances. With the present substance in the spontaneously hypertensive rat~ a reduction o blood pressure of 25 mm. of Hg occurs at a dose of 100 mg/kg of body weight orally with only a minimal reduction in heart rate.
This is thought to be indicative of utility in hypertensive indications where other adrenergic ~-receptor blocking drugs are inoperative or less desirable.
The substance of Procedure 10 also causes a reduction in blood pressure when ad~ninistered intravenously to the anesthetized _ ~ _ b;S~B
dog in ~ dose of 3.33 mg/kg of body weight. It is further distJn-gulshed in that it does not depress heart rate or right ventricular cnntractile force as is the case with many prior adrenergic ~-receptor blocking agents. Both a positive inotropic and a positive chronotropic effect are exhibited by the substance, and th~se effects are apparent even when the animal is first treated wlth an adrenergic ~-recptor blocking agent such as sotalol. Pulmonary artery pressure remains substantially unchanged, while aortic blood flow and total peripheral resistance are decreased, all of the foregoing ln the anesthetized dog.
I~le compound of Procedure 10 possesses vasodilator activity which may account, in part, for its unique anti-hypertensive action.
In the anèsthetized ganglion blocked (chlorisondamine chloride) angiotension supported rat, direct acting vasodilators such as diazoxide exert a reduction in blood pressure. The substance of Procedure 10 ls equivalent in potency to diazoxide in this test.
The vasodilator action thereof can also be shown in the pump-perfused hind limb of the dog in doses of from 0.03 to 1.0 mg/min.
of perfuslon. Following oral administration to rats a decrease in urine volume and a decrease in sodium ion excretion occurs whicll is typical of vasodilator compounds.
The antithrombogenic action of the substance of Procedure 10 is reflected by its ability to reduce p]atelet aggregation in vitro in platelet-rich plasma following challenge with ADP or collagen.
It is comparable in in vitro activity to suloctidil or to papaverine.
A hazard exists in the use oE a preponderance of adrenergic B-receptor blocking agents in patients suffering from non-allergic i5~B
bronchodpasm in view of the telldency of these agents to provoke an asthmatic attack or to render the subject re~ractory to treatment with adrenergic ~-receptor stimulants such as isoproterenol which are used in the treatment of acute attacks. The substance of Procedure 10 lacks bronchospastic liability as is demonstrated by the Eact that it does not reduce pulmonary ventriculatory pressure, and evokes only moderate enhancement of the response of sensitized rats to immunologically induced broncho-constriction at a dose of 0.5 mgtkg of body weight intravenously. In contrast~ propranolol at a dose of 0.5 mg/kg of body weight intravenously reduces pulmonary ventilatory pressure and precipitates an acute bronchospastic response in sensitized rats to immunologically-induced broncho-constriction.
For the preparation of pharmaceutical compositions con-taining the compounds of Formula I or Formula II in the form of dosage units for oral administrationl the compound is mixed with a solid, pulverulent carrier such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin, as well as with glidents such as magnesium stearate, calcium stearate, polyethylene glycol waxes or the like and pressed into tablets. The tablets may be used uncoated or coated by known techniques to delay disintegration and absorption in the gastro-intestinal tract and thereby provide a sustained action over a longer period. When coated tablets are wanted, the above prepared core may be coated with a concentrated solution of sugar, which solution may contain e.g. gum arabic, gelatin, talc~ titanium dioxide or the like. Furthermore, the tablets may be coated with a 5~i~
lac~uer dis.solve~ In an easlly volat~le orgallic solvent or mlxture of solvenc~ and lf deslred, dye may be added to this coatlng.
In the preparatlon of so~t gelatin capsules conslsting of gelatin an~ e.g. ~lycerine and the like, the active ingredient is mixed with a vegetahle oil and encapsulated in conventional manner.
Hard gelatin capsules may contain granules of the active lngredient in combination with a solid, pulverulent carrier such as lactose, saccharose, sorbitol, mannitol, starch (such as e.g. potato starch, corn starch, or amylopectin), cellulose derivatives or gelatin.
Dose units for rectal administration may be prepared in the form of suppositories containing the compound in a mixture with a neutra] fàt base, or in the form of a gelatin-rectal capsule with a mixture of vegetable oil or paraffin oil.
Liquld preparations suitable for oral administration are suspensions, syrups and elixirs containing from about 0.2% by weight to about 20% by weight of the active ingredient.
A suitable injectible composition comprises an aqueous solution of a water soluble pharmaceutically acceptable acid addition salt ad~usted to physiologically acceptable pH.
The compounds of Formula I and Formula II are prepared by application of known processes to the appropriate starting mater~als.
Representative known methods for the preparation of aryloxypropanol-amine compounds are disclosed in the foregoing patents and publications rited above under Description of the ~rior Art of which the Troxler Canadian patent No. 834,751 and the Jaeg~l, et al., U.S. Patent No. 3,984~436 are illustrativeO More specifically, the present invention provides a proc~ss for the preparation of the compounds of Formulas I and II
accordlng to the following reaction schcme.
~6S~
O (2~ CH3 Ar' O-CH~CI1C112 3-Indolyl-c~2c-NH2 (l) ~ CH~
CH3 (3) (4~
Ar'-011 + 3-Indolyl-Ci12C-B ~ ormulas I and II
C~2C6~1 1 ~ CH20SO2R
B a -N-CH2CHCH2 , or 1 1---N~_~,O
III IV
In the foregoing reaction scheme, the symbol Ar' represents the groups ArXr~ and ArHet as they are defined in Formula I and Fo~lula II, and the symbol B is deEined by Formulas III and IV in which R
is a lower alkyl group of 4 or fewer carbon atoms. The preferred method is according to reactions (l) and (2) in which step ~l) involves reactin~ the appropriately substituted phenolic cornpound Ar'-OH with epichlorohydrin in the presence of a catalytic quantity of an amine followed by treatment with aqueous alkali metal hydroxide, or conducting the reaction in an aqueous alkali metal hydroxide reaction medium whence the amine catalyst is not required. There is produced in step ~l) an Arl epoxypropyl ether which is caused to react in step (2) with 2-(3-indolyl)~ dimethylethylamine to yield a product o Formula I or Formula II depending upon the nature of - tl-e Ar'OH starting material employed. Each of reaction steps (l) ~nd (2) takes place acilely in ordinary laboratory or plant equip-ment under convenient operating conditions.
5~
HcatLns of epichlorohydrin in s~lbstantial molecu]ar excess amount wlth a phenol Ar'O}I containing a drop or two of plperidine as catalyst on a steam bath overnight results in the condensatlon shown in step (1)~ Some of the corresponding halohydrin intermedlate is also produced and i8 converted without isolation to the oxirane shown by treatment of the mixture with aqueous alkali metal hydroxide. Alternatively, the Ar'OH phenol and epichloro-hydrin can be caused to react in the presence of a sufficient amount of a dilute aqueous alkali metal hydroxide to neutrali~e the acidic Ar 7 OH
group at room temperature with formation of the desired intermediate Ar'OCII2C~CH~. Step (2) is carried out simply by heatin8 the o~irane intermediate produced in step (1) with 2-(3-indolyl)-1,1-dimethyl-ethylamine either neat or in the presence of a reaction inert organic solvent. No catalyst or condensation agent is required. Suitable solvents include 95% ethanol but other reaction inert organic liquids in wllich the reactants are solu~le may he employed. Th~se include but are not limited to benzene, tetrahydrofuran, dibutyl ether, butanol, hexanol, methctnGl, dimethoxyethane, ethylene glycol, etc.
Suitable reaction temperatures are from about 60-200C.
An alternate variation of the process for the preparation of compounds of Formulas I and II involves reaction of the Ar'OH
starting material as defined above with a reactant of the formula ÇH9 3-Indolyl-CH2,C-B according to reaction (3) of the scheme to yield an lntermediate which is transformed to the final product by hydrolysis or hydrogenolysis. The substituent B in the reactant used in step (3) is a group such as shown by IIL or IV which is reactive with the phenolic hydroxyl group Ar'OH to incorporate into the product an incipient propanolaminc slde chain.
. 6 ~
Thc reactarlts for step (3) wherein B has Formula III are prepared by formlng the N--benzyl derivative of 2-(3--indolyl)~
dimethylethylaaline and rcacting the lattcir with epichlorohydrin by adaptation of ~e ~ethod of L. Villa et al., Il. Farmaco. Sci., Ed., 2_, (3) 349 (1CJ69).
Those reactants wherein B has Formula IV are prepared by reductive alkylation of 2-53-indolyl)-19l-dimethylethylamine with glyceraldehvde according to known methocls, for instance, employing 5X palladium-on-carbon catalyst in an atmosphere of hydrogen with methanol or other suitable non-reactive liquid as solvent. When using an opticaliy active form of glyceraldehyde, an optically active end product of Formula I or Formula II is obtained. The amino prepanediol resulting from the foregoing reductive alkylation reaction is then converted to the desired 2-(3-indolyl)-1,1-dimethyl-ethyloxazolidinone reactant wherein B has Formula IV by reaction with formaldehyde employing 37~ aqueous formaldehyde in refluxihg benzene with continued removal of the water by distillation. Esterification with an alkanesulfonyl chloride of the formula RS02Cl in which R is a lower alkyl group of 1 to 4 carbon atoms introduces the necessary group which is reactive with Ar'OH.
The intermediate produced by step (3? wherein the B has Formula III is converted in step (4) to a product of Formula I or Formula II by debenzylation by known means such as catalytic hydro-genation or reaction with sodium in liquid ammonia. The intermediates 2$ produced in step (3) ~herein B has formula IV are converted to the products of formulas I and II in step (4) by mild acid hydrol~sis.
In this instaoce, care must be taken to a~oid clecomposition of the 65i~3 rCaCtallt SillCe the 3-indolyl substitucnt is acld sen~sitlve. Aqueous mineral nclds of from 0.1 N to 1 N concentration at temperatures of from 20-100C. sre suitable. The product is recovered as the free base from the hydrolysis mixture by neutrallzation thereof and collectlng the precipitate.
Description of Speciflc Embodiment~
The 2-(3-indolyl)-1,1-dimethylethylamine employed is prepared by tlle method of H. R. Snyder, et al., J. Am. Chem. Soc., 69, 3140 (19S7) from 3~indoly]methyldimethylamine and 2-nitro-lG propane followed by reductlon of the resulting 2-(3-indolyl)-1,1-dimethylnitroethane.
In the following procedures temperatures are expressed in degrees centigrade t). Melting points are corrected values according to the U.S.P. method where indicated (corr.). The nuclear magnetic resonance (MMR) spectral characteristics refer to chemical shift (~) expressed as parts yer million (ppm) versus tetrarnethylsilane (TMS) as reference standard. The relative area reported for the various shifts corresponds to the number of hydrogen atoms of the particular functional type in the molecule 9 and the nature of the shift as to multiplicity is reported as broad singlet (bs), singlet (s), multiplet (m)l doublee (d), triplet (t), or quadruplet (q) with coupling constants (J) reported where appropriate. The format is N~ (solvent): ~(relative area~ multiplicity, J value). Abbreviations employed are MeOH (methanol), DMSO-d6 (deuterodimethylsulfoxide), i-PrOH (isopropanol), abs.EtOH (absolute ethanol), EtOAc (ethyl acetate), EtOH (95~ ethanol), i-PrOH (isopropanol), i-PrOAc (isopropyl 1~l16~
acetate), i-Pr2O tdi-lsoplopyl ether), d (decomposltion). Other abbreviations have conventional established nleanings. The infrared (IR) spectral descriptions include only absorption wave numbers (cm ) having functional group identification value. KBr was employed as diluent for ail IR spectral determinations. T~S was used as internal reference for the NMR spectral determination. The elemental analyses are reported as percent by weight.
Procedure 1. 4-(Methylsulfonyl)-m-tolyloxymethyl Oxirane.-To a mixture of 3~methyl-4-methylsulfonylphenol, 8.1 g. (0.0435 mole), and 20.0 g. (0.216 mole) of epichlorohydrin, there are added two drops of piperidine to serve as condensation catalyst and the mixture is heated at 105-108 for 18 hrs. The excess epichlor-hydrin is then removed by distillation using toluene as a chaser.
A solution of 2.1 g. of sodium hydroxide in 50 ml. of water and 70 ml. of dimethoxyethane is then added and the mixture is stirred for 2 hrs. with occasional warming on the steam bath to convert any phenoxychlorohydrin compound to the ox:lrane. The solvent is then removed by distillation in vacuo and the residue is dissolved in a 1:1 (VIV) mixture of ether and benzene. ThP ~olution is dried over ~nhydrous sodium carbonate and examined by thin layer chromatography for purity of the desired oxirane using a 9:1 mixture of chloroform aud a methanol for development (Rf = 0.8). The solvent is then removed by distillation to yield 10.7 g. of a residue constituting the desired oxirane. ~easurement of th~ infrared absorption spectrum is employed to confirm the substantial absence ~f hydroxyl containing contaminallts. This material is suitable for further reaction in Procedure 3 without further purification.
~6;5~ `
Procedure 2. 2-CIllorophen_~ymethyl Oxlrane.- A solution of 12.9 g. of 2-chlorophenol (0.1 mole) in 125 ml. of water con-tainln~ 6.5 g. (0.162 mole) of sodium hydro~ide, and 18.5 g.
(0.2 mole) of epichlorohydrin are stirred together at 25 for 20 hrs. The mixture is then extracted twice with 70 ml. portions of methylene chloride. The extract is dried over anhydrous sodium carbo~ate and tlle solvent removed by distillation in vacuo. The residue constltutes the desired oxirane and is suitable for further transformation as is described in Procedure 4.
Procedure 3. 1-C[2-(3-Indolyl)-l,l-dimethylethyl]amino]-3-[4-(methylsulfonyl)-m-tolyloxy~-2-propanol.- The oxirane of Procedure 1, 10.7 g.,was dissolved in 150 ml. of toluene, 8.2 g.
(0.044 mole) of 2-t3-indolyl)-1,1-dimethylethylamine was added and the mixture was refiuxed for 18 hrs. The toluene was removed by distillation in vacuo and a portion of the residue was converted _ to the acetate salt, m.p. 142 147C. The structure was confirmed by examination of the infrared absorption and nuclear megne~ic resonance spec~ra. The remainder of the sample was converted to the hydrochloride salt by treatment of an acetonitrile solution thereof with 8 N ethanolic HCl. After recrystalli~ation from CH3CNIMeOH 12.5 g. of product was obtained, m.p. 174.0-177.0 (corr.).
Anal. Found: C, 59.40; H, 6.90; N, 5.87.
NMR (DMSO-d6): 1.29 ~6, s); 2.52 (3, s); 3.12 (3, s);
3.16 (4, ~); 4.18 (3, m); 5.95 (1, bs); 7.10 (8, m); 9.00 (2, bs);
and 11.12 (1, bs).
IR: 740, 765, 1120, 1290, 1450, 1590, and 3270.
Proccd~lr~ 4 . 1- (?- L ~)~, I_ -dlmettl~leLhy11a ino]~ ropano1.- A portlc-n of thc oxirane produced in Procedu1e 2, 7 g. (0.033 mole), was reflu~ed in solution with 6.3 g. ~0.033 mole) of 2--(3-indolyl)~ dimethyl-ethylamine ln 70 ml. oE ethanol. Afeer 24 hrs. the solvent wa.sremoved hy distlllation in vacuo and the viscous liquld residue was dissolved in 200 ml. of ether, acidified with 8 N ethanolic HCl and the solvents again removed by distl]lation. Crystallization was induced by adding acetonitrile and rubbing with a glass rod.
Recystallized from acetonitrile and di-isopropyl ether to yield
the presence of a reaction inert organic liquid medium such as a lower alkanol including methanol, ethanol, : butanol, or hexanol, a hydrocarbon such as benzene or toluene, an ether such as tetrahydrofuran, dibutylether, or dimethoxyethane, or ethyleneglycol at a temperature of from about 60-200C. to yield a compound of Formula I
or Formula II, or - 4a -(b) contacting a phenolic compound of tl~e formula ~r'-OH
wherein Ar' is AR-X or Ar-Het as defined above with an intermediate of Formula III or Formula IV
3-Indolyl-CH2-C - N - CH~CHCH2 Formula III
tCH3 ~ CH20S02R
3-Indolyl-CH2-C - N ~ ~ Formula IV
wherein R is a lower alkyl group of 4 or fewer carbon S atoms under reaction conditions and when employing an intermediate of Formula III debenzylating the resulting product by Icnown means such as catalytic hydrogenation or reaction with sodium in liquid ammonia to produce a compound of Formula I or Formula II, and when employing an intermediate of Formula IV recovering and converting the resulting product to a product of Formula I or Formula II by contact thereof with dilute aqueous mineral acid at a temperature from 20-100C., and if desired when the base of Formula I or Formula II i9 obtained converting said base to a pharmaceutically acceptable acid addition salt.
- 4b -5i~
The compounds of the present invention are unique as anti-hypertensive agents in that they combine adrenergic ~-blocking and vasodilator activity. They also have utility as anti-anginal agents, anti-stress agents, antiarrhythmic agents, antithrombogenic agents S and in the treatment of conditions where it is desirable to reduce the oxyg~n demand of the heart such as post-myocardial infarct management. Preferred members have a particularly desirable com-bination of the foregoing actions, and ancillary pharmacological effects, or a lack thereof, which particularly suits them for specific indications from among those listed. Those of Formula I
- wherein Ar is phenyl, n = 1, and X is located in the ortho position are preferred for antihypertensive use. The utility of the compounds of Formulas I and II can be demonstratecl in various animal models including antagonism of isoproterenol in the conscious rat treated orally (adrenergic ~-receptor blocking action), the spontaneous X
i5~
hyperterlslve rat ~antihypertcnsive actioll), the dog hind limb prepara-tion ~vasodilator actlon), ouabain-induced ventric~lar tachycardia in the dog (antiarrllythmic action), in the coronary artery occluded dog (antiarrhytlmlic action), in vitro by measuring platelet aggregation ln platelet-rlch plasma photometrically followlng chal]enge with a thrombogenic agent such as adenosine diphosphate or collagen (anti-thrombogenic action), and in various other animal and laboratory models.
De ailed Description of the Invention The invention includes compounds havirg the foregoing structural formulas and the acid addition sal~s thereof. For medical use, the pharmaceutically acceptable acid addition salts are pre~erred. The pharmaceutically acceptable acid addition salts are tho~e salts in which the anion does not contribute significantly to the toxicity or pharmacological activity of the salt, and as such, they are the pharmacological equivalents of the bases having the foregoing structural formulas. In some instances, the salts have physical properties which make them more desirable for pharmaceutical formulation purposes such as solubility, lack of hygroscopicity, compressibiliey with respect to tablet formation and compatibllity Wittl other ingredi~nts with which the substances may be used for pharmaceutical purposes. Acid addition salts which do not meet the foregoing criterla for pharmaceutical acceptability, for instance as to toxicity, are sometimes useful as intermediates for isolation and purification of the present suhstances nr for other chemical synthetic purposes such ag separation of optical isomers. Such salts are also part of the invention.
6S~?~3 The acld addltlon salts are made by reaction of a base o the foregoing structural formula with the acid pre.erably by contact in solution. They may also be made by metathesis or treatm~nt with an anion exchange resin whereby the anion of one salt of the substance is replaced by another anion under conditions which allows for separation of the undesired species such as by precipitation ~rom solution or extraction into a solvent or elution from or retention on an anion exchange resin. Pharmaceutically acceptable aciæs for the purposes of salt formation include hydro-chloric, hydrobromic, hydroiodic, Gitric, acetic, benzoic, phosphor~c,nitric, mucic, isethionic, me~hanesulfonic, p-toluenesulfonic, glucosaccharic, palmitic, heptanoic, oxalic, cyclamic, and others.
The compounds of the present invention shown by the fore-going structural formula contain an asymmetric carbon atom in the propanolamine side chain and occur as optically active isomers as well as racemic mixtures thereof. The present invention is intended to include each of the optically active and racemic forms. Some of the substances o~ the present invention contain an asymmetric carbon atom in the X or Het substituent, and diastereoisomeric pairs of Iacemates exis~. These forms are also included.
Resolution of racemic mixtures to provide the optically active isomers of the foregoing compounds is carried out, for e~ample, by forming a salt with an optically active acid many of which are known to those s~illed in the art such as optically active tartaric, mandelic, cholic, 0,0-di-p-toluoyl tartaric, and 0,0-dibenzoyl tartaric acids, or other acids conventional]y employed for this purpose. The claims, therefore, will bc ~mder-stood to embrace the products in the forfn of the several racemic i5~3 mixtures as well as in the form oE the optically active isomers where appropriate.
The therayeutic processes of this invention comprise systemic administration of an effective, non-toxic amount of a compound of Formula I or TFormula II or a pharmaceutically acceptable acid addition salt of either to a mammal having a disease state resulting from excessive stimulation of the adrenergic ~-receptors, or to a mammal requiring vasodilation, or to a mammal having hyper-tension. An effective amount is construed to mean a dose which exerts an adrenergic ~-receptor blocking action, a vasodilator effect, or antihypertensive action in the affected animal without undue toxic side effects. ~y systemic administration, it is intended to include both oral and parenteral routes. Examples of parenteral administration are intravenous injection or infusion, and intraperitoneal, intra-muscular or subcutaneous injection. Rectal administration by ointmentor suppository may be employed. Dosage will vary according to the route of administration with from about 0.1 mcg to 100 mg/kg body weight of a compound of Formula I or Formula II or a pharmaceutically acceptable acid addition salt thereof generally providing the desired therapeutic effect. Acute toxicities measured in the mouse treated orally are within the range of about ALD50 250 mg/kg to >2000 mg/kg of body weight, with non-lethal signs of drug effect such as central nervous system stimulation or depression, mydriasis, or lacrimation appearing at from l/2 to l/lO that dose.
The combination of pharmacological properties of the com-pound of Procedure lO, 1-[[2-~3-indolyl)-1,1-dimethylethyl]amino]-3-(2-methylphenoxy)-2-propanol hydrochloride, indicates that it is B
partlcularly d~sirable for antihypertensive use. It has five-fold ~he adrenergic ~-receptor blocking potency o~ propranolol shown by oral ad~inlstration to rats followed by challenge of the animals with isoproterenol administered intravenously. The latter is a well known adrener~ic ~-receptor stil~ulant which causes an increase ln heart rate and a decrease in blood pressure. These effects of isoproterenol are antagonized by adrenergic ~-receptor blocklng agents, and the relative potency values given above were prepared by regression analysis of log dose-response data for the two compounds.
For therapeutic use, dosage size and Erequency will vary with the sub~ect and the route of administration, with from about 0.2 mg. for intravenous administration up to about 100 mg orally being suitable for man.
The substance of Procedure 10 is distinguished from other adrenergic B-receYtor blocking drugs in that it is effective in lowering the blood pressure in the spontaneously hypertensive rat.
Although adrenergic ~-receptor blocking agents have come into widespread usc ln human medicine for the treatment of hypertension, their mechanism of action is unknown and their antihypertensive activity cannot be detected by this animal test in most instances. With the present substance in the spontaneously hypertensive rat~ a reduction o blood pressure of 25 mm. of Hg occurs at a dose of 100 mg/kg of body weight orally with only a minimal reduction in heart rate.
This is thought to be indicative of utility in hypertensive indications where other adrenergic ~-receptor blocking drugs are inoperative or less desirable.
The substance of Procedure 10 also causes a reduction in blood pressure when ad~ninistered intravenously to the anesthetized _ ~ _ b;S~B
dog in ~ dose of 3.33 mg/kg of body weight. It is further distJn-gulshed in that it does not depress heart rate or right ventricular cnntractile force as is the case with many prior adrenergic ~-receptor blocking agents. Both a positive inotropic and a positive chronotropic effect are exhibited by the substance, and th~se effects are apparent even when the animal is first treated wlth an adrenergic ~-recptor blocking agent such as sotalol. Pulmonary artery pressure remains substantially unchanged, while aortic blood flow and total peripheral resistance are decreased, all of the foregoing ln the anesthetized dog.
I~le compound of Procedure 10 possesses vasodilator activity which may account, in part, for its unique anti-hypertensive action.
In the anèsthetized ganglion blocked (chlorisondamine chloride) angiotension supported rat, direct acting vasodilators such as diazoxide exert a reduction in blood pressure. The substance of Procedure 10 ls equivalent in potency to diazoxide in this test.
The vasodilator action thereof can also be shown in the pump-perfused hind limb of the dog in doses of from 0.03 to 1.0 mg/min.
of perfuslon. Following oral administration to rats a decrease in urine volume and a decrease in sodium ion excretion occurs whicll is typical of vasodilator compounds.
The antithrombogenic action of the substance of Procedure 10 is reflected by its ability to reduce p]atelet aggregation in vitro in platelet-rich plasma following challenge with ADP or collagen.
It is comparable in in vitro activity to suloctidil or to papaverine.
A hazard exists in the use oE a preponderance of adrenergic B-receptor blocking agents in patients suffering from non-allergic i5~B
bronchodpasm in view of the telldency of these agents to provoke an asthmatic attack or to render the subject re~ractory to treatment with adrenergic ~-receptor stimulants such as isoproterenol which are used in the treatment of acute attacks. The substance of Procedure 10 lacks bronchospastic liability as is demonstrated by the Eact that it does not reduce pulmonary ventriculatory pressure, and evokes only moderate enhancement of the response of sensitized rats to immunologically induced broncho-constriction at a dose of 0.5 mgtkg of body weight intravenously. In contrast~ propranolol at a dose of 0.5 mg/kg of body weight intravenously reduces pulmonary ventilatory pressure and precipitates an acute bronchospastic response in sensitized rats to immunologically-induced broncho-constriction.
For the preparation of pharmaceutical compositions con-taining the compounds of Formula I or Formula II in the form of dosage units for oral administrationl the compound is mixed with a solid, pulverulent carrier such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin, as well as with glidents such as magnesium stearate, calcium stearate, polyethylene glycol waxes or the like and pressed into tablets. The tablets may be used uncoated or coated by known techniques to delay disintegration and absorption in the gastro-intestinal tract and thereby provide a sustained action over a longer period. When coated tablets are wanted, the above prepared core may be coated with a concentrated solution of sugar, which solution may contain e.g. gum arabic, gelatin, talc~ titanium dioxide or the like. Furthermore, the tablets may be coated with a 5~i~
lac~uer dis.solve~ In an easlly volat~le orgallic solvent or mlxture of solvenc~ and lf deslred, dye may be added to this coatlng.
In the preparatlon of so~t gelatin capsules conslsting of gelatin an~ e.g. ~lycerine and the like, the active ingredient is mixed with a vegetahle oil and encapsulated in conventional manner.
Hard gelatin capsules may contain granules of the active lngredient in combination with a solid, pulverulent carrier such as lactose, saccharose, sorbitol, mannitol, starch (such as e.g. potato starch, corn starch, or amylopectin), cellulose derivatives or gelatin.
Dose units for rectal administration may be prepared in the form of suppositories containing the compound in a mixture with a neutra] fàt base, or in the form of a gelatin-rectal capsule with a mixture of vegetable oil or paraffin oil.
Liquld preparations suitable for oral administration are suspensions, syrups and elixirs containing from about 0.2% by weight to about 20% by weight of the active ingredient.
A suitable injectible composition comprises an aqueous solution of a water soluble pharmaceutically acceptable acid addition salt ad~usted to physiologically acceptable pH.
The compounds of Formula I and Formula II are prepared by application of known processes to the appropriate starting mater~als.
Representative known methods for the preparation of aryloxypropanol-amine compounds are disclosed in the foregoing patents and publications rited above under Description of the ~rior Art of which the Troxler Canadian patent No. 834,751 and the Jaeg~l, et al., U.S. Patent No. 3,984~436 are illustrativeO More specifically, the present invention provides a proc~ss for the preparation of the compounds of Formulas I and II
accordlng to the following reaction schcme.
~6S~
O (2~ CH3 Ar' O-CH~CI1C112 3-Indolyl-c~2c-NH2 (l) ~ CH~
CH3 (3) (4~
Ar'-011 + 3-Indolyl-Ci12C-B ~ ormulas I and II
C~2C6~1 1 ~ CH20SO2R
B a -N-CH2CHCH2 , or 1 1---N~_~,O
III IV
In the foregoing reaction scheme, the symbol Ar' represents the groups ArXr~ and ArHet as they are defined in Formula I and Fo~lula II, and the symbol B is deEined by Formulas III and IV in which R
is a lower alkyl group of 4 or fewer carbon atoms. The preferred method is according to reactions (l) and (2) in which step ~l) involves reactin~ the appropriately substituted phenolic cornpound Ar'-OH with epichlorohydrin in the presence of a catalytic quantity of an amine followed by treatment with aqueous alkali metal hydroxide, or conducting the reaction in an aqueous alkali metal hydroxide reaction medium whence the amine catalyst is not required. There is produced in step ~l) an Arl epoxypropyl ether which is caused to react in step (2) with 2-(3-indolyl)~ dimethylethylamine to yield a product o Formula I or Formula II depending upon the nature of - tl-e Ar'OH starting material employed. Each of reaction steps (l) ~nd (2) takes place acilely in ordinary laboratory or plant equip-ment under convenient operating conditions.
5~
HcatLns of epichlorohydrin in s~lbstantial molecu]ar excess amount wlth a phenol Ar'O}I containing a drop or two of plperidine as catalyst on a steam bath overnight results in the condensatlon shown in step (1)~ Some of the corresponding halohydrin intermedlate is also produced and i8 converted without isolation to the oxirane shown by treatment of the mixture with aqueous alkali metal hydroxide. Alternatively, the Ar'OH phenol and epichloro-hydrin can be caused to react in the presence of a sufficient amount of a dilute aqueous alkali metal hydroxide to neutrali~e the acidic Ar 7 OH
group at room temperature with formation of the desired intermediate Ar'OCII2C~CH~. Step (2) is carried out simply by heatin8 the o~irane intermediate produced in step (1) with 2-(3-indolyl)-1,1-dimethyl-ethylamine either neat or in the presence of a reaction inert organic solvent. No catalyst or condensation agent is required. Suitable solvents include 95% ethanol but other reaction inert organic liquids in wllich the reactants are solu~le may he employed. Th~se include but are not limited to benzene, tetrahydrofuran, dibutyl ether, butanol, hexanol, methctnGl, dimethoxyethane, ethylene glycol, etc.
Suitable reaction temperatures are from about 60-200C.
An alternate variation of the process for the preparation of compounds of Formulas I and II involves reaction of the Ar'OH
starting material as defined above with a reactant of the formula ÇH9 3-Indolyl-CH2,C-B according to reaction (3) of the scheme to yield an lntermediate which is transformed to the final product by hydrolysis or hydrogenolysis. The substituent B in the reactant used in step (3) is a group such as shown by IIL or IV which is reactive with the phenolic hydroxyl group Ar'OH to incorporate into the product an incipient propanolaminc slde chain.
. 6 ~
Thc reactarlts for step (3) wherein B has Formula III are prepared by formlng the N--benzyl derivative of 2-(3--indolyl)~
dimethylethylaaline and rcacting the lattcir with epichlorohydrin by adaptation of ~e ~ethod of L. Villa et al., Il. Farmaco. Sci., Ed., 2_, (3) 349 (1CJ69).
Those reactants wherein B has Formula IV are prepared by reductive alkylation of 2-53-indolyl)-19l-dimethylethylamine with glyceraldehvde according to known methocls, for instance, employing 5X palladium-on-carbon catalyst in an atmosphere of hydrogen with methanol or other suitable non-reactive liquid as solvent. When using an opticaliy active form of glyceraldehyde, an optically active end product of Formula I or Formula II is obtained. The amino prepanediol resulting from the foregoing reductive alkylation reaction is then converted to the desired 2-(3-indolyl)-1,1-dimethyl-ethyloxazolidinone reactant wherein B has Formula IV by reaction with formaldehyde employing 37~ aqueous formaldehyde in refluxihg benzene with continued removal of the water by distillation. Esterification with an alkanesulfonyl chloride of the formula RS02Cl in which R is a lower alkyl group of 1 to 4 carbon atoms introduces the necessary group which is reactive with Ar'OH.
The intermediate produced by step (3? wherein the B has Formula III is converted in step (4) to a product of Formula I or Formula II by debenzylation by known means such as catalytic hydro-genation or reaction with sodium in liquid ammonia. The intermediates 2$ produced in step (3) ~herein B has formula IV are converted to the products of formulas I and II in step (4) by mild acid hydrol~sis.
In this instaoce, care must be taken to a~oid clecomposition of the 65i~3 rCaCtallt SillCe the 3-indolyl substitucnt is acld sen~sitlve. Aqueous mineral nclds of from 0.1 N to 1 N concentration at temperatures of from 20-100C. sre suitable. The product is recovered as the free base from the hydrolysis mixture by neutrallzation thereof and collectlng the precipitate.
Description of Speciflc Embodiment~
The 2-(3-indolyl)-1,1-dimethylethylamine employed is prepared by tlle method of H. R. Snyder, et al., J. Am. Chem. Soc., 69, 3140 (19S7) from 3~indoly]methyldimethylamine and 2-nitro-lG propane followed by reductlon of the resulting 2-(3-indolyl)-1,1-dimethylnitroethane.
In the following procedures temperatures are expressed in degrees centigrade t). Melting points are corrected values according to the U.S.P. method where indicated (corr.). The nuclear magnetic resonance (MMR) spectral characteristics refer to chemical shift (~) expressed as parts yer million (ppm) versus tetrarnethylsilane (TMS) as reference standard. The relative area reported for the various shifts corresponds to the number of hydrogen atoms of the particular functional type in the molecule 9 and the nature of the shift as to multiplicity is reported as broad singlet (bs), singlet (s), multiplet (m)l doublee (d), triplet (t), or quadruplet (q) with coupling constants (J) reported where appropriate. The format is N~ (solvent): ~(relative area~ multiplicity, J value). Abbreviations employed are MeOH (methanol), DMSO-d6 (deuterodimethylsulfoxide), i-PrOH (isopropanol), abs.EtOH (absolute ethanol), EtOAc (ethyl acetate), EtOH (95~ ethanol), i-PrOH (isopropanol), i-PrOAc (isopropyl 1~l16~
acetate), i-Pr2O tdi-lsoplopyl ether), d (decomposltion). Other abbreviations have conventional established nleanings. The infrared (IR) spectral descriptions include only absorption wave numbers (cm ) having functional group identification value. KBr was employed as diluent for ail IR spectral determinations. T~S was used as internal reference for the NMR spectral determination. The elemental analyses are reported as percent by weight.
Procedure 1. 4-(Methylsulfonyl)-m-tolyloxymethyl Oxirane.-To a mixture of 3~methyl-4-methylsulfonylphenol, 8.1 g. (0.0435 mole), and 20.0 g. (0.216 mole) of epichlorohydrin, there are added two drops of piperidine to serve as condensation catalyst and the mixture is heated at 105-108 for 18 hrs. The excess epichlor-hydrin is then removed by distillation using toluene as a chaser.
A solution of 2.1 g. of sodium hydroxide in 50 ml. of water and 70 ml. of dimethoxyethane is then added and the mixture is stirred for 2 hrs. with occasional warming on the steam bath to convert any phenoxychlorohydrin compound to the ox:lrane. The solvent is then removed by distillation in vacuo and the residue is dissolved in a 1:1 (VIV) mixture of ether and benzene. ThP ~olution is dried over ~nhydrous sodium carbonate and examined by thin layer chromatography for purity of the desired oxirane using a 9:1 mixture of chloroform aud a methanol for development (Rf = 0.8). The solvent is then removed by distillation to yield 10.7 g. of a residue constituting the desired oxirane. ~easurement of th~ infrared absorption spectrum is employed to confirm the substantial absence ~f hydroxyl containing contaminallts. This material is suitable for further reaction in Procedure 3 without further purification.
~6;5~ `
Procedure 2. 2-CIllorophen_~ymethyl Oxlrane.- A solution of 12.9 g. of 2-chlorophenol (0.1 mole) in 125 ml. of water con-tainln~ 6.5 g. (0.162 mole) of sodium hydro~ide, and 18.5 g.
(0.2 mole) of epichlorohydrin are stirred together at 25 for 20 hrs. The mixture is then extracted twice with 70 ml. portions of methylene chloride. The extract is dried over anhydrous sodium carbo~ate and tlle solvent removed by distillation in vacuo. The residue constltutes the desired oxirane and is suitable for further transformation as is described in Procedure 4.
Procedure 3. 1-C[2-(3-Indolyl)-l,l-dimethylethyl]amino]-3-[4-(methylsulfonyl)-m-tolyloxy~-2-propanol.- The oxirane of Procedure 1, 10.7 g.,was dissolved in 150 ml. of toluene, 8.2 g.
(0.044 mole) of 2-t3-indolyl)-1,1-dimethylethylamine was added and the mixture was refiuxed for 18 hrs. The toluene was removed by distillation in vacuo and a portion of the residue was converted _ to the acetate salt, m.p. 142 147C. The structure was confirmed by examination of the infrared absorption and nuclear megne~ic resonance spec~ra. The remainder of the sample was converted to the hydrochloride salt by treatment of an acetonitrile solution thereof with 8 N ethanolic HCl. After recrystalli~ation from CH3CNIMeOH 12.5 g. of product was obtained, m.p. 174.0-177.0 (corr.).
Anal. Found: C, 59.40; H, 6.90; N, 5.87.
NMR (DMSO-d6): 1.29 ~6, s); 2.52 (3, s); 3.12 (3, s);
3.16 (4, ~); 4.18 (3, m); 5.95 (1, bs); 7.10 (8, m); 9.00 (2, bs);
and 11.12 (1, bs).
IR: 740, 765, 1120, 1290, 1450, 1590, and 3270.
Proccd~lr~ 4 . 1- (?- L ~)~, I_ -dlmettl~leLhy11a ino]~ ropano1.- A portlc-n of thc oxirane produced in Procedu1e 2, 7 g. (0.033 mole), was reflu~ed in solution with 6.3 g. ~0.033 mole) of 2--(3-indolyl)~ dimethyl-ethylamine ln 70 ml. oE ethanol. Afeer 24 hrs. the solvent wa.sremoved hy distlllation in vacuo and the viscous liquld residue was dissolved in 200 ml. of ether, acidified with 8 N ethanolic HCl and the solvents again removed by distl]lation. Crystallization was induced by adding acetonitrile and rubbing with a glass rod.
Recystallized from acetonitrile and di-isopropyl ether to yield
4.8 g. of product, m.p. 150.5-153.5C. (corr.).
Anal. Found: C, 61.54; H, 6.41; N, 6.94.
N~fR (DMS0-d6): 1.28 (6, s); 3.22 (4, m); 4.25 (3, m); 5.96 (1, bs);
7.23 (9, m); 8.84 (2, bs); and 11.12 (1, bs).
IR: 745, 1250, 1455, 1480, 1590, and 2780.
By adaptation o~ the foregoing procedures, the products listed in the following table were prepared.
,. 19 S~
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Anal. Found: C, 61.54; H, 6.41; N, 6.94.
N~fR (DMS0-d6): 1.28 (6, s); 3.22 (4, m); 4.25 (3, m); 5.96 (1, bs);
7.23 (9, m); 8.84 (2, bs); and 11.12 (1, bs).
IR: 745, 1250, 1455, 1480, 1590, and 2780.
By adaptation o~ the foregoing procedures, the products listed in the following table were prepared.
,. 19 S~
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Procedllre 15. Tablets.- ~e following ingredients are blended in the proportion by weight indicated according to con-ventional pharmaceutical technigues to provide a tablet base.
Ingredient ~mount Lactose 79 Corn starch 10 Talcum 6 Tragacanth 4 Magnesium steara-te This tablet base is blended with sufficient 1-[[2-(3-indolyl)-l,l-dimethylethyl]amino]-3-(2-methylphenoxy)-2-propanol hydrochloride (Procedure 10) to provide tablets containing 10,-20, 40, 80, 160 and 320 mg. oE active ingredient, and compressed in a conven-tional tablet press.
Procedure 16. Dry ~illed Capsules.- The following ingredients are blended in a conventional manner in the proportion by weight indicated.
Ingredient Amount Lactose, U.S.P. 50 Starch 5 Magnesium stearate 2 Sufficient 1-[[2-(3-indolyl)-1,1-dimethylethyl]amino]-3-(2-methylphenoxy)-2-propanol hydrochloride (Procedure 10) is added to the blend to provide capsules containing 10, 20, 40, 80, 160, and 320 mg. of active ingredient which is filled into hard gelatin capsules of a suitable size.
~16~
Proc_dllr~ 17. So~ution.- /~ solution of l-Cc2-(3~ dolyl)-1,1-dlmc-hylethyl]a~ lo]-3~ methylphenoxy)-2-propanol hydrochloride (Procedure lO) is prepared from the followlng ingredients.
Inp~redient Amount Ac.tive ingredient 20 g.
Sucrose, U.S.P. 400 g.
Sorbitol~ U.S.P. 100 g.
Bentonite 20 g.
Flavors, q.s.
Water, q.s. to make l liter Each milllli.ter of the solution contains approximately 20 mg.
of the active ingredient.
By application of the methods of Procedures l or 2 to the ap~-ropriate phcnol,~or by other conventional method~, the following oxiranes are prepared and then converted to products of Formula I
- or II by reaction ~ith 2-(3-indolyl)-l ! l-dimethyl.ethylamine according to Procedures 3 or 4.
~ O-CH,CHCH, ~ CH,CH-CH
Proc. 18 Proc. l9 O
Cll,CH=CHC - ~ _ OCU,CIICH, Cl1350 ~ OCH,CNCH~
Proc. 20 Proc. 21 - 25 - ~
5~ ~
OCH2CH~H2 C
Proc. 22 Proc. 23 O O
OCH2 ~CH2 ~ OCH2CHCH2 Proc. 24 Proc. 25 OCII, ~CH, ~ OCH,CHCU~
N OCH2CH=CH2 Proc. 26 Proc. 27 O O
Cl ~ OCH2CHCH, F ~ OCII,CHCH, Cl Proc. 28 Proc. 29 O O
OCH,C~ICH, ~ D~H ~CH, CONHC~13 Proc~ 30 Proc. 31 , oc~l2c~lCI~2 / I
C}12CHCH2 CON(CI13) 2 Pr~c. 32 Proc. 33 --OCH2fHCH2 ~CH2CHCH2 Proc. 34 - Proc. 35 pCH 2 CH)CH 2 ~OCH 2CHCH2 CONI12 ~r Proc. 36 Proc. 37 ;lUCN~ OCU l~l~C I
~ CO2C2H5 ~
Proc. 38 Proc. 39 s~
~OCI},CHC}I ~U;II 1, Proc. 40 Proc. 41 / ~ /01 2~GCH 2 CHC:H 2G( QCH 2 CUCH 2 CH9CO H2CN CH2CH(C~3) 2 Proc. ~2 Proc. 43 ~HCH, ~C2H~
Proc. 44 Proc. 45 ~OCH,CHCII, ex OC'.12CI}CH, SO2CH~, CF9 Proc. 45 Prclc. 47 -- 2~ --~6~
o o OCH2CHC}I2 ~ OCH2CHCH2 Proc. 48 Proc. 49 o n ~ ~ oru,c/u~cu. ~ \cu~
Proc. ~O Proc. 51 ~ UCH, ~ OCU,CUCH:
Proc. 52 Proc. 53 Physic~l properties were deter~lned as follows:
.~9 _ 5~3 _roccdurc 1'3.- 1-Cr2-(3-indolyl~ dime~hylethyllam1no~-3-~2-(2-prope~yl)phenoxy } 2-propanol hydrochloride, m.p. 163.0-168.6 (corr.), recrystallized from MeOI~/i-Pr~O.
_ . Found: C, 69.22; H, 7.56; N, 6.70.
NMR (DMSO-d6): 1.30 (6,s); 3.32 (6,m); 4.20 (3,m); 5.03 (~,m); 6.00 (2,m); 7.25 (9,m); 8.90 (l,bs); 9.60 (l,bs); and 11.40 (l,bs).
IR: 752, 1120, 1245, 1455, 1490~ 1590, 1600, 2790, 2980, and 3350.
Procedure 43. 1-~C2-(3-Indolyl)-1,1-dimethylethyl]amino~-3-C2-(2-methyl-1-propyl)phenoxy }2-propanol hydrochloride, m.p.
163.0-166.0~ tcorr-), recrystallized from MeOH/CH3CN.
_nal. Found: C, 69.34; H, 8.19; N, 6.49.
NMR (DMSO-d6): 0.81 (3,t, 7.0 Hz); 1.17 (3,d, 7.0 Hz);
1.32 (6,s); 1.39 (2,m); 3.28 (5,m); 4.22 (3,m); 6.04 (l,bs); 7.22 (9,m); 9.00 (l,bs); 9.60 (l,bs); 11.20 (l,bs).
IR: 750, 1100, 1240, 1450, ;1490, 1582, 1600, 2780, 2960, and 3320.
Procedure 45.- 3-~2-Ethylphenoxy)-1-~C2-(3-indolyl)-1,1-di~leehyleehyl]am~no]-2-propanol hydrochloride, m.p. 170.0-171.5 ~Corr.) recrystallized from EtOH.
Anal. Found: C, 68.36; H, 7.95; N, 6.85.
N~ MSO-d~): 1.21 (3,5, 7.0 Hz); 1.33 (6.s); 2.64 (2,m); 3.24 (4,m); 4.21 (3,m); 6.00 ~l,bs); 7.25 (9,m); 9.00 (l,bs);
and 9.55 (l,bs~
IR: 750, 1130, 1240, 1460, 1495, 1590, 1605, 2800, 2970, and 3350.
o o o oo ôô
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n ~D ~ ~ ~ t~ O ~ u~ ~ t~ r~
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Procedllre 15. Tablets.- ~e following ingredients are blended in the proportion by weight indicated according to con-ventional pharmaceutical technigues to provide a tablet base.
Ingredient ~mount Lactose 79 Corn starch 10 Talcum 6 Tragacanth 4 Magnesium steara-te This tablet base is blended with sufficient 1-[[2-(3-indolyl)-l,l-dimethylethyl]amino]-3-(2-methylphenoxy)-2-propanol hydrochloride (Procedure 10) to provide tablets containing 10,-20, 40, 80, 160 and 320 mg. oE active ingredient, and compressed in a conven-tional tablet press.
Procedure 16. Dry ~illed Capsules.- The following ingredients are blended in a conventional manner in the proportion by weight indicated.
Ingredient Amount Lactose, U.S.P. 50 Starch 5 Magnesium stearate 2 Sufficient 1-[[2-(3-indolyl)-1,1-dimethylethyl]amino]-3-(2-methylphenoxy)-2-propanol hydrochloride (Procedure 10) is added to the blend to provide capsules containing 10, 20, 40, 80, 160, and 320 mg. of active ingredient which is filled into hard gelatin capsules of a suitable size.
~16~
Proc_dllr~ 17. So~ution.- /~ solution of l-Cc2-(3~ dolyl)-1,1-dlmc-hylethyl]a~ lo]-3~ methylphenoxy)-2-propanol hydrochloride (Procedure lO) is prepared from the followlng ingredients.
Inp~redient Amount Ac.tive ingredient 20 g.
Sucrose, U.S.P. 400 g.
Sorbitol~ U.S.P. 100 g.
Bentonite 20 g.
Flavors, q.s.
Water, q.s. to make l liter Each milllli.ter of the solution contains approximately 20 mg.
of the active ingredient.
By application of the methods of Procedures l or 2 to the ap~-ropriate phcnol,~or by other conventional method~, the following oxiranes are prepared and then converted to products of Formula I
- or II by reaction ~ith 2-(3-indolyl)-l ! l-dimethyl.ethylamine according to Procedures 3 or 4.
~ O-CH,CHCH, ~ CH,CH-CH
Proc. 18 Proc. l9 O
Cll,CH=CHC - ~ _ OCU,CIICH, Cl1350 ~ OCH,CNCH~
Proc. 20 Proc. 21 - 25 - ~
5~ ~
OCH2CH~H2 C
Proc. 22 Proc. 23 O O
OCH2 ~CH2 ~ OCH2CHCH2 Proc. 24 Proc. 25 OCII, ~CH, ~ OCH,CHCU~
N OCH2CH=CH2 Proc. 26 Proc. 27 O O
Cl ~ OCH2CHCH, F ~ OCII,CHCH, Cl Proc. 28 Proc. 29 O O
OCH,C~ICH, ~ D~H ~CH, CONHC~13 Proc~ 30 Proc. 31 , oc~l2c~lCI~2 / I
C}12CHCH2 CON(CI13) 2 Pr~c. 32 Proc. 33 --OCH2fHCH2 ~CH2CHCH2 Proc. 34 - Proc. 35 pCH 2 CH)CH 2 ~OCH 2CHCH2 CONI12 ~r Proc. 36 Proc. 37 ;lUCN~ OCU l~l~C I
~ CO2C2H5 ~
Proc. 38 Proc. 39 s~
~OCI},CHC}I ~U;II 1, Proc. 40 Proc. 41 / ~ /01 2~GCH 2 CHC:H 2G( QCH 2 CUCH 2 CH9CO H2CN CH2CH(C~3) 2 Proc. ~2 Proc. 43 ~HCH, ~C2H~
Proc. 44 Proc. 45 ~OCH,CHCII, ex OC'.12CI}CH, SO2CH~, CF9 Proc. 45 Prclc. 47 -- 2~ --~6~
o o OCH2CHC}I2 ~ OCH2CHCH2 Proc. 48 Proc. 49 o n ~ ~ oru,c/u~cu. ~ \cu~
Proc. ~O Proc. 51 ~ UCH, ~ OCU,CUCH:
Proc. 52 Proc. 53 Physic~l properties were deter~lned as follows:
.~9 _ 5~3 _roccdurc 1'3.- 1-Cr2-(3-indolyl~ dime~hylethyllam1no~-3-~2-(2-prope~yl)phenoxy } 2-propanol hydrochloride, m.p. 163.0-168.6 (corr.), recrystallized from MeOI~/i-Pr~O.
_ . Found: C, 69.22; H, 7.56; N, 6.70.
NMR (DMSO-d6): 1.30 (6,s); 3.32 (6,m); 4.20 (3,m); 5.03 (~,m); 6.00 (2,m); 7.25 (9,m); 8.90 (l,bs); 9.60 (l,bs); and 11.40 (l,bs).
IR: 752, 1120, 1245, 1455, 1490~ 1590, 1600, 2790, 2980, and 3350.
Procedure 43. 1-~C2-(3-Indolyl)-1,1-dimethylethyl]amino~-3-C2-(2-methyl-1-propyl)phenoxy }2-propanol hydrochloride, m.p.
163.0-166.0~ tcorr-), recrystallized from MeOH/CH3CN.
_nal. Found: C, 69.34; H, 8.19; N, 6.49.
NMR (DMSO-d6): 0.81 (3,t, 7.0 Hz); 1.17 (3,d, 7.0 Hz);
1.32 (6,s); 1.39 (2,m); 3.28 (5,m); 4.22 (3,m); 6.04 (l,bs); 7.22 (9,m); 9.00 (l,bs); 9.60 (l,bs); 11.20 (l,bs).
IR: 750, 1100, 1240, 1450, ;1490, 1582, 1600, 2780, 2960, and 3320.
Procedure 45.- 3-~2-Ethylphenoxy)-1-~C2-(3-indolyl)-1,1-di~leehyleehyl]am~no]-2-propanol hydrochloride, m.p. 170.0-171.5 ~Corr.) recrystallized from EtOH.
Anal. Found: C, 68.36; H, 7.95; N, 6.85.
N~ MSO-d~): 1.21 (3,5, 7.0 Hz); 1.33 (6.s); 2.64 (2,m); 3.24 (4,m); 4.21 (3,m); 6.00 ~l,bs); 7.25 (9,m); 9.00 (l,bs);
and 9.55 (l,bs~
IR: 750, 1130, 1240, 1460, 1495, 1590, 1605, 2800, 2970, and 3350.
Claims (24)
1. A process for the preparation of a compound having Formula I or Formula II
(Formula I), and (Formula II) and the acid addition salts thereof wherein Ar is selected from the group consisting of phenyl and naphthyl, X refers to optional Ar-attached substituents which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkanoyl, alkenoyl, alkanoyloxy, alkenoyloxy, alkylsulfonyl, alkylsulfinyl, alkylthio, alkanoamido, cycloalkyl having 3 to 5 ring members and 1 to 3 optional alkyl substituents, cycloalkylalkyl having 3 to 6 ring members and 1 to 3 optional alkyl sub-stituents, wherein each of the foregoing groups has up to 8 carbon atoms, phenyl, trifluoromethyl, nitro, amino, hydroxyl, halogen, carboxamido, cyano, and cyanoalkyl having from 2 to 4 carbon atoms, is the integer 0, 1, or 2 signifying the number of X groups, and Het is an Ar-attached heterocyclic substituent selected from the group consisting of l-pyrrolyl, 2-oxo-1-pyrrolidinyl having a substituent in the 4-position selected from aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, and alkoxycarbonyl, wherein said alkyl and alkoxy groups have 1 to 4 carbon atoms, 4-morpholinyl, 4-thiamorpholinyl, 3-oxo-1-pyrazolidinyl, and 2-imidazolyl, wherein (a) an epoxypropyl ether starting material of the formula wherein Ar' is Ar-Xn or Ar-Het as defined above is contacted under reaction conditions with [2-(3-indolyl)-1,1-dimethylethyl]amine wherein said reaction conditions involve either heating neat or in the presence of a reaction inert organic liquid medium such as a lower alkanol including methanol, ethanol, butanol, or hexanol, a hydrocarbon such as benzene or toluene, an ether such as tetrahydrofuran, dibutylether, or dimethoxyethane, or ethyleneglycol at a temperature of from about 60-200°C. to yield a compound of Formula I
or Formula II, or (b) contacting a phenolic compound of the formula Ar'-OH
wherein Ar' is AR-X or Ar-Het as defined above with an intermediate of Formula III or Formula IV
Formula III
Formula IV
wherein R is a lower alkyl group of 4 or fewer carbon atoms under reaction conditions and when employing an Intermediate of Formula III debenzylating the resulting product by known means such as catalytic hydrogenation or reaction with sodium in liquid ammonia to produce a compound of Formula I or Formula II and when employing an intermediate of Formula IV recovering and converting the resulting product to a product of Formula I or Formula II by contact thereof with dilute aqueous mineral acid at a temperature from 20-100°C., and if desired when the base of Formula I or Formula II is obtained converting said base to a pharmaceutically acceptable acid addition salt.
(Formula I), and (Formula II) and the acid addition salts thereof wherein Ar is selected from the group consisting of phenyl and naphthyl, X refers to optional Ar-attached substituents which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkanoyl, alkenoyl, alkanoyloxy, alkenoyloxy, alkylsulfonyl, alkylsulfinyl, alkylthio, alkanoamido, cycloalkyl having 3 to 5 ring members and 1 to 3 optional alkyl substituents, cycloalkylalkyl having 3 to 6 ring members and 1 to 3 optional alkyl sub-stituents, wherein each of the foregoing groups has up to 8 carbon atoms, phenyl, trifluoromethyl, nitro, amino, hydroxyl, halogen, carboxamido, cyano, and cyanoalkyl having from 2 to 4 carbon atoms, is the integer 0, 1, or 2 signifying the number of X groups, and Het is an Ar-attached heterocyclic substituent selected from the group consisting of l-pyrrolyl, 2-oxo-1-pyrrolidinyl having a substituent in the 4-position selected from aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, and alkoxycarbonyl, wherein said alkyl and alkoxy groups have 1 to 4 carbon atoms, 4-morpholinyl, 4-thiamorpholinyl, 3-oxo-1-pyrazolidinyl, and 2-imidazolyl, wherein (a) an epoxypropyl ether starting material of the formula wherein Ar' is Ar-Xn or Ar-Het as defined above is contacted under reaction conditions with [2-(3-indolyl)-1,1-dimethylethyl]amine wherein said reaction conditions involve either heating neat or in the presence of a reaction inert organic liquid medium such as a lower alkanol including methanol, ethanol, butanol, or hexanol, a hydrocarbon such as benzene or toluene, an ether such as tetrahydrofuran, dibutylether, or dimethoxyethane, or ethyleneglycol at a temperature of from about 60-200°C. to yield a compound of Formula I
or Formula II, or (b) contacting a phenolic compound of the formula Ar'-OH
wherein Ar' is AR-X or Ar-Het as defined above with an intermediate of Formula III or Formula IV
Formula III
Formula IV
wherein R is a lower alkyl group of 4 or fewer carbon atoms under reaction conditions and when employing an Intermediate of Formula III debenzylating the resulting product by known means such as catalytic hydrogenation or reaction with sodium in liquid ammonia to produce a compound of Formula I or Formula II and when employing an intermediate of Formula IV recovering and converting the resulting product to a product of Formula I or Formula II by contact thereof with dilute aqueous mineral acid at a temperature from 20-100°C., and if desired when the base of Formula I or Formula II is obtained converting said base to a pharmaceutically acceptable acid addition salt.
2. The product of formula I or formula II in Claim 1 when produced by the process of Claim 1.
3. The process of claim 1 wherein said epoxypropyl ether starting material of the formula Ar' is contacted with [2-(3-indolyl)-1,1-dimethylethyl]amine in the presence of a lower alkanol as reaction medium at the reflux temperature.
4. The product of formula I or formula II in Claim 1 when produced by the process of Claim 1 or the process of Claim 3.
5. The process of claim 3 wherein ethanol is employed as reaction medium and 2-[(2,3-epoxy)propoxy]benzonitrile is used as epoxypropyl ether starting material.
6. 2-[2-Hydroxy-3-[[2-(3-indolyl)-1,1-dimethylethyl]amino]-propoxy]benzonitrile when produced by the processes of Claims 1, 3 or 5.
7. The process of Claim 5 wherein the resulting product is converted to the hydrochloride salt by dissolving in isopropanol and treatment of the solution with HCl.
8. 2-[2-Hydroxy-3-[[2-(3-indolyl)-l,l-dimethylethyl]amino]-propoxy]benzonitrile hydrochloride when produced by the processes of Claims l, 3 or 5.
9. The process of Claim 1 wherein said epoxypropyl ether starting material is contacted with [2-(3-indolyl)-l,l-dimethylethyl]-amine neat at a temperature of from 60-200°C.
10. The product of formula I or formula II in Claim 1 when produced by the processes of Claim 1 or Claim 9.
11. The process of Claim 9 wherein [(2-methylphenoxy)-methyl]oxirane is contacted with [2-(3-indolyl)-1,1-dimethylethyl]-amine neat at a temperature of 140°C. for one-half hour.
12. 1-[[2-(3-Indolyl)-l,l-dimethyletllyl]amino]-3-(2-methyl-phenoxy)-2-propanol when produced by the processes of Claims 1, 9 or 11.
13. The process of Claim 11 wherein the resulting product is converted to the hydrochloride salt.
14. 1-[[2 (3-Indolyl)-l,l-dimethylethyl]amino]-3-(2-methyl-phenoxy)-2-propanol hydrochloride when produced by the processes of Claims 9, 11 or 13.
15. The process of Claim 3 wherein said epoxypropyl ether starting material is 2-[(2,3-epoxy)propoxy]benzamide.
16. 2-[2-Hydroxy 3-[[2-(3-indolyl)-1,1-dimethylethyl]amino]-propoxy]benzamide when produced by the processes of Claims 1, 3 or 15.
17. The process of Claim 3 wherein said epoxypropyl ether starting material is 2-[[2-(trifluoromethyl)phenoxy]methyl]oxirane.
18. 1-[[2-(3-Indolyl)-l,l-dimethylethyl]amino]-3-[2-(trifluoromethyl)phenoxy]-2-propanol when produced by the processcs of Claims 1, 3 or 17.
19. The process of Claim 3 wherein said epoxypropyl ether starting material is 2-[(2-aminophenoxy)methyl]oxirane.
20. 1-(2-Aminophenoxy)-3-[[2-(3-indolyl)-1,1-dimethyl-ethyl]amino]-2-propanol when produced by the processes of Claims 1, 3 or 19.
21. The process of Claim 19 wherein the resulting product is converted to the dihydrochloride salt.
22. 1-(2-Aminophenoxy) 3-[[2-(3-indolyl)-l,l-dimethylethyl]-amino]-2-propanol dihydrochloride when produced by the processes of Claims 3, 19 or 21.
23. The process of Claim 3 wherein said epoxypropyl ether starting material is 2-[(2,4-dimethylphenoxy)ethyl]oxirane.
24. 1-(2,4-Dimethylphenoxy)-3-[[2-3-indolyl)-1,1-dimethyl-ethyl]amino]-2-propanol when produced by the processes of Claims 1, 3 or 23.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US81513877A | 1977-07-13 | 1977-07-13 | |
US815,138 | 1977-07-13 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1116598A true CA1116598A (en) | 1982-01-19 |
Family
ID=25216976
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000305281A Expired CA1116598A (en) | 1977-07-13 | 1978-06-12 | 3-indolyl-tertiary butylaminopropanols |
Country Status (30)
Country | Link |
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JP (1) | JPS5419972A (en) |
AR (1) | AR225274A1 (en) |
AT (1) | AT364821B (en) |
AU (1) | AU525064B2 (en) |
BE (1) | BE868943A (en) |
CA (1) | CA1116598A (en) |
CH (1) | CH642066A5 (en) |
CY (1) | CY1274A (en) |
DE (1) | DE2830884A1 (en) |
DK (1) | DK156568C (en) |
ES (1) | ES471674A1 (en) |
FI (1) | FI69835C (en) |
FR (1) | FR2397404A1 (en) |
GB (1) | GB2001633B (en) |
GR (1) | GR74488B (en) |
HK (1) | HK1385A (en) |
HU (1) | HU178992B (en) |
IE (1) | IE47122B1 (en) |
IL (1) | IL55115A (en) |
IT (1) | IT1105091B (en) |
KE (1) | KE3485A (en) |
LU (1) | LU79966A1 (en) |
MY (1) | MY8500946A (en) |
NL (1) | NL189946C (en) |
NO (1) | NO149311C (en) |
NZ (1) | NZ187763A (en) |
SE (1) | SE429339B (en) |
SG (1) | SG82584G (en) |
YU (1) | YU40528B (en) |
ZA (1) | ZA783744B (en) |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2463765A1 (en) * | 1979-08-17 | 1981-02-27 | Clin Midy | NEW ACTIVE INDOLE DERIVATIVES ON THE CARDIOVASCULAR SYSTEM |
US4321398A (en) * | 1981-05-07 | 1982-03-23 | Mead Johnson & Company | Thienyl and benzothienyl-tertiary butylaminophenoxypropanols |
DE3119796A1 (en) * | 1981-05-19 | 1982-12-23 | Hoechst Ag, 6000 Frankfurt | SUBSTITUTED TRYPTAMINE DERIVATIVES OF THIENYLOX PROPANOLAMINES, METHODS FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS BASED ON THESE COMPOUNDS AND THEIR USE |
FR2523964B1 (en) * | 1982-03-23 | 1985-09-27 | Sanofi Sa | NOVEL TRYPTAMINE DERIVATIVES ACTIVE IN PARTICULAR ON THE CARDIOVASCULAR SYSTEM AND PROCESS FOR THEIR PREPARATION |
NZ208337A (en) * | 1983-06-10 | 1988-10-28 | Bristol Myers Co | 2-(2-hydroxy-3-((2-(ar-hydroxy-1h-aminopropoxy-yl)ethyl benzonitriles and pharmaceutical compositions |
FR2601008B1 (en) * | 1986-07-03 | 1990-03-30 | Sanofi Sa | PROCESS FOR THE STEREOSPECIFIC SYNTHESIS OF INDOLE DERIVATIVES |
CA2421594A1 (en) | 2000-11-10 | 2002-05-16 | John Arnold Werner | 3-substituted oxindole beta 3 agonists |
DE60211199T2 (en) | 2001-08-14 | 2007-02-01 | Eli Lilly And Co., Indianapolis | 3-SUBSTITUTED OXINDOL BETA-3 AGONISTS |
ES2272749T3 (en) * | 2001-08-14 | 2007-05-01 | Eli Lilly And Company | DERIVATIVES OF INDOL AS BETA-3 ADRENERGIC AGONISTS FOR THE TREATMENT OF TYPE 2 DIABETES. |
JP2005518357A (en) | 2001-11-20 | 2005-06-23 | イーライ・リリー・アンド・カンパニー | Beta 3 adrenergic agonist |
ATE297925T1 (en) | 2001-11-20 | 2005-07-15 | Lilly Co Eli | 3-SUBSTITUTED OXINDOL BETA 3 AGONISTS |
US7009060B2 (en) | 2002-01-11 | 2006-03-07 | Eli Lilly And Company | 2-oxo-benzimidazolyl substituted ethanolamine derivatives and their use as β3 agonists |
CA2960254A1 (en) | 2008-08-01 | 2010-02-04 | Arca Biopharma, Inc. | Methods and compositions involving (s)-bucindolol |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR1532210A (en) * | 1963-06-21 | 1968-07-12 | Ici Ltd | Heterocyclic compounds and their preparation process |
CH495983A (en) * | 1968-02-09 | 1970-09-15 | Sandoz Ag | Process for the preparation of levorotatory 4- (2-hydroxy-3-isopropylaminopropoxy) indole |
US3371098A (en) * | 1966-11-29 | 1968-02-27 | Philips Corp | 5- and 6-methoxy-3-(phenoxyethyl-aminoethyl)-indoles |
US3946009A (en) * | 1972-05-05 | 1976-03-23 | Merck Sharp & Dohme (I.A.) Corporation | 2-(3-Substituted amino-2-hydroxypropoxy)-3-substituted pyrazines |
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1978
- 1978-06-12 CA CA000305281A patent/CA1116598A/en not_active Expired
- 1978-06-29 ZA ZA00783744A patent/ZA783744B/en unknown
- 1978-07-03 AU AU37704/78A patent/AU525064B2/en not_active Expired
- 1978-07-03 NZ NZ187763A patent/NZ187763A/en unknown
- 1978-07-05 YU YU1611/78A patent/YU40528B/en unknown
- 1978-07-07 AR AR272873A patent/AR225274A1/en active
- 1978-07-10 IL IL55115A patent/IL55115A/en unknown
- 1978-07-10 SE SE7807700A patent/SE429339B/en not_active IP Right Cessation
- 1978-07-10 FI FI782205A patent/FI69835C/en not_active IP Right Cessation
- 1978-07-10 IT IT50228/78A patent/IT1105091B/en active
- 1978-07-10 CY CY1274A patent/CY1274A/en unknown
- 1978-07-10 GB GB787829333A patent/GB2001633B/en not_active Expired
- 1978-07-11 NO NO782407A patent/NO149311C/en unknown
- 1978-07-11 GR GR56751A patent/GR74488B/el unknown
- 1978-07-12 IE IE1400/78A patent/IE47122B1/en not_active IP Right Cessation
- 1978-07-12 CH CH759378A patent/CH642066A5/en not_active IP Right Cessation
- 1978-07-12 DK DK313878A patent/DK156568C/en not_active IP Right Cessation
- 1978-07-12 LU LU79966A patent/LU79966A1/en unknown
- 1978-07-12 FR FR7820851A patent/FR2397404A1/en active Granted
- 1978-07-12 BE BE189237A patent/BE868943A/en not_active IP Right Cessation
- 1978-07-12 HU HU78BI569A patent/HU178992B/en unknown
- 1978-07-12 ES ES471674A patent/ES471674A1/en not_active Expired
- 1978-07-13 AT AT0508978A patent/AT364821B/en not_active IP Right Cessation
- 1978-07-13 DE DE19782830884 patent/DE2830884A1/en active Granted
- 1978-07-13 NL NLAANVRAGE7807564,A patent/NL189946C/en not_active IP Right Cessation
- 1978-07-13 JP JP8461378A patent/JPS5419972A/en active Granted
-
1984
- 1984-11-19 SG SG825/84A patent/SG82584G/en unknown
- 1984-12-07 KE KE3485A patent/KE3485A/en unknown
-
1985
- 1985-01-03 HK HK13/85A patent/HK1385A/en not_active IP Right Cessation
- 1985-12-30 MY MY946/85A patent/MY8500946A/en unknown
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