Carboxamide compounds as SRS-A antagonists

BACKGROUND OF THE INVENTION
This invention relates to new chemical compounds, and more particularly it relates to derivatives of propenamide, 2-methylpropenamide, 2-butenamide, 2-methyl-2-butenamide and cyclopropanecarboxamide. Said derivatives are substituted on the nitrogen atom by an alkyl or cycloalkyl group. Additionally, said propenamide, 2-methylpropenamide, 2-butenamide and 2-methyl-2-butenamide derivatives are further substituted at the 3-position by a (4-carboxy-2-oxo-pyrrolidino)phenyl group, and said cyclopropanecarboxamide derivatives are further substituted at the 2-position by a (4-carboxy-2-oxo-pyrrolidino)phenyl group. These compounds are useful as antagonists of the slow-reacting substance of anaphylaxis (SRS-A).
It is known that certain substances, known as mediators of anaphylaxis, play an important role in inducing an allergic reaction, such as bronchospastic attack or allergic rhinitis, in a human subject. Two examples of such mediators are histamine and the slow-reacting substance of anaphylaxis (SRS-A), the latter substance being a very important mediator in allergic bronchial asthma. SRS-A is a substance which is synthesized and released in or near target tissues, in a sensitive (allergic) human subject, shortly after challenge with the appropriate antigen. The human bronchus is particularly sensitive to SRS-A.
Rational approaches to drug therapy to prevent, remove or ameliorate the symptoms of allergic reactions have focussed on either blocking the release of mediators of anaphylaxis, or, on the other hand, on antagonizing their effects. Disodium cromoglycate (The Merck Index, Merck and Co., Inc., Rahway, N.J., 9th Edition, 1976, 2585) is a drug which has recently been introduced and which blocks the release of mediators of anaphylaxis, and commercially available drugs which antagonize histamine (antihistamines) are well-known (e.g. methapyrilene, diphenhydramine, chlorpheniramine). Conversely, there is a paucity of substances known which antagonize SRS-A, and none of them is used in clinical practice today. One agent has been widely studied (FPL 55712--Agents and Actions, 9, 133 [1979]).
SUMMARY OF THE INVENTION
This invention provides novel carboxamide compounds of the formula ##STR1## and the pharmaceutically acceptable salts thereof;
wherein R.sup.1 is selected from the group consisting of hydrogen, alkyl having 1 to 4 carbons, and --CH.sub.2 --CH.sub.2 --NR.sup.3 R.sup.4, wherein R.sup.3 and R.sup.4 are each alkyl having 1 to 3 carbons;
R.sup.2 is selected from the group consisting of alkyl having 8 to 15 carbons and cycloalkyl having from 6 to 12 carbons;
and Q is selected from the group consisting of ##STR2## wherein R.sup.5 and R.sup.6 are each selected from the group consisting of hydrogen and methyl;
with the proviso that when Q is ##STR3## the two groups attached to the ##STR4## have a trans relationship to each other.
When either of R.sup.1 and R.sup.2 is an alkyl group, it can be straight-chain or branched-chain. R.sup.3 and R.sup.4 can be straight-chain or branched-chain.
This invention also provides a method of antagonizing the spasmogenic activity of the slow-reacting substance of anaphylaxis (SRS-A) in a human subject, which comprises administering to said subject an effective amount of a compound of the formula I, or a pharmaceutically-acceptable salt thereof. The compounds of formula I are antagonists of the effects of slow-reacting substance of anaphylaxis (SRS-A), and they are useful therefore for preventing and treating certain obstructive airways diseases, notably allergic bronchial asthma, allergic rhinitis and certain skin disorders, in human subjects.
Still further, this invention provides pharmaceutical compositions, suitable for administration to a human subject, which comprise a pharmaceutically-acceptable carrier and a compound of the formula I, or a pharmaceutically-acceptable salt thereof.
A first preferred group of compounds of this invention is the group of compounds of formula I, wherein R.sup.1 is hydrogen and Q is --CH.dbd.CH--. Within this first group, the compounds wherein R.sup.2 is said alkyl are particularly preferred. An especially preferred individual compound is N-decyl-3-(3-[4-carboxy-2-oxopyrrolidino]phenyl)propenamide, the compound of formula I, wherein R.sup.1 is hydrogen, R.sup.2 is decyl, Q is --CH.dbd.CH-- and the two groups on the phenyl ring are in a meta relationship to each other.
A second preferred group of compounds of this invention is the group of compounds of formula I, wherein R.sup.1 is hydrogen and Q is ##STR5## Within this second group, the compounds wherein R.sup.2 is said alkyl, and the two groups on the phenyl ring are in a para relationship to each other, are particularly preferred.
DETAILED DESCRIPTION OF THE INVENTION
In this specification, the compounds of formula I, and several of the intermediates leading thereto, are named as derivatives of propenamide, 2-methylpropenamide, 2-butenamide, 2-methyl-2-butenamide and cyclopropanecarboxamide, which have structures II, III, IV, V and VI, respectively, viz: ##STR6##
When R.sup.2 is an alkyl group, it can be straight-chain or branched-chain. However, in this specification, when the R.sup.2 group is an alkyl group it is named according to the system of the Chemical Abstracts Service of the American Chemical Society. This means that within a given name each individual term denotes a straight-chain radical, having the free valency at the 1-position. For example, decyl denotes the group CH.sub.3 (CH.sub.2).sub.8 CH.sub.2 --, the group (CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2).sub.2 CH-- is named 1-pentylhexyl and the group (CH.sub.3).sub.2 CHCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 -- is named 6-methylheptyl.
The carboxamide compounds of formula I, wherein R.sup.1 is hydrogen, can be prepared by reaction of itaconic acid with the appropriate amine of the formula ##STR7## The reaction is conveniently carried out by contacting substantially equimolar quantities of the reagents, at elevated temperature, in the molten state. Temperatures in the range from about 100.degree. to about 180.degree. C. are commonly used, with temperatures from about 135.degree. to 155.degree. C. being preferred. At about 145.degree. C., the reaction commonly takes about 0.5 to about 2.0 hours substantially to reach completion. At the end of the reaction, the product can be recovered by conventional methods. One convenient method involves cooling the reaction medium to about 60.degree.-80.degree. C. and then adding about a 10-fold excess of a solvent in which the product is only slightly soluble but in which the starting materials are readily soluble. The mixture is then cooled to room temperature, with stirring, and the product is recovered by filtration. The particular solvent which is used for this purpose will vary according to the precise structure of the product, but an appropriate solvent will be chosen readily by one skilled in the art. Lower alkanols, such as methanol, ethanol and isopropanol, and low molecular weight esters, such as ethyl acetate, are commonly used.
An alternate method of isolating the compound of formula I involves cooling the reaction mixture to about 60.degree.-80.degree. C., and then dissolving it in a two-phase system of water and a water-immiscible organic solvent such as ethyl acetate. The pH of the aqueous phase is raised to about seven, using a reagent such as sodium or potassium hydroxide, and then the organic layer is removed and discarded. Fresh organic solvent is added, and the pH is lowered below 3.5 using a mineral acid, e.g. hydrochloric acid. The organic layer is then removed and dried. Removal of the solvent by evaporation affords the compound of formula I.
Alternatively, the compound of formula I can be obtained by heating substantially equimolar quantities of itaconic acid and a compound of formula VII in a reaction-inert solvent. A wide variety of solvents can be used for this purpose. The major requirements for such a solvent are that it substantially dissolves at least one of the reactants, it does not adversely interact with either of the reactants or the product, and the product can be recovered from it at the end of the reaction. Typical solvents which can be used are hydrocarbons, such as cyclohexane, decalin, tetralin, benzene, toluene and xylene; ethers such as 1,2-dimethoxyethane and dioxane; ketones, such as methyl isobutyl ketone and cyclohexanone; low molecular weight esters, such as ethyl acetate and butyl acetate; alkanols, such as methanol, ethanol and isopropanol; and mixtures of these solvents. The reaction is usually conducted at a temperature in the range from about 100.degree. to about 180.degree. C., and preferably from about 135.degree. to 155.degree. C. At about 145.degree. C. the reaction normally takes about 0.5 to about 2.0 hours. After the reaction is substantially complete, the compound of formula I is isolated in conventional fashion, e.g. by removal of the solvent by evaporation.
A compound of formula I can be purified by conventional means, e.g. chromatography and/or recrystallization from an appropriate solvent.
The compounds of formula VII are obtained by reduction of the corresponding nitro compound of the formula ##STR8## A convenient way of carrying out this reduction is to use iron in glacial acetic acid. Thus, in one method, the compound of formula VIII is dissolved in glacial acetic acid, the solution is heated to 85.degree.-90.degree. C., and then an approximately equal weight of iron powder is added portionwise with stirring, during about 10 to 15 minutes. The reaction mixture is stirred an additional 15 minutes and then the solids are removed by filtration. The solids are washed with acetic acid, and then the combined acetic acid solutions are evaporated to give the compound of formula VII. In many instances, the compound of formula VII is sufficiently pure in its crude state for reaction with itaconic acid or an ester thereof. However, it can be purified by conventional techniques such as chromatography and/or recrystallization, if desired.
The compounds of formula VIII can be obtained from the corresponding compound of the formula ##STR9## Conversion of a compound of the formula IX into a compound of the formula VIII involves activation of the carboxy group followed by reaction with the appropriate amine of formula R.sup.2 --NH.sub.2.
One convenient way of activating the carboxy group in a compound of formula IX involves conversion into the corresponding acid chloride. This is normally carried out by heating the acid with about 1.5 molar equivalents of thionyl chloride, in benzene, at reflux temperature, for about two hours. Removal of all volatile materials by evaporation in vacuo then affords the acid chloride in essentially quantitative yield. In most instances the acid chloride is sufficiently pure for direct reaction with the amine of formula R.sup.2 --NH.sub.2 ; however, it can be purified further by recrystallization from a solvent such as carbon tetrachloride, if desired.
Reaction of the acid chloride of a compound of formula IX with an amine of formula R.sup.2 --NH.sub.2 is normally accomplished by dissolving the amine in a reaction-inert organic solvent such as tetrahydrofuran, cooling the solution of about 0.degree. C., and then adding a solution of about 0.5 equivalents of the acid chloride, in a small volume of the reaction-inert solvent, dropwise, with stirring, during about 10 to 20 minutes. At a temperature of about 0.degree. to 25.degree. C., the reaction takes about one to about four hours substantially to reach completion. At the end of the reaction, the reaction medium is partitioned between water and a volatile, water-immiscible, organic solvent. The organic solvent is removed, washed with water at pH 7.0 and with water at pH 3.5, and then dried. Removal of the solvent by evaporation in vacuo affords the compound of formula VIII.
A second convenient way of activating the carboxy group in a compound of the formula IX involves formation of a mixed anhydride. Mixed anhydride formation entails suspending or dissolving a carboxylate salt (e.g. the triethylamine salt) in a reaction-inert organic solvent (e.g. dichloromethane) and then adding about one molar equivalent of a hindered alkanoyl chloride (e.g. pivaloyl chloride) or a lower-alkyl chloroformate (e.g. ethyl chloroformate). The reaction is usually carried out at about 0.degree. C., and it normally takes about 30 minutes to one hour to reach completion. Although the mixed anhydride can be isolated by solvent evaporation, it is usual simply to use it in situ for reaction with the amine of formula R.sup.2 --NH.sub.2. In this case a solution of about one molar equivalent of the amine is added to the mixed anhydride solution, dropwise, at about 0.degree. C. The reaction is allowed to proceed for about 30 minutes to one hour at about 0.degree. to 25.degree. C. If a water-immiscible solvent has been used, the product is isolated by washing the solvent with 1 N potassium hydroxide and with water. The solution is then dried and evaporated in vacuo to give the compound of formula VIII. If a water-miscible solvent has been used, the product can be isolated by removing the solvent by evaporation in vacuo, replacing it with a water-immiscible sovlent, and then proceding as described above.
The compounds of formula IX, wherein Q is ##STR10## and R.sup.5 is hydrogen and R.sup.6 is selected from the group consisting of hydrogen and methyl, can be prepared by condensation of the appropriate nitrobenzaldehyde with a phosphorane of the formula ##STR11## followed by basic hydrolysis of the ethyl ester grouping.
The compounds of formula IX, wherein Q is ##STR12## and R.sup.5 is methyl and R.sup.6 is selected from the group consisting of hydrogen and methyl, can be prepared by reaction of the appropriate nitroacetophenone and a phosphonate compound of the formula ##STR13## in the presence of one equivalent of sodium hydride, followed by basic hydrolysis of the ethyl ester grouping.
Some of the compounds of formula IX are known (see further Baker et al., Journal of Medicinal Chemistry, 11, 672 [1968]), and some are commercially available. The compounds of formula X are either commercially available or known (see further Isler et al., Helvetica Chimica Acta, 40, 1242 [1957]). The compounds of formula XI are either commercially available or known (see further Arbusor et al., Chemische Berichte, 60, 291 [1927] and Chemical Abstracts, 23, 4444 [1929]).
The compounds of formula IX, wherein Q is ##STR14## are prepared by known methods, or methods analogous to known methods.
The compounds of formula I, wherein R.sup.1 is alkyl, can be prepared by reaction of the corresponding compound of formula I, wherein R.sup.1 is hydrogen, with the appropriate diazoalkane. In this case, the free acid is dissolved or suspended in a reaction-inert solvent, and then a slight excess of an ethereal solution of the diazoalkane is added. The reaction mixture is stirred at ambient temperature for about two to 24 hours, and then any excess diazoalkane is decomposed by the addition of a small amount of acetic acid. Removal of the solvent in vacuo affords the required compound of formula I, wherein R.sup.1 is alkyl. Suitable solvents for this esterification procedure are those which do not adversely interact with either the starting material or the product, and from which the product can be recovered readily. Typical examples are chlorinated hydrocarbons, such as chloroform and dichloromethane; ethers, such as tetrahydrofuran, dioxane and 1,2-dimethoxyethane; and acetonitrile.
The compounds of formula I, wherein R.sup.1 is --CH.sub.2 CH.sub.2 --NR.sup.3 R.sup.4 can be prepared from the corresponding compound of formula I, wherein R.sup.1 is hydrogen, by esterification with a compound of the formula HO--CH.sub.2 CH.sub.2 --NR.sup.3 R.sup.4. This reaction can be carried out conveniently by first activating the compound of formula I, wherein R.sup.1 is hydrogen, by reaction with carbonyldiimidazole. The activated derivative is then reacted with the appropriate 2-(N,N-dialkylamino)ethanol. In a typical procedure, substantially equimolar quantities of a compound of formula I, wherein R.sup.1 is hydrogen, and carbonyldiimidazole are reacted for a few minutes at about 60.degree. to 70.degree. C., in a reaction inert solvent such as tetrahydrofuran, and then one to two equivalents of the 2-(N,N-dialkylamino)ethanol are added. After a reaction time of about 15 to 30 minutes at about 60.degree. to 70.degree. C., the solvent is removed. The residue is dissolved in a water-immiscible, volatile solvent and the solution is washed with water and dilute sodium hydroxide, and then it is dried. Evaporation affords the compound of formula I, wherein R.sup.1 is --CH.sub.2 CH.sub.2 --NR.sup.3 R.sup.4.
As will be appreciated by one skilled in the art, a compound of the formula I, wherein Q is ##STR15## can exist as two geometrical isomers. In one isomer, the (4-carboxy-2-oxo-pyrrolidino)phenyl group is on the opposite side of the double bond from the --CO--NHR.sup.2 group (the trans-isomer); in the other isomer, the (4-carboxy-2-oxo-pyrrolidino)phenyl group is on the same side of the double bond as the --CO--NHR.sup.2 group (the cis-isomer). Both isomers, and mixtures thereof, are within the scope of this invention. However, the trans-isomers are preferred. Additionally, as will be appreciated by one skilled in the art, if it is desired to prepare a trans-isomer of the formula I, the synthetic sequence IX to VIII to VII to I is carried out starting with a compound of formula IX, in which the nitrophenyl and the carboxy groups are on opposite sides of the double bond from each other. Conversely, operation of the synthetic scheme IX to VIII to VII to I, starting with a compound of formula IX in which the nitrophenyl group and the carboxy group are on the same side of the double bond as each other, leads to the cis-isomer.
In the compounds of this invention in which Q is ##STR16## the two groups attached to the cyclopropane ring are always trans to each other.
The compounds of the formula I, wherein R.sup.1 is hydrogen, are acidic and they form base salts. All such base salts are within the scope of this invention. They can be prepared by conventional methods for carboxylic acid compounds. For example, they can be prepared readily and conveniently simply by contacting the acidic and basic entities, usually in a stoichiometric ratio, in either an aqueous, non-aqueous or partially aqueous medium, as appropriate. The salts are recovered either by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent, as appropriate, or, in the case of aqueous solutions, by lyophilization. Basic agents suitably employed in salt formation belong to both the organic and inorganic types, and they include ammonia, organic amines, alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, alkali metal alkoxides, alkaline earth metal hydroxides, alkaline earth metal carbonates, alkaline earth metal hydrides and alkaline earth metal alkoxides. Representative examples of such bases are primary amines, such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, p-toluidine and octylamine; secondary amines, such as diethylamine, N-methylaniline, morpholine, pyrrolidine and piperidine; tertiary amines, such as triethylamine, N,N-dimethylaniline, N-ethylpiperidine, N-methylmorpholine and 1,5-diazobicyclo[4.3.0]non-5-ene; hydroxides, such as sodium hydroxide; alkoxides, such as sodium methoxide and potassium methoxide; hydrides, such as calcium hydride and sodium hydride; and carbonates, such as potassium carbonate and sodium carbonate.
Additionally, the compounds of formula I, wherein R.sup.1 is --CH.sub.2 CH.sub.2 --NR.sup.3 R.sup.4, are basic and they will form acid-addition salts. All such acid-addition salts are within the scope of this invention. They can be prepared by conventional methods for tertiary amine compounds. For example, they can be prepared by contacting said compound of formula I, wherein R.sup.1 is --CH.sub.2 CH.sub.2 --NR.sup.3 R.sup.4, with a stoichiometric amount of the appropriate acid in an appropriate solvent. The salt can then be recovered by filtration, by precipitation with a non-solvent followed by filtration, or by evaporation of the solvent, as appropriate. Acid-addition salts of compounds of formula I, wherein R.sup.1 is --CH.sub.2 --CH.sub.2 --NR.sup.3 R.sup.4, can be prepared from both inorganic and organic acids, and typical salts are the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate and 4-toluenesulfonate.
As indicated hereinbefore, the compounds of formula I are of value as antagonists of the slow-reacting substance of anaphylaxis (SRS-A). This activity can be detected and evaluated by methods known in the art. In one method, the ability of a compound of formula I to antagonize SRS-A induced contractions in isolated guinea pig ileal muscle is measured. Terminal ileum segments, 2.5 cm. long, are removed from Reed-Willet guinea pigs, 350-450 g., and suspended in 10 ml. muscle baths containing Tyrode's solution (NaCl-136.9 mM, KCl-2.68 mM, CaCl.sub.2 -1.8 mM, NaH.sub.2 PO.sub.4 -0.42, mM, MgCl.sub.2 -2.0 mM, NaHCO.sub.3 -11.9 mM, glucose-5.5 mM) saturated with 95% O.sub.2 -5% CO.sub.2 and maintained at 38.degree. C. The tissue is attached by silk thread to a Statham force displacement transducer (FT 0.03) under 2 g. tension and muscle activity is recorded via a Grass Model 5 polygraph. For initial testing submaximal contractions to SRS-A (.about.1 unit/ml.) are obtained in a total of six preparations (three from each of two animals). Each antagonist is added to all baths one minute prior to the addition to SRS-A at a concentration of 10.sup.-4 M, and the percentage inhibition of contraction is measured.
The ability of the compounds of formula I to antagonize the effects of SRS-A makes them useful for inhibiting the symptoms induced by SRS-A in a human subject. The compounds are valuable therefore in the prevention and treatment of such disease states in which SRS-A is the causative factor, e.g. skin disorders, allergic rhinitis, and obstructive airways diseases. The compounds are particularly valuable in the prevention and treatment of allergic bronchial asthma.
A compound of formula I, or a pharmaceutically-acceptable salt thereof, can be administered to a human subject either alone, or, preferably, in combination with pharmaceutically-acceptable carriers or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. A compound can be administered orally or parenterally. Parenteral administration includes intravenous, intramuscular, intraperitoneal, subcutaneous and topical administration, and also administration by inhalation and insufflation.
In a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically-acceptable salt thereof, the weight ratio of carrier to active ingredient will normally be in the range from 1:6 to 6:1, and preferably 1:2 to 4:1. However, in any given case, the ratio chosen will depend on such factors as the solubility of the active component, the dosage contemplated and the precise route of administration.
For oral use of an SRS-A anatgonist of this invention, the compound can be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added. For oral administration in capsule form, useful diluents are lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents can be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic. For administration by inhalation or insufflation, it is convenient to prepare an aqueous or partially aqueous solution of a compound of formula I or salt thereof, and then this solution is administered in the form of an aerosol.
When a compound of formula I or salt thereof is used as an SRS-A antagonist in a human subject, the daily dosage will normally be determined by the prescribing physician. Moreover, the dosage will vary according to the age, weight and response of the individual patient, as well as the severity of the patent's symptoms. However, in most instances, an effective daily dosage will be in the range from about 0.02 g. to about 1.0 g., and preferably 0.05 g. to 0.5 g., in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.
The following examples are provided solely for the purpose of further illustration. Infrared (IR) spectra were measured as potassium bromide discs (KBr discs), and diagnostic absorption bands are reported in reciprocal centimeters (cm.sup.-1). Nuclear magnetic resonance spectra (NMR) were measured in deuterochloroform (CDCl.sub.3), perdeutero dimethyl sulfoxide (CD.sub.3 SOCD.sub.3), deuterated trifluoroacetic acid (CF.sub.3 COOD) or perdeutero pyridine (C.sub.5 D.sub.5 N), and peak positions are expressed in parts per million (ppm) downfield from internal tetramethylsilane. The following abbreviations for peak shaps are used: s, singlet; d, doublet; t, triplet, q, quartet; and m, multiplet.

EXAMPLE 1
N-Decyl-3-[3-(4-carboxy-2-oxo-pyrrolidino)phenyl]propenamide
A mixture of 9.0 g. of N-decyl-3-(3-aminophenyl)propenamide and 3.9 g. of itaconic acid was heated as a melt at 140.degree.-145.degree. C. for 1 hour, and then ca. 70 ml. of ethyl acetate was added to the hot mass. The resulting mixture was stirred, and a solid appeared. The mixture was cooled to room temperature, and the solid was recovered by filtration to give 9.5 g. of the title compound. This product was recrystallized from acetonitrile to give 8.4 g. (69% yield) of product having a melting point of 152.5.degree.-153.5.degree. C.
A sample of the title compound from a similar experiment, and having a melting point of 151.degree.-152.degree. C. was analyzed.
Analysis: Calcd. for C.sub.24 H.sub.34 N.sub.2 O.sub.4 : C, 69.54; H, 8.27; N, 6.76%. Found: C, 69.53; H, 8.23; N, 6.56%.
The ultraviolet spectrum was measured of a further sample of the title compound from a further similar experiment, and having a melting point of 152.5.degree.-153.5.degree. C. The ultraviolet spectrum in methanol showed an absorption maximum at 253 millimicrons (epsilon 31,872), with a shoulder at 272 millimicrons (epsilon 24,303). The ultraviolet spectrum in methanol/0.1 N hydrochloric acid showed an absorption maximum at 252 millimicrons (epsilon 32,283), with a shoulder at 271 millimicrons (epsilon 24,606). The ultraviolet spectrum in methanol/0.1 N sodium hydroxide showed an absorption maximum at 253 millimicrons (epsilon 30,645), with a shoulder at 271 millimicrons (epsilon 24,395).
EXAMPLE 2
N-Octyl-2-methyl-3-[3-(4-carboxy-2-oxo-pyrrolidino)phenyl]propenamide
A mixture of 4.3 g. of N-octyl-2-methyl-3-(3-aminophenyl)propenamide and 2.0 g. of itaconic acid was heated at ca. 140.degree. C. for 1.25 hours. The reaction mixture was allowed to cool somewhat and then a small volume of ethyl acetate was added. This gave a clear solution. The solution was diluted to ca. 75 ml. with further ethyl acetate, and then it was extracted with 1 N potassium hydroxide. The potassium hydroxide solution was washed with ethyl acetate and then it was acidified using concentrated hydrochloric acid. This caused a gum to precipitate. The gum was extracted into ethyl acetate, and the ethyl acetate solution was dried using sodium sulfate. The dried solution was evaporated in vacuo to give 4.5 g. of an oil. The oil was triturated under ether causing formation of a solid. The solid was collected by filtration to give 2.5 g. of a solid, which was recrystallized from ethyl acetate-cyclohexane and then from acetonitrile. This afforded 1.3 g. of the title compound, m.p. 120.degree.-121.degree. C.
Analysis: Calcd. for C.sub.23 H.sub.32 N.sub.2 O.sub.4 : C, 68.97; H, 8.05; N, 7.00%. Found: C, 68.71; H, 7.91; N, 7.01%.
EXAMPLE 3
Reaction of the appropriate N-alkyl-3-(aminophenyl) or N-cycloalkyl-3-(aminophenyl) derivative of propenamide, 2-methylpropenamide or 2-butenamide from Preparation 25 with itaconic acid, according to the procedure of Example 1 (Procedure 1) or Example 2 (Procedure 2), afforded the following compounds:
__________________________________________________________________________ ##STR17## Position Mass of Spectro- Pyrroli- Melting scopy Analysis (%) dino Pro- Yield Point (Parent Calculated FoundR.sup.2 R.sup.5 R.sup.6 Group* cedure (%) (.degree.C.) Ion) C H N C H N__________________________________________________________________________octyl H H 4 1 15 210-203 386 68.36 7.82 7.24 68.25 7.86 7.19octyl H H 3 1 15 150-152 68.36 7.82 7.24 68.33 7.84 7.221-methyl- H H 4 2 6 166-168 386 68.36 7.82 7.24 68.29 7.76 7.24heptyl1-methyl- H H 3 1 28 177-178 68.36 7.82 7.24 68.42 7.91 7.23heptyldecyl H H 4 1 14 197-198 414 69.53 8.26 6.76 69.45 8.36 6.731-methyl- H H 4 1 6 173-175 428 70.06 8.46 6.53 69.71 8.34 6.28decyl1-methyl- H H 3 1 35 150-152 70.06 8.46 6.53 69.98 8.50 6.51decylcyclo- H H 3 1 51 180-182 370 68.09 7.07 7.56 67.92 7.03 7.71heptylcyclodo- H H 4 1 17 235-237 440 70.88 8.24 6.36 70.32 8.35 6.25decyldecyl H CH.sub.3 4 1 65 187.5-188.5 70.06 8.47 6.54 70.27 8.53 6.62decyl H CH.sub.3 3 2 36 125-127 70.06 8.47 6.54 70.03 8.39 6.521-methyl- H CH.sub.3 4 1 42 194-195.5 70.55 8,65 6.33 70.62 8.56 6.42decyl1-methyl- H CH.sub.3 3 2 11 137.5-138.5 70.55 8.65 6.33 70.31 8.45 6.26decyldecyl CH.sub.3 H 4 1 10 185-187 428 70.06 8.47 6.54 70.38 8.26 6.481-methyl CH.sub.3 H 4 1 206-208 442 70.55 8.65 6.33 70.61 8.57 6.24decyl__________________________________________________________________________ *The numeral in this column indicates the position of the pyrrolidino group on the phenyl ring; ##STR18##
______________________________________Spectral Data Posi- tion of pyrro- lidinoR.sup.2 R.sup.5 R.sup.6 group* IR (cm.sup.-1) NMR (ppm)______________________________________cyclo- H H 3 3390, 2941, 2899, 1.5 (s), 2.8 (d),heptyl 1739, 1695, 1667 4.1 (m), 6.5 (s), (KBr disc) 6.8 (s), 7.7 (m) (CD.sub.3 SOCD.sub.3)cyclodo- H H 4 3390, 2985, 2874, 1.4 (s), 3.15 (d),decyl 1709, 1667, 1613 4.2 (d), 6.35 (s), (KBr disc) 6.6 (s), 7.4 (m) (CF.sub.3 COOD)decyl CH.sub.3 H 4 3333, 2941, 2857, 0.85 (m), 1.2 (s), 1695, 1653, 1626 2.6 (m), 3.0 (m), (KBr disc) 3.85 (m), 6.0 (s), 7.45 (m) (CD.sub.3 SOCD.sub.3)1-methyl- CH.sub.3 H 4 3333, 2941, 2857, 1.0 (m), 2.8 (d),decyl 1695, 1653, 1626 4.1 (m), 6.3 (s), (KBr disc) 7.7 (m) (CD.sub.3 SOCD.sub.3)______________________________________ *The numeral in this column indicates the position of the pyrrolidino group on the phenyl ring; ##STR19##
EXAMPLE 4
The appropriate product from Preparation 24, 25 or 26 is heated with an equimolar amount of itaconic acid at 140.degree.-145.degree. C. for 1 hour. The reaction mixture is cooled to 80.degree. C., and then a ten-fold volume of ethyl acetate is added with stirring. The resulting mixture is allowed to cool to room temperature with stirring. If the product is out of solution at this stage, it is isolated by the procedure of Example 1. If the product dissolves in the ethyl acetate, it is isolated by the procedure of Example 2. This affords the following compounds:
______________________________________ ##STR20## Position of PyrrolidinoR.sup.2 R.sup.5 R.sup.6 Group*______________________________________6-methylheptyl H H 21-pentylhexyl H H 2dodecyl H H 2pentadecyl H H 3pentadecyl H H 42-methyltetradecyl H H 3cyclohexyl H H 4cyclohexyl H H 3cycloheptyl H H 4cyclododecyl H H 3octyl H CH.sub.3 4nonyl H CH.sub.3 2pentadecyl H CH.sub.3 4cyclohexyl H CH.sub.3 3cycloheptyl H CH.sub.3 4cyclododecyl H CH.sub.3 4octyl CH.sub.3 H 21-methyldecyl CH.sub.3 H 3tridecyl CH.sub.3 H 3pentadecyl CH.sub.3 H 4cyclohexyl CH.sub.3 H 4cyclodecyl CH.sub.3 H 2cyclododecyl CH.sub.3 H 3octyl CH.sub.3 CH.sub.3 21-methylnonyl CH.sub.3 CH.sub.3 3tridecyl CH.sub.3 CH.sub.3 4pentadecyl 34 CH.sub.3 3cyclohexyl CH.sub.3 CH.sub.3 4cyclononyl CH.sub.3 CH.sub.3 2cycloundecyl CH.sub.3 CH.sub.3 3cyclododecyl CH.sub.3 CH.sub.3 4______________________________________ *The numeral in this column indicates the position of the pyrrolidino group on the phenyl ring; ##STR21##
EXAMPLE 5
N-Decyl-3-(3-[4-Methoxycarbonyl-2-oxo-pyrrolidino]phenyl)propenamide
To a stirred mixture of 415 mg. of N-decyl-3-(3-[4-carboxy-2-oxo-pyrrolidino]phenyl)propenamide and 15 ml. of 1,2-dimethoxyethane is added a solution of 1.5 mmoles of diazomethane in 5 ml. of ether. The reaction mixture is stirred at room temperature for 16 hours, and then the excess diazomethane is decomposed by the addition of a few drops of acetic acid. The total solvents are removed by evaporation in vacuo, and the residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with 1 N sodium hydroxide, followed by water, followed by saturated sodium chloride solution, and then dried using sodium sulfate. Evaporation of the dried ethyl acetate solution in vacuo affords the title compound.
EXAMPLE 6
By esterification of the requisite product from Examples 1 to 4 with the appropriate diazoalkane, using the procedure of Example 5, the following compounds can be prepared:
______________________________________ ##STR22## Position of PyrrolidinoR.sup.1 R.sup.2 R.sup.5 R.sup.6 Group*______________________________________ethyl octyl H H 4propyl octyl H H 3butyl 6-methylheptyl H H 2methyl decyl H H 4ethyl decyl H H 2methyl 1-methyldecyl H H 4propyl 1-methyldecyl H H 3butyl 1-pentylhexyl H H 2methyl pentadecyl H H 3ethyl cyclohexyl H H 4butyl cycloheptyl H H 4propyl cycloheptyl H H 3methyl cyclododecyl H H 4ethyl octyl H CH.sub.3 4butyl nonyl H CH.sub.3 2propyl decyl H CH.sub.3 3methyl 1-methyldecyl H CH.sub.3 4ethyl 1-methyldecyl H CH.sub.3 3methyl pentadecyl H CH.sub.3 4methyl cyclohexyl H CH.sub.3 3butyl cycloheptyl H CH.sub.3 4propyl cyclododecyl H CH.sub.3 4methyl octyl CH.sub.3 H 2ethyl decyl CH.sub.3 H 4butyl 1-methyldecyl CH.sub.3 H 4propyl tridecyl CH.sub.3 H 3methyl pentadecyl CH.sub.3 H 4methyl cyclohexyl CH.sub.3 H 4ethyl cyclodecyl CH.sub.3 H 2butyl cyclododecyl CH.sub.3 H 3methyl octyl CH.sub.3 CH.sub.3 2butyl 1-methylnonyl CH.sub.3 CH.sub.3 3ethyl tridecyl CH.sub.3 CH.sub.3 4methyl pentadecyl CH.sub.3 Ch.sub.3 3butyl cyclohexyl CH.sub.3 CH.sub.3 4propyl cyclononyl CH.sub.3 CH.sub.3 2ethyl cycloundecyl CH.sub.3 CH.sub.3 3methyl cyclododecyl CH.sub.3 CH.sub.3 4______________________________________ *The numeral in this column indicates the position of the pyrrolidino group on the phenyl ring; ##STR23##
EXAMPLE 7
N-Decyl-3-(3-[4-(2-[N,N-diethylamino]ethoxycarbonyl)-2-oxo-pyrrolidino]phenyl)propenamide
To a stirred solution of 829 mg. of N-decyl-3-(3-[4-carboxy-2-oxo-pyrrolidino]phenyl)propenamide in 25 ml. of tetrahydrofuran was added 357 mg. of carbonyldiimidazole. The mixture was heated under reflux for 10 minutes, and then 258 mg. of 2-(N,N-diethylamino)ethanol was added. The mixture was again heated under reflux for 10 minutes, and then an additional 258 mg. of 2-(N,N-diethylamino)ethanol was added. The mixture was heated under reflux for 15 minutes and then it was cooled to room temperature. The solvent was removed by evaporation in vacuo, and the residue was dissolved in 75 ml. of ethyl acetate. The ethyl acetate solution was washed successively with water, 1 N sodium hydroxide, water and saturated sodium chloride solution. The ethyl acetate solution was then dried using sodium sulfate, and the ethyl acetate was removed by evaporation in vacuo. The residue (960 mg.) was recrystallized from isopropyl ether giving 570 mg. of the title compound, m.p. 78.degree.-80.degree. C.
Analysis: Calcd. for C.sub.30 H.sub.47 N.sub.3 O: C, 70.14; H, 9.22; N, 8.18%. Found: C, 69.96; H, 9.10; N, 8.17%.
EXAMPLE 8
By esterification of the requisite product from Examples 1 to 4 with the appropriate 2-(N,N-dialkyl-amino)ethanol and carbonyldiimidazole, using the procedure of Example 7, the following compounds can be prepared:
______________________________________ ##STR24## Position of PyrrolidinoR.sup.2 R.sup.3 R.sup.4 R.sup.5 R.sup.6 Group*______________________________________octyl methyl methyl H H 4octyl methyl ethyl H H 36-methylheptyl methyl propyl H H 2decyl methyl methyl H H 4decyl propyl ethyl H H 21-methyldecyl methyl methyl H H 41-methyldecyl propyl propyl H H 31-pentylhexyl ethyl ethyl H H 2pentadecyl methyl methyl H H 3cyclohexyl methyl propyl H H 4cycloheptyl ethyl propyl H H 4cycloheptyl ethyl ethyl H H 3cyclododecyl methyl methyl H H 4octyl ethyl ethyl H CH.sub.3 4nonyl propyl methyl H CH.sub.3 2decyl propyl ethyl H CH.sub. 3 31-methyldecyl methyl methyl H CH.sub.3 41-methyldecyl ethyl ethyl H CH.sub.3 3pentadecyl propyl propyl H CH.sub.3 4cyclohexyl methyl methyl H CH.sub.3 3cycloheptyl ethyl ethyl H CH.sub.3 4cyclododecyl propyl propyl H CH.sub.3 4octyl methyl ethyl CH.sub.3 H 2decyl ethyl propyl CH.sub.3 H 41-methyldecyl methyl methyl CH.sub.3 H 4tridecyl ethyl methyl CH.sub.3 H 3pentadecyl methyl propyl CH.sub.3 H 4cyclohexyl methyl methyl CH.sub.3 H 4cyclodecyl ethyl ethyl CH.sub.3 H 2cyclododecyl propyl propyl CH.sub.3 H 3octyl methyl methyl CH.sub.3 H 21-methylnonyl ethyl ethyl CH.sub.3 CH.sub.3 3tridecyl propyl propyl CH.sub.3 CH.sub.3 4pentadecyl methyl ethyl CH.sub.3 CH.sub.3 3cyclohexyl propyl methyl CH.sub.3 CH.sub.3 4cyclononyl methyl methyl CH.sub.3 CH.sub.3 2cycloundecyl ethyl ethyl CH.sub.3 CH.sub.3 3cyclododecyl propyl propyl CH.sub.3 CH.sub.3 4______________________________________ *The numeral in this column inidcates the position of the pyrrolidino group on the phenyl ring; ##STR25##
EXAMPLE 9
N-Decyl-3-(3-[4-carboxy-2-oxo-pyrrolidino]phenyl)propenamide, Sodium Salt
To 40 ml. of methanol was added 3.1 g. of N-decyl-3-(3-[4-carboxy-2-oxo-pyrrolidino]phenyl)-propenamide, followed by 7.5 ml. of 1 N sodium methoxide in methanol. The mixture was warmed slightly and filtered, and then the filtrate was diluted with 200 ml. of ether. The solid which formed was filtered off and recrystallized from ethanol. This afforded 2.0 g. of the title sodium salt, m.p. 240.degree.-242.degree. C.
Analysis: Calcd. for C.sub.24 H.sub.23 N.sub.2 O.sub.4 Na: C, 66.03; H, 7.62; N, 6.24%. Found: C, 65.94; H, 7.53; N, 6.44%.
EXAMPLE 10
trans-N-Octyl-2-[4-(4-carboxy-2-oxo-pyrrolidino)phenyl]cyclopropanecarboxamide
A mixture of 2.2 g. of trans-N-octyl-2-(4-aminophenyl)cyclopropanecarboxamide and 989 mg. of itaconic acid were heated as a melt at 140.degree.-145.degree. C. for 1 hour. The reaction mixture was cooled slightly and then it was triturated with 25 ml. of ethyl acetate. The white solid which formed was filtered off. It was recrystallized from ethanol containing a small amount of acetonitrile, and then from acetic acid, to give 1.09 g. of the title compound as a white solid, m.p. 213.5.degree.-214.5.degree. C. The infrared spectrum (KBr disc) showed absorptions at 3280, 3125, 1695 and 1625 cm.sup.1.
Analysis: Calcd. for C.sub.23 H.sub.32 N.sub.2 O.sub.4 : C, 68.97; H, 8.05; N, 7.00%. Found: C, 69.20; H, 7.89; N, 7.15%.
EXAMPLE 11
trans-N-Decyl-2-[4-(4-carboxy-2-oxo-pyrrolidino)-phenyl]cyclopropanecarboxamide
The title compound was prepared from trans-N-decyl-2-(4-aminophenyl)cyclopropanecarboxamide and itaconic acid, substantially according to the procedure of Example 10. It was recrystallized twice from ethanol to give a 47% yield of material having a melting point of 214.degree.-215.degree. C. The infrared spectrum (KBr disc) showed absorptions at 3280, 3125, 1680 and 1625 cm.sup.-1.
Analysis: Calcd. for C.sub.25 H.sub.36 N.sub.2 O.sub.4 : C, 70.06; H, 8.47; N, 6.54%. Found: C, 69.82; H, 8.28; N, 6.74%.
EXAMPLE 12
Trans-N-[1-Methyldecyl]-2-[4-(4-carboxy-2-oxo-pyrrolidino)phenyl]cyclopropanecarboxamide
The title compound was prepared from trans-N-(1-methyldecyl)-2-(4-aminophenyl)cyclopropanecarboxamide and itaconic acid, substantially according to the procedure of Example 10. It was recrystallized from acetic acid to give a 21% yield of material having a melting point of 226.degree.-228.degree. C. The infrared spectrum (KBr disc) showed absorptions at 3280, 2900, 1695 and 1625 cm.sup.-1.
Analysis: Calcd. for C.sub.26 H.sub.38 N.sub.2 O.sub.4 : C, 70.55; H, 8.65; N, 6.33%. Found: C, 70.59; H, 8.63; N, 6.30%.
EXAMPLE 13
Reaction of the appropriate N-alkyl-(2-aminophenyl)cyclopropanecarboxamide or N-cycloalkyl-2-(aminophenyl)cyclopropanecarboxamide from Preparation 37 with itaconic acid, according to the procedure of Example 10, affords the following compounds:
______________________________________ ##STR26## Position ofR.sup.2 pyrrolidino group*______________________________________1-methylheptyl 4nonyl 4nonyl 3nonyl 2tridecyl 4tetradecyl 3pentadecyl 41-heptyloctyl 3cyclohexyl 4cycloheptyl 2cyclooctyl 3cyclodecyl 4cyclododecyl 3______________________________________ *The numeral in this column indicates the position of the pyrrolidino group on the phenyl ring; ##STR27##
EXAMPLE 14
By esterification of the requisite product from Example 13, with the appropriate diazoalkane, using the procedure of Example 5, the following compounds can be prepared:
______________________________________ ##STR28## Position ofR.sup.1 R.sup.2 pyrrolidino group*______________________________________methyl 1-methylheptyl 4ethyl nonyl 4propyl nonyl 3butyl nonyl 2ethyl tridecyl 4isopropyl tetradecyl 3methyl pentadecyl 4ethyl 1-heptyloctyl 3methyl cyclohexyl 4butyl cycloheptyl 2propyl cyclooctyl 3isopropyl cyclodecyl 4methyl cyclododecyl 3______________________________________ *The numeral in this column indicates the position of the pyrrolidino group on the phenyl ring; ##STR29##
EXAMPLE 15
By esterification of the requisite product from Example 13, with the appropriate 2-(N,N-dialkylamino)-ethanol and carbonyldiimidazole, using the procedure of Example 7, the following compounds can be prepared:
______________________________________ ##STR30## Position of pyrrolidinoR.sup.2 R.sup.3 R.sup.4 group*______________________________________1-methylheptyl methyl methyl 4nonyl methyl ethyl 4nonyl ethyl methyl 3nonyl methyl propyl 2tridecyl propyl methyl 4tetradecyl isopropyl ethyl 3pentadecyl methyl isopropyl 41-heptyloctyl ethyl ethyl 3cyclohexyl methyl methyl 4cycloheptyl methyl ethyl 2cyclooctyl ethyl methyl 3cyclodecyl isopropyl methyl 4cyclododecyl methyl propyl 3______________________________________ *The numeral in this column indicates the position of the pyrrolidino group on the phenyl ring; ##STR31##
PREPARATION 1
Ethyl 3-(4-Nitrophenyl)-2-butenoate
A 50% suspension of sodium hydride in mineral oil (10.7 g.) was washed with petroleum ether to remove the mineral oil, and then the residue was suspended in 300 ml. of 1,2-dimethoxyethane, under nitrogen. To this suspension was added, dropwise, during 45 minutes, 52.5 g. of diethyl ethoxycarbonylmethylphosphonate. After the evolution of gas had ceased, a solution of 35.0 g. of 4-nitroacetophenone in 200 ml. of 1,2-dimethoxyethane was added during 50 minutes. The resulting mixture was stirred overnight, and then the solvent was removed by evaporation in vacuo. The residue was partitioned between ethyl acetate and water, and then the ethyl acetate layer was removed. The ethyl acetate layer was dried using sodium sulfate and then it was evaporated in vacuo. This afforded an oil which was induced to solidify by scratching. The solid was recrystallized from ethanol to give 16.6 g. (33% yield) of the title product, m.p. 71.degree.-74.degree. C.
PREPARATION 2
Ethyl 3-(2-Nitrophenyl)-2-butenoate
The procedure of Preparation 1 is repeated, except that the 4-nitroacetophenone replaced by an equal weight of 2-nitroacetophenone. This affords the title compound.
PREPARATION 3
Reaction of 2-nitroacetophenone, 3-nitroacetophenone and 4-nitroacetophenone with diethyl 1-(ethoxycarbonyl)-ethylphosphonate, according to the procedure of Preparation 1, affords:
ethyl 2-methyl-3-(2-nitrophenyl)-2-butenoate,
ethyl 2-methyl-3-(3-nitrophenyl)-2-butenoate and
ethyl 2-methyl-3-(4-nitrophenyl)-2-butenoate, respectively.
PREPARATION 4
Ethyl 3-(3-Nitrophenyl)-2-butenoate
A 50% suspension of sodium hydride in mineral oil (28.32 g.) was washed with petroleum ether to remove the mineral oil, and then the residue was suspended in 500 ml. of 1,2-dimethoxyethane under nitrogen. To this suspension was added dropwise, with stirring, 139.5 g. of diethyl ethoxycarbonylmethylphosphonate, during 50 minutes. After gas evolution had ceased, a solution of 92.5 g. of 3-nitroacetophenone in 300 ml. of 1,2-dimethoxyethane was added during 90 minutes. The reaction mixture was stirred overnight, and then the solvent was removed by evaporation in vacuo. The residue was partitioned between ethyl acetate and water, and then the ethyl acetate layer was removed. The ethyl acetate layer was washed with saturated sodium chloride solution and dried using sodium sulfate. Evaporation in vacuo afforded an oil, which was chromatographed on ca. 400 g. of silica gel, using 2:1 hexane-ethyl acetate as eluant. The product-containing fractions were combined and evaporated, giving 124.5 g. of the title compound.
PREPARATION 5
Ethyl 2-Methyl-3-(3-Nitrophenyl)propenoate
To a stirred slurry of 79.8 g. of triphenyl(1[ethoxycarbonyl]ethylidene)phosphorane in 300 ml. of benzene was added 30.2 g. of 3-nitrobenzaldehyde and the resulting mixture was heated under reflux overnight. The reaction mixture was cooled and the solvent was removed by evaporation in vacuo. The residue was extracted with 300 ml. of isopropyl ether. The isopropyl ether solution was filtered, and the filtrate was evaporated in vacuo. The residue was distilled under reduced pressure, giving 37.6 g. of the title product, b.p. 147.degree.-162.degree. C./0.25 mm Hg. The NMR spectrum (in CDCl.sub.3) showed absorptions at 1.4 (t), 2.1 (d), 4.3 (q), 7.4 (m) and 8.1 (m) ppm.
PREPARATION 6
Ethyl 2-Methyl-3-(4-Nitrophenyl)propenoate
The title compound was prepared from triphenyl(1-[ethoxycarbonyl]ethylidene)phosphorane and 4-nitrobenzaldehyde, substantially according to Preparation 5. The product was obtained in 56% yield, as an orange-yellow solid, m.p. 70.5.degree.-73.degree. C.
PREPARATION 7
Ethyl 2-Methyl-3-(2-Nitrophenyl)propenoate
The title compound is prepared from triphenyl(1-[ethoxycarbonyl]ethylidene)phosphorane and 2-nitrobenzaldehyde, using the procedure of Preparation 5.
PREPARATION 8
3-(4-Nitrophenyl)-2-butenoic Acid
A mixture of 16.6 g. of ethyl 3-(4-nitrophenyl)-2-butenoate, 75 ml. of ethanol and 94.7 ml. of 1.5 N potassium hydroxide was heated on a steam bath for 70 minutes, and then it was cooled to room temperature. To the reaction mixture was added 200 ml. of water and 200 ml. of ethyl acetate. The aqueous phase was removed and acidified with concentrated hydrochloric acid, and then the solid was recovered by filtration. This latter solid was recrystallized from aqueous ethanol to give 9.8 g. (67% yield) of the title compound, m.p. 167.degree.-169.degree. C.
PREPARATION 9
2-Methyl-3-(4-Nitrophenyl)propenoic Acid
The title compound was prepared in 60% yield by hydrolysis of its ethyl ester, according to the procedure of Preparation 8. Melting point: 201.degree.-203.degree. C. (dec.).
PREPARATION 10
2-Methyl-3-(3-Nitrophenyl)propenoic Acid
The title compound was prepared in 100% yield by hydrolysis of its ethyl ether substantially according to the procedure of Preparation 8. Melting point: 201.degree.-202.degree. C.
PREPARATION 11
By hydrolysis of the corresponding ethyl ester, according to the procedure of Preparation 8, the following compounds are prepared:
3-(2-nitrophenyl)-2-butenoic acid,
2-methyl-3-(2-nitrophenyl)-2-butenoic acid,
2-methyl-3-(3-nitrophenyl)-2-butenoic acid,
2-methyl-3-(4-nitrophenyl)-2-butenoic acid and
2-methyl-3-(2-nitrophenyl)propenoic acid.
PREPARATION 12
3-(3-Nitrophenyl)-2-butenoic Acid
A stirred mixture of 119.5 g. of ethyl 3-(3-nitrophenyl)-2-butenoate (from Preparation 4), 100 ml. of ethanol and 1,500 ml. of 1 N potassium hydroxide was heated on a steam bath for 1.25 hours. The reaction was cooled and then acidified with concentrated hydrochloric acid. The solid which precipitated was recovered by filtration (92.6 g.).
A portion (76.9 g.) of the above crude product was recrystallized from isopropanol, giving 48.9 g. of the title product, m.p. 208.degree.-210.degree. C. In this material, the nitrophenyl group and the carboxy group had a trans relationship across the double bond. The NMR spectrum (in CD.sub.3 SOCD.sub.3) showed absorptions at 2.5 (d), 6.2 (m), and 7.9 (m) ppm.
Analysis: Calcd. for C.sub.10 H.sub.9 NO.sub.4 : C, 57.97; H, 4.38; N, 6.76%. Found: C, 57.92; H, 4.52; N, 6.87%.
The mother liquors from the above recrystallization were evaporated in vacuo, and the residue was recrystallized from acetonitrile. This afforded 13.8 g. of the title product, m.p. 147.degree.-149.degree. C. In this material, the nitrophenyl group and the carboxy group had a cis relationship across the double bond. The NMR spectrum (in perdeutero pyridine) showed absorptions at 2.0 (d), 6.1 (m), 7.25 (m) and 8.05 (m) ppm.
PREPARATION 13
2-Methyl-3-(3-Nitrophenyl)propenoic Acid
A mixture of 75 g. of 3-nitrobenzaldehyde, 98 g. of propionic anhydride and 48 g. of sodium propionate was heated at 170.degree. to 175.degree. C. for 1.25 hours, and then it was cooled and poured into 750 ml. of ice-water. Concentrated ammonium hydroxide was then added until a basic pH was obtained. The mixture was warmed on a steam bath for a few minutes and then the small amount of insoluble material was removed by filtration. The filtrate was acidified with concentrated hydrochloric acid and the solid was recovered by filtration. This crude product was recrystallized from aqueous ethanol to give 81 g. of the title compound, m.p. 200.5.degree.-202.degree. C.
PREPARATION 14
3-(3-Nitrophenyl)propenoyl Chloride
A mixture of 50 g. of 3-(3-nitrophenyl)propenoic acid, 24.54 ml. of thionyl chloride and 300 ml. of benzene were heated under reflux for 2.5 hours. The cooled solution was filtered and then it was evaporated in vacuo. The residue was recrystallized from carbon tetrachloride, to give 49.9 g. (91% yield) of the title compound, m.p. 81.degree.-83.5.degree. C.
PREPARATION 15
Starting with the appropriate propenoic or butenoic acid, and following substantially the procedure of Preparation 14, the following acid chlorides were prepared:
3-(4-nitrophenyl)propenyl chloride (m.p. 150.degree.-152.degree. C.),
2-methyl-3-(4-nitrophenyl)propenoyl chloride (m.p. 87.5.degree.-88.5.degree. C.),
2-methyl-3-(3-nitrophenyl)propenoyl chloride and
3-(4-nitrophenyl)butenoyl chloride (m.p. 93.degree.-96.degree. C.).
PREPARATION 16
Starting with the appropriate propenoic or butenoic acid, and using the method of Preparation 14, the following acid chlorides can be prepared:
3-(2-nitrophenyl)-2-butenoyl chloride,
3-(3-nitrophenyl)-2-butenoyl chloride,
2-methyl-3-(2-nitrophenyl)-2-butenoyl chloride,
2-methyl-3-(3-nitrophenyl)-2-butenoyl chloride,
2-methyl-3-(4-nitrophenyl)-2-butenoyl chloride and
2-methyl-3-(2-nitrophenyl)propenoyl chloride.
PREPARATION 17
N-(1-Methyldecyl)-3-(3-Nitrophenyl)propenamide
To a stirred solution of 31.0 g. of 2-aminoundecane in 100 ml. of tetrahydrofuran, was added a solution of 19.0 g. 3-(3-nitrophenyl)propenoyl chloride in 100 ml. of tetrahydrofuran, dropwise, during 75 minutes, at ca. 5.degree. C. After the addition, the mixture was allowed to warm to room temperature, and stirring was continued for 45 minutes. The solvent was removed by evaporation in vacuo, and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was removed, washed successively with 1 N hydrochloric acid and water, and dried. Evaporation of the solvent in vacuo, followed by recrystallization of the residue from hexane, afforded 26 g. (83% yield) of the title product, m.p. 81.degree.-83.degree. C.
PREPARATION 18
Reaction of the appropriate acid chloride from Preparation 14 or Preparation 15 with the requisite alkylamine or cycloalkylamine, substantially according to Preparation 17, afforded the following compounds.
______________________________________ ##STR32## Position of nitro Yield m.p.R.sup.2 R.sup.5 R.sup.6 group* (%) (.degree.C.)______________________________________octyl H H 4 53 95-97octyl H H 3 45 76-781-methylheptyl H H 4 92 68-701-methylheptyl H H 3 66 69-71decyl H H 4 79 106-108decyl H H 3 30 97-991-methyldecyl H H 4 84 91-94cycloheptyl H H 4 73 180-182cycloheptyl H H 3 88 144-145.5cyclododecyl H H 4 96cyclododecyl H H 3 185-187octyl H CH.sub.3 4 90 71.5-72.5octyl H CH.sub.3 3 100 58.5-59.5decyl H CH.sub.3 4 94 79-80decyl H CH.sub.3 3 92 65-66.51-methyldecyl H CH.sub.3 4 77.5-79.5cycloheptyl H CH.sub.3 4 93 135-137decyl CH.sub.3 H 4 721-methyldecyl CH.sub.3 H 4 621-methyldecyl CH.sub.3 H 3 37______________________________________ *The numeral in this column indicates the position of the nitro group on the phenyl ring; ##STR33##
PREPARATION 19
By reacting the appropriate acid chloride from Preparations 14-16 with the requisite alkylamine or cycloalkylamine, the following compounds can be prepared:
______________________________________ ##STR34## Position of nitroR.sup.2 R.sup.5 R.sup.6 group*______________________________________6-methylheptyl H H 21-pentylhexyl H H 2dodecyl H H 2pentadecyl H H 3pentadecyl H H 42-methyltetradecyl H H 3cyclohexyl H H 4cyclohexyl H H 3nonyl H CH.sub.3 2pentadecyl H CH.sub.3 4cyclohexyl H CH.sub.3 3cyclododecyl H CH.sub.3 4octyl CH.sub.3 H 2tridecyl CH.sub.3 H 3pentadecyl CH.sub.3 H 4cyclohexyl CH.sub.3 H 4cyclodecyl CH.sub.3 H 2cyclododecyl CH.sub.3 H 3octyl CH.sub.3 CH.sub.3 21-methylnonyl CH.sub.3 CH.sub.3 3tridecyl CH.sub.3 CH.sub.3 4pentadecyl CH.sub.3 CH.sub.3 3cyclohexyl CH.sub.3 CH.sub.3 4cyclononyl CH.sub.3 CH.sub.3 2cycloundecyl CH.sub.3 CH.sub.3 3cyclododecyl CH.sub.3 CH.sub.3 4______________________________________ *The numeral in this column indicates the position of the nitro group on the phenyl ring; ##STR35##
PREPARATION 20
N-Octyl-3-(2-Nitrophenyl)propenamide
A mixture of 9.7 g. of 3-(2-nitrophenyl)propenoic acid, 5.6 g. of triethylamine and 240 ml. of dichloromethane was stirred at room temperature for 20 minutes, and then it was cooled in an ice-bath. To the mixture was then added, dropwise, during 15 minutes, a solution of 6.0 g. of ethyl chloroformate in 20 ml. of dichloromethane. After 15 minutes of stirring, a solution of 7.1 g. of octylamine in 20 ml. of dichloromethane was added dropwise, during 10 minutes. The reaction mixture was allowed to warm to room temperature, and then it was washed successively with 1 N potassium carbonate, 1 N hydrochloric acid, water and saturated sodium chloride. The resulting solution was dried and evaporated in vacuo, leaving 14.5 g. (95%) yield of the title compound as a tan solid.
PREPARATION 21
Starting with 3-(2-nitrophenyl)propenoic acid or 2-methyl-3-(3-nitrophenyl)propenoic acid, as appropriate, and decylamine or 1-methyldecylamine, as appropriate, and following substantially the procedure of Preparation 20, the following compounds were prepared as waxy solids, in essentially quantitative yield.
N-decyl-3-(2-nitrophenyl)propenamide,
N-(1-methyldecyl)-3-(2-nitrophenyl)propenamide,
N-decyl-2-methyl-3-(3-nitrophenyl)propenamide and
N-(1-methyldecyl)-2-methyl-3-(3-nitrophenyl)-propenamide.
PREPARATION 22
N-(1-Methyldecyl)-3-(3-Nitrophenyl)-2-butenamide
To a stirred slurry of 5.2 g. of the 3-(3-nitrophenyl)-2-butenoic acid from Preparation 12 having a melting point of 208.degree.-210.degree. C., in 100 ml. of dichloromethane, was added 2.8 g. of triethylamine in 10 ml. of dichloromethane. This was followed by the addition of a solution of 3.0 g. of ethyl chloroformate in 20 ml. of dichloromethane, during 20 minutes. Stirring was continued for 30 minutes, and then a solution of 1-methyldecylamine in 20 ml. of dichloromethane was added dropwise during 25 minutes. Stirring was continued overnight, and the the reaction mixture was washed successively with 1 N potassium carbonate, water and saturated sodium chloride. The resulting solution was dried using sodium sulfate, and then it was evaporated in vacuo leaving an oil which solidified on trituration under petroleum ether. This afforded 4.9 g. of the title compound, m.p. 72.5.degree.-74.degree. C.
PREPARATION 23
N-(1-Methyldecyl)-3-(3-Nitrophenyl)-2-butenamide
The 3-(3-nitrophenyl)-2-butenoic acid from Preparation 12 having a melting point of 147.degree.-149.degree. C. was reacted with ethyl chloroformate, followed by 1-methyldecylamine, according to the procedure of Preparation 22. This afforded a 72% yield of the title product.
PREPARATION 24
N-Decyl-3-(2-Aminophenyl)propenamide
A stirred solution of 15.3 g. of N-decyl-3-(2-nitrophenyl)propenamide in 200 ml. of glacial acetic acid was heated to 85.degree. C. on a steam bath, and then 12.9 g. of iron powder was added portionwise, during 25 minutes. The reaction temperature was kept between 85.degree. and 95.degree. C. during the addition. The reaction mixture was filtered hot, and the residue was washed with hot glacial acetic acid. The cooled, combined acetic acid solutions were evaporated in vacuo, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed several times with water and then with saturated sodium chloride solution. The resulting solution was dried using sodium sulfate, and then it was evaporated in vacuo to give the crude title product.
The crude product was chromatographed on ca. 350 g. of silica gel, eluting with 1% ethanol in chloroform. The appropriate fractions were combined and evaporated, and the residue was triturated with hexane, to give 10.5 g. of the title compound.
PREPARATION 25
Reduction of the appropriate nitro compound from Preparations 17, 18, 20 and 21 with iron powder in acetic acid, substantially according to Preparation 24, afforded the following compounds.
In many instances, the crude product was an oil, which was used in the next step without purification.
______________________________________ ##STR36## Posi- tion Melt- of Chrom- ing amino ato- Yield PointR.sup.2 R.sup.5 R.sup.6 group* graphy** (%) (.degree.C.)______________________________________octyl H H 4 No 84 oiloctyl H H 3 No oiloctyl H H 2 Yes 851-methylheptyl H H 4 No 63 oil1-methylheptyl H H 3 No oildecyl H H 4 Yes 50 107- 109decyl H H 3 Yes 691-methyldecyl H H 4 Yes 41 123- 1261-methyldecyl H H 3 Yes 581-methyldecyl H H 2 Yes 119- 120.5cycloheptyl H H 4 No 98 gumcycloheptyl H H 3 Yes 67cyclododecyl H H 4 Yes 54cyclododecyl H H 3 Yesoctyl H CH.sub.3 4 No 87 gumoctyl H CH.sub.3 3 No 82 gumdecyl H CH.sub.3 4 Yes 75 91.5- 92.5decyl H CH.sub.3 3 Yes 90 81.5- 83.51-methyldecyl H CH.sub.3 4 No 87 88-901-methyldecyl H CH.sub.3 3 Yes 59cycloheptyl H CH.sub.3 4 Yes 95decyl CH.sub.3 H 4 Yes 76 oil1-methyldecyl CH.sub.3 H 4 Yes 81 oil1-methyldecyl CH.sub.3 H 3 No 77 oil______________________________________ *The numeral in this column indicates the position of the amino group on the phenyl ##STR37## **The entry "Yes" indicates that the product was purified by chromatography; the entry "No" indicates that the product was not purifie by chromatography.
PREPARATION 26
By reduction of the appropriate nitro compound from Preparation 19, using iron and glacial acetic acid according to the procedure of Preparation 24, the following compounds can be prepared.
______________________________________ ##STR38## Position of aminoR.sup.2 R.sup.5 R.sup.6 group*______________________________________6-methylheptyl H H 21-pentylhexyl H H 2dodecyl H H 2pentadecyl H H 3pentadecyl H H 42-methyltetradecyl H H 3cyclohexyl H H 4cyclohexyl H H 3nonyl H CH.sub.3 2pentadecyl H CH.sub.3 4cyclohexyl H CH.sub.3 3cyclododecyl H CH.sub.3 4octyl CH.sub.3 H 2tridecyl CH.sub.3 H 3pentadecyl CH.sub.3 H 4cyclohexyl CH.sub.3 H 4cyclodecyl CH.sub.3 H 2cyclododecyl CH.sub.3 H 3octyl CH.sub.3 CH.sub.3 21-methylnonyl CH.sub.3 CH.sub.3 3tridecyl CH.sub.3 CH.sub.3 4pentadecyl CH.sub.3 CH.sub.3 3cyclohexyl CH.sub.3 CH.sub.3 4cyclononyl CH.sub.3 CH.sub.3 2cycloundecyl CH.sub.3 CH.sub.3 3cyclododecyl CH.sub.3 CH.sub.3 4______________________________________ *The numeral in this column indicates the position of the amino group on the phenyl ##STR39##
PREPARATION 27
N-(1-Methyldecyl)-3-(3-Aminophenyl)-2-butenamide
A stirred solution of 7.0 g. N-(1-methyldecyl)-3-(3-nitrophenyl)-2-butenamide (4.9 g. from Preparation 22 and 2.1 g. of substantially equivalent material from a similar preparation) in 80 ml. of glacial acetic acid was heated to 85.degree. C. on a steam bath. To this solution was added portionwise, during 20 minutes, 5.4 g. of iron powder. The reaction mixture was filtered hot and the residue was washed with hot glacial acetic acid. The combined acetic acid solutions were evaporated in vacuo, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed liberally with water, and then with saturated sodium chloride solution, and then it was dried using sodium sulfate. Removal of the solvent by evaporation in vacuo afforded the product as an oil.
The oil was purified by chromatography on ca. 280 g. of silica gel, eluting with a 1% solution of ethanol in ethyl acetate. The appropriate fractions were combined and evaporated, giving 5.8 g. of the title product, as an oil.
PREPARATION 28
N-(1-Methyldecyl)-3-(3-Aminophenyl)-2-butenamide
The N-(1-methyldecyl)-3-(3-nitrophenyl)-2-butenamide from Preparation 23 (6.5 g.) was reduced with iron powder (5.0 g.) in glacial acetic acid (80 ml.) in a manner analogously to Preparation 27. After chromatography, 4.5 g. of the title compound was obtained, as an amber oil.
PREPARATION 29
trans-2-(4-Nitrophenyl)cyclopropanecarboxylic Acid
To 300 ml. of concentrated nitric acid (specific gravity 1.42) was added, portionwise, during 20-25 minutes, at 23.degree.-25.degree. C., 50 g. of trans-2-phenylcyclopropanecarboxylic acid, with stirring. Stirring was continued for a further 1 hour and then the mixture was cooled to 10.degree. C. The precipitate was removed by filtration and washed with water. It was recrystallized twice from xylene, to give 23 g. of trans-2-(4-nitrophenyl)cyclopropanecarboxylic acid, m.p. 195.degree.-96.degree. C.
PREPARATION 30
trans-N-Octyl-2-(4-nitrophenyl)-cyclopropanecarboxamide
To a stirred slurry of 4.1 g. of trans-2-(4-nitrophenyl)cyclopropanecarboxylic acid in 50 ml. of chloroform was added 2.2 g. of triethylamine. The clear solution thus obtained was cooled to ca. 5.degree. C., and a solution of 2.4 g. of ethyl chloroformate in 15 ml. of chloroform was added dropwise with stirring during 15 minutes. Stirring was continued for 20 minutes, and then a solution of 2.8 g. of octylamine in 15 ml. of chloroform was added dropwise with stirring, at 0.degree.-5.degree. C., during 10-15 minutes. The cooling bath was removed, and stirring was continued for 1 hour. At this point, the solvent was removed by evaporation in vacuo, and the residue was triturated under a mixture of 70 ml. of water and 15 ml. of ethanol. The solid which remained out of solution was recovered by filtration, washed with water, and dried, to give 6.2 g. of the title compound as a white solid, m.p. 126.degree. -129.degree. C.
PREPARATION 31
trans-N-Decyl-2-(4-nitrophenyl)cyclopropanecarboxamide
The title compound was prepared from trans-2-(4-nitrophenyl)cyclopropanecarboxylic acid and decylamine, substantially according to the procedure of Preparation 30. A 98% yield of a white, waxy solid, m.p. 127.degree.-129.degree. C., was obtained.
PREPARATION 32
trans-N-(1-Methyldecyl)-2-(4-nitrophenyl)cyclopropanecarboxamide
To a stirred slurry of 2.1 g. of trans-2-(4-nitrophenyl)cyclopropanecarboxylic acid in 30 ml. of tetrahydrofuran was added 1.1 g. of triethylamine. The clear solution thus obtained was cooled to ca. 5.degree. C., and a solution of 1.2 g. of ethyl chloroformate in 5 ml. of chloroform was added dropwise, with stirring, during 15 minutes. Stirring was continued for 20 minutes, and then a solution of 1.9 g. of 1-methyldecylamine in 5 ml. of chloroform was added dropwise during 15 minutes. The cooling bath was removed, and stirring was continued for 1 hour. At this point the solvent was removed in vacuo and the residue was triturated with ether. The solid which remained out of solution was removed by filtration and discarded. The ether was evaporated in vacuo, and the residue was recrystallized from a 1:1 mixture of isopropanol and petroleum ether. This afforded 2.9 g. of the title compound as a waxy solid.
PREPARATION 33
The requisite trans-2-(nitrophenyl)cyclopropanecarboxylic acid is converted to a mixed anhydride using ethyl chloroformate, and then the mixed anhydride is reacted with the appropriate amine, both according to the procedure of Preparation 30, to give the following compounds.
______________________________________ ##STR40## Position ofR.sup.2 nitro group*______________________________________1-methylheptyl 4nonyl 4nonyl 3nonyl 2tridecyl 4tetradecyl 3pentadecyl 41-heptyloctyl 3cyclohexyl 4cycloheptyl 2cyclooctyl 3cyclodecyl 4cyclododecyl 3______________________________________ *The numeral in this column indicates the position of the nitro group on the phenyl ##STR41##
PREPARATION 34
trans-N-Octyl-2-(4-aminophenyl)cyclopropanecarboxamide
To a stirred solution of 6.2 g. of trans-N-octyl-2-(4-nitrophenyl)cyclopropanecarboxamide in 70 ml. of glacial acetic acid, at 85.degree. C., was added 5.3 g. of iron powder, portionwise, during 10 minutes. The temperature was kept between 85.degree. and 90.degree. C. during the addition. At the end of the addition, stirring was continued at 85.degree.-90.degree. C. for 10 minutes, and then the hot reaction mixture was filtered. The filtrate was evaporated in vacuo, and the residue thus obtained was partitioned between 350 ml. of ethyl acetate and 150 ml. of saturated sodium chloride solution. The ethyl acetate layer was removed, dried using sodium sulfate, and evaporated in vacuo. This gave 5.4 g. of the title compound as a yellow solid.
PREPARATION 35
trans-N-Decyl-2-(4-aminophenyl)cyclopropanecarboxamide
The title compound was prepared in 87% yield by reducing trans-N-decyl-2-(4-nitrophenyl)cyclopropanecarboxamide with iron powder in glacialacetic acid, in a manner analogous to Preparation 34.
PREPARATION 36
trans-N-(1-Methyldecyl)-2-(4-aminophenyl)cyclopropanecarboxamide
The title compound was prepared in essentially quantitative yield by reducing trans-N-(1-methyldecyl)-2-(4-nitrophenyl)cyclopropanecarboxamide with iron powder in glacial acetic acid, in a manner analogous to Preparation 34.
PREPARATION 37
Reduction of the appropriate N-alkyl-2-(nitrophenyl)cyclopropanecarboxamide or N-cycloalkyl-2-(nitrophenyl)cyclopropanecarboxamide from Preparation 33 with iron powder in glacial acetic acid, according to the procedure of Preparation 34, affords the following compounds.
______________________________________ ##STR42## Position ofR.sup.2 amino group*______________________________________1-methylheptyl 4nonyl 4nonyl 3nonyl 2tridecyl 4tetradecyl 3pentadecyl 41-heptyloctyl 3cyclohexyl 4cycloheptyl 2cyclooctyl 3cyclodecyl 4cyclododecyl 3______________________________________ *The numeral in this column indicates the position of the amino group on the phenyl ring; ##STR43##

Carboxamide compounds as SRS-A antagonists

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