CA1118448A - Compositions containing cis-2-benzoyl-3-hydroxy- crotononitrile and method of use to treat inflammation and joint deterioration - Google Patents
Compositions containing cis-2-benzoyl-3-hydroxy- crotononitrile and method of use to treat inflammation and joint deteriorationInfo
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- CA1118448A CA1118448A CA000304830A CA304830A CA1118448A CA 1118448 A CA1118448 A CA 1118448A CA 000304830 A CA000304830 A CA 000304830A CA 304830 A CA304830 A CA 304830A CA 1118448 A CA1118448 A CA 1118448A
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Abstract
Case 26729 ABSTRACT OF THE DISCLOSURE
This disclosure describes compositions of matter useful as anti-inflammatory agents and as inhibitors of the progressive joint deterioration characteristic of arthritic disease, and the methods of meliorating inflammation and of inhibiting joint deterioration in mammals therewith, the active ingredients of said compositions of matter being cer-tain cis-2-benzoyl-3-hydroxy-2-alkenonitriles and/or the pharmacologically acceptable cationic salts thereof.
This disclosure describes compositions of matter useful as anti-inflammatory agents and as inhibitors of the progressive joint deterioration characteristic of arthritic disease, and the methods of meliorating inflammation and of inhibiting joint deterioration in mammals therewith, the active ingredients of said compositions of matter being cer-tain cis-2-benzoyl-3-hydroxy-2-alkenonitriles and/or the pharmacologically acceptable cationic salts thereof.
Description
~ 8 BRIEF SUMMARY OF THE INVENTION
This invention relates to novel compositions of matter useful as anti-inflammatory agents and as inhibitors of the progressive joint deterioration characteristic of arthritic disease. More particularly, it relates to thera-peutic compositions containing certain cis-2-benzoyl-3-hydroxy-2-alkenonitriles or cationic salts thereof which melio-rate inflammation and inhibit arthritic joint deterioration in mammals. The invention includes the new compositions of matter and the methods of meliorating inflammation and of inhibiting joint deteriora~ion in mammals therewith. The active ingredients of the novel compositions of this inven-tion may be represented by the following structural formula:
~ C~ ~CN
1~
Mo~C~R
wherein R is alkyl having from one to four carbon atoms and M is hydrogen or a pharmaceutically acceptable cation. The useful pharmaceutically acceptable salts of the compounds of the above structural formula wherein M is hydrogen are those with pharmacologically acceptable metal cations, ammonium, amine cations or quaternary ammonium cations. Preferred metal cations are those derived from the alkali metals, e.g.
lithium, sodium and potassium, and from the alkaline earth metals, e.g. magnesium and calcium, although cationic forms of other metals, e.g. aluminum, zinc, iron and in particular 1~184~8 copper, are within the scope of the invention.
Pharmacologically acceptable amine cations and those derived from primary, secondary or tertiary amines such as mono-, di- or trimethylamine, ethylamine, dibutylamine, tri-isopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, mono- or dibenzylamine, ~- or ~-phenylethylamine, ethylenedi-amine, diethylenetriamine, and aryliphatic amines containing up to and including 18 carbon atoms, as well as heterocyclic amines, e.g. piperidine, morpholine, pyrrolidine, piperazine and lower alkyl derivative thereof, e.g. l-methylpiperidine, 4-ethylmorpholine, l-isopropylpyrrolidine, 2-methylpyrroli-dine, 1,4-dimethylpiperazine, 2-methylpiperidine, and the like, as well as amines containing water-solubilizing or hy-drophilic groups, e.g. mono-, di-, or triethanolamine, ethyl-diethanolamine, N-butylethanolamine, 2-amino-1-butanol, 2--amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, tris(hydroxy-methyl)aminomethane, N-phenylethanolamine, N--(p-tert-amylphenyl)diethanolamine, galactamine, N-methylgluc-amine, N-methylglucosamine, ephedrine, phenylephrine, epi-nephrine, procaine, and the like.
Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetra-ethylammonium, benzyltrimethylammonium, phenyltriethylammonium and the like.
The cis-2-benzoyl-3-hydroxy-2-alkenonitriles of the present invention may exist in other tautomeric forms as fol-lows:
4'~8 o _ ._ C6H5-C f N 8 M \ /
C ~ ~ C6115- C- C- CN \ C
C \ O=C-R / C \
MO R R-IC CN
In another aspect, the present invention provides a process of forming a cis-2-benzoyl-3-hydroxy-2-alkenonitrile having the following general formula H c f CN
MO-C-R
wherein R is an alkyl group having from 2 to 4 carbon atoms and M is hydrogen or a pharmacologically acceptable cation and the tautomers thereof, which comprises:
a) acylation of a benzoylacetonitrile anion (I) with an acyl halide (II) as follows:
OM
C6H5 -C=CHCN + R.COX ~ C6H5CO-C-CN
(I) (II) /C\ (III) HO R
whcrein M and R as hereinbefore defined, and X is a halogen;
b) condensation of benzoylacetonitrile with a trialkyl artho-cstcr as follows:
CGH5co-cH2cN 3` C6H5CO-C-CN > C6H5CO-!CI-CN
/ C / C \ (III) R' R HO R
(IV) whcrcirl 1~ is a hcrcirlbci~orc dcfincd and R' is alkoxy, rmd then hyclrolyzing ttlC compoulld (~[V) unde-r acidic conditions to provide (II[); or c) addition of a cyanoenolate (V) to benzoyl chloride as follows:
ONa C H COCl -~ R-l=CIICN ~ C61-15CO-6-CN
(V) /C (III) HO
wherein R is as hereinbefore defined;
d) condensation of an acylacetophenone (VI) with N,N-dimethyl formamide dimethyl acetal to give a compound of general formula (VII) as follows:
H N(CH3)2 (VI) (VII) wherein R is as hereinbefore defined and then treating the compound VII
1,~ with hydroxylamine to give a mixture of products of formulae VIII and IX
which are then reacted with a strong basa to give a cis-2-benzoyl-3-hydroxy-
This invention relates to novel compositions of matter useful as anti-inflammatory agents and as inhibitors of the progressive joint deterioration characteristic of arthritic disease. More particularly, it relates to thera-peutic compositions containing certain cis-2-benzoyl-3-hydroxy-2-alkenonitriles or cationic salts thereof which melio-rate inflammation and inhibit arthritic joint deterioration in mammals. The invention includes the new compositions of matter and the methods of meliorating inflammation and of inhibiting joint deteriora~ion in mammals therewith. The active ingredients of the novel compositions of this inven-tion may be represented by the following structural formula:
~ C~ ~CN
1~
Mo~C~R
wherein R is alkyl having from one to four carbon atoms and M is hydrogen or a pharmaceutically acceptable cation. The useful pharmaceutically acceptable salts of the compounds of the above structural formula wherein M is hydrogen are those with pharmacologically acceptable metal cations, ammonium, amine cations or quaternary ammonium cations. Preferred metal cations are those derived from the alkali metals, e.g.
lithium, sodium and potassium, and from the alkaline earth metals, e.g. magnesium and calcium, although cationic forms of other metals, e.g. aluminum, zinc, iron and in particular 1~184~8 copper, are within the scope of the invention.
Pharmacologically acceptable amine cations and those derived from primary, secondary or tertiary amines such as mono-, di- or trimethylamine, ethylamine, dibutylamine, tri-isopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, mono- or dibenzylamine, ~- or ~-phenylethylamine, ethylenedi-amine, diethylenetriamine, and aryliphatic amines containing up to and including 18 carbon atoms, as well as heterocyclic amines, e.g. piperidine, morpholine, pyrrolidine, piperazine and lower alkyl derivative thereof, e.g. l-methylpiperidine, 4-ethylmorpholine, l-isopropylpyrrolidine, 2-methylpyrroli-dine, 1,4-dimethylpiperazine, 2-methylpiperidine, and the like, as well as amines containing water-solubilizing or hy-drophilic groups, e.g. mono-, di-, or triethanolamine, ethyl-diethanolamine, N-butylethanolamine, 2-amino-1-butanol, 2--amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, tris(hydroxy-methyl)aminomethane, N-phenylethanolamine, N--(p-tert-amylphenyl)diethanolamine, galactamine, N-methylgluc-amine, N-methylglucosamine, ephedrine, phenylephrine, epi-nephrine, procaine, and the like.
Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetra-ethylammonium, benzyltrimethylammonium, phenyltriethylammonium and the like.
The cis-2-benzoyl-3-hydroxy-2-alkenonitriles of the present invention may exist in other tautomeric forms as fol-lows:
4'~8 o _ ._ C6H5-C f N 8 M \ /
C ~ ~ C6115- C- C- CN \ C
C \ O=C-R / C \
MO R R-IC CN
In another aspect, the present invention provides a process of forming a cis-2-benzoyl-3-hydroxy-2-alkenonitrile having the following general formula H c f CN
MO-C-R
wherein R is an alkyl group having from 2 to 4 carbon atoms and M is hydrogen or a pharmacologically acceptable cation and the tautomers thereof, which comprises:
a) acylation of a benzoylacetonitrile anion (I) with an acyl halide (II) as follows:
OM
C6H5 -C=CHCN + R.COX ~ C6H5CO-C-CN
(I) (II) /C\ (III) HO R
whcrein M and R as hereinbefore defined, and X is a halogen;
b) condensation of benzoylacetonitrile with a trialkyl artho-cstcr as follows:
CGH5co-cH2cN 3` C6H5CO-C-CN > C6H5CO-!CI-CN
/ C / C \ (III) R' R HO R
(IV) whcrcirl 1~ is a hcrcirlbci~orc dcfincd and R' is alkoxy, rmd then hyclrolyzing ttlC compoulld (~[V) unde-r acidic conditions to provide (II[); or c) addition of a cyanoenolate (V) to benzoyl chloride as follows:
ONa C H COCl -~ R-l=CIICN ~ C61-15CO-6-CN
(V) /C (III) HO
wherein R is as hereinbefore defined;
d) condensation of an acylacetophenone (VI) with N,N-dimethyl formamide dimethyl acetal to give a compound of general formula (VII) as follows:
H N(CH3)2 (VI) (VII) wherein R is as hereinbefore defined and then treating the compound VII
1,~ with hydroxylamine to give a mixture of products of formulae VIII and IX
which are then reacted with a strong basa to give a cis-2-benzoyl-3-hydroxy-
2-alkenonitrile of general formula III as follows:
_ _ O
/ \ ,0 ' 11 R-C N + C6H5-1C N 6 5 ll C - Cll IC - Cl-l HO - C - R
_ COC6~15 COR l (VII[) (IX) (III) whcrein R :is as hereinbefore defined.
ETAILED DESCRIPTION OF THE INVENTION
The cis-2-benzoyl-3-hydroxy-2-alkenonitriles and cationic salts -thercof of the present invention have been found to be higllly useful for mcliorilting, inEIalnmati.on and inhibiting joint deterioratioll in man~nals when a~ inistcrcd in an10urlts ranging from about one milligralll to about 250 mg.
2() per ki,logralll of body weight per day. A preferred dosagc rcgimen Eor optimum - 3a -<,, , i~l84413 results would be from about 5 mg. to about 100 mg. per kilogram of body weight per day, and such dosage units are employed that a total of from about 0.35 gram to about 7.0 grams of the active ingredient for a subject of about 70 kg. of body weight are administered in a 24 hour period. This dosage regimen may be adjusted to provide the optimum therapeutic response.
For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the thera-peu~ic situation. A decided practical advantage of this invention is that the active ingredient may be administered in any convenient manner such as by the oral, intravenous, intramuscular, topical or subcutaneous routes.
Compositions according to the present invention having the desired clarity, stability and adaptability for parenteral use are obtained by dissolving from 0.10% to . .,.~s ' 10.0% by weight of active compound in a vehicle consisting of a polyhydric aliphatic alcohol or mixtures thereof. Es-pecially satisfactory are glycerin, propylene glycol, and polyethylene glycols. The polyethylene glycols consist of a mixture of non-volatile, normally liquid, polyethylene glycols which are soluble in both water and organic liquids and which have molecular weights of from about 200 to 1500.
Although the amount of active compound dissolved in the above vehicle may vary from 0.10 to 10.0% by weight, it is pre-ferred that the amount of active compound employed be from about 3.0 to about 9.0% by weight. Although various mixtures of the aforementioned non-volatile polyethylene glycols may be employed, it is preferred to use a mixture having an aver-age molecular weight of from about 200 to about 400~
In addition to the active compound, the parenteral solutions may also contain various preservatives which may be used to prevent bacterial and fungal contamination. The preservatives which may be used for these purposes are, for example, myristyl-gamma-picolinium chloride, phenyl mercuric nitrate, benzalkonium chloride, phenethyl alcohol, p-chloro-phenyl-~-glycerol ether, methyl and propyl parabens, and thimerosal. As a practical matter it is also convenient to employ antioxidants. Suitable antioxidants include, for ex-ample, sodium bisulfite, sodium metabisulfite, and sodium formaldehyde sulfoxylate. Generally, from about 0~05 to about 0.2% concentrations of antioxidant are employed.
For intramuscular injection, the preferred con-centration of active compound is 0.25 to 0.50 mg./ml. of the finished compositions. The cls-2-benzoyl-3-hydroxy-2-alkeno-nitriles are equally adapted to intravenous administration ~ ~Lh~34'i8 when diluted with water or diluents employed in intravenous therapy such as isotonic glucose in appropriate quantities~
For intravenous use, initial concentrations down to about 0.05 to 0.25 mg./ml. of active compound are satisfactory.
The active compounds of the present invention may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsules, or they may be com-pressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administra-tion, the active compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active com-pound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2% to about 60% of the weight of the unit. The amount of active ingredient in such therapeutically useful composi-tions is such that a suitable dosage will be obtained. Pre-ferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form con-tains between about 50 and 250 milligrams of active compound.
The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum traga-canth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubri-cant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen, or cherry fla-4'~
voring. When the dosage unit form is a capsule, it may con-tain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or cap-sules may be coated with shellac, sugar or both~ A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor~ Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
The following test shows the activity of the ClS--2-benzoyl-3-hydroxy-2-alkenonitriles against chronic inflam-mation in adjuvant induced arthritis which is accompanied by joint destruction. Groups of three Royal Hart, Wistar strain rats weighing 200+10 grams each were injected intradermally in the right hind paw with Freund's adjuvant (dried human tuber-cle bacilli in a mineral oil vehicle) at a dose of 2 mg./kg.
of body weight. Test compound was administered orally in a 1.5% starch vehicle at various doses once daily on days 0 through 13 post challenge. Control rats were treated in a similar manner, but given only starch vehicle. On the 14th and 21st day post challenge the diameter of the injected paw (pr (primary lesion) was measured by micrometer caliper. The volume of inflamed paws were estimated from these measurements and the results are expressed as percent inhibition of swell-ing as compared to controls. At the same time, the other inflamed sites, such as ears, paws and tail (seconday lesions) were observed and each rat was graded as to degree of inflam-mation and swelling present. The grading is based on a scale of 0 to 24, where 0 represents a complete absence of induced arthritic nodules and 24 represents the maximum degree of in-flammation. The mean grade for each treated group is calcu-lated and the effects of each compound are expressed as per-cent inhibition of the control grade. Table I records the results of tests conducted with a typical compound of the pre-sent invention and known anti-inflammatory agents. The c~s--2-benzoyl-3-hydroxycrotononitrile appears to suppress the progression of the arthritis and associated joint deteriora-tion.
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_ g _ 34~8 Adjuvant induced experimental polyarthritis is a specific systemic desease of the rat which shares interesting similarities with rheumatoid arthritis. Specifically, the his-tology of the two diseases bears a remarkable resemblence as shown by C. M. Pearson et al., Am. J. Path. 42, 73 (1963).
E. M. Glenn, Am. J. Vet. Res. 27 (116), 339 (1966) has classi-fied adjuvant induced polyarthritis as a crippling and perm-anent deformity resulting from diffuse connective tissue in-volvement around certain susceptible joints in the rat. Zahiri et al, Can. Med. Ass. J. 101, 269 (1969) have shown that the fusiform swelling of the distal joints is associated with edema, congestion and synovitis including pannus formation, all of which precede the ultimate destruction of bone and cartilage.
Furthermore, Zahiri et al. indicate that the cartilage destruc-tion in the joint is due to an invasive pannus which originates in the marginal synovium and extends across the articular sur-face to erode it. When non-steroidal, anti-inflammatory agents such as indomethacin inhibit arthritic paw swelling, which is -composed of inflammatory cell infiltrates, they have also been shown to prevent joint and bone deterioration [see S. Wong et al., J. Pharm. & Exp. Ther. 185, 127 (1973) and G. R. Bobalick et al., Agents and Actions 4, 364 (1974)]. The most pertinent reference showing the relationship between arthritis and joint ; deterioration is an X-ray analysis of adjuvant arthritis in the rat by Blackham et al., Agents and Actions 7, 145 (1977).
In a similar manner, inhibition of the progress of arthritis in paws of rats treated with the compounds of this invention ~ also lessens associated joint deterioration.
4~
Another method of determining a drug effect on con-ditions which result in inflammation is by measuring the ef-fect on ultraviolet induced erythema in guinea pigs. Albino guinea pigs were depilitated on their flanks, the evening be-fore testing, with a standard mixture of barium sulfide and gum acacia. On the morning of the test, groups of four guinea pigs were dosed by gavage one hour prior (-l hour) to ultra-violet exposure. At 0 hour they were restrained in a plastic container which allows exposure of 3 circular spots. They were then exposed to ultraviolet irradiation from a "Hanovia"
Kromayer lamp, model 10, for 60 seconds. At one and four hours, the degree of erythema for each of the three sites was assessed according to the following scoring system: 0 = no erythema, 0.5 = incomplete circle or faint erythema, and 1.0 = complete circle of distinct erythema. Thus, the maximum score for each animal was 3Ø The following Table II summarizes the results of this test with a typical compound of the present invention and other drugs known to have a beneficial anti-inflammatory effect in suppressing ultra-violet induced erythema in warm blooded animals.
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34~8 In determining the acute anti-inflammatory acti-vity of the cls-2-benzoyl-3-hydroxy-2-alkenonitriles of the present invention, Royal Hart, Wistar strain rats, ranging in weight from 80 to 90 grams were used. The rats were fasted overnight prior to dosing but had free access to water. The test compounds were administered in aqueous suspension, by gavage, in a volume of 1.7 ml. per 50 grams of rat [corres-ponds to hydration volume used by Winter, et al., Proc. Soc.
Exp. Biol. & Med., 111, 544-547 (1962)]. The phlogistic agent used was carrageenin prepared as a sterile 1% suspension in 0.9~ aqueous sodium chloride for routine testing. A volume of 0.05 ml. was injected through a 26 gauge needle into the plantar tissue of the right hind paw. Measurements were made 5 hours after drug administration (4 hours after carrageenin challenge). Volumes of both the normal and carrageenin in-- flammed feet were determined. The difference between the two measurements is considered to be the increased edema due to the carrageenin administration. Results are expressed as a CtT efficacy ratio (edema of control animals/edema of treated animals) and a C/T ratio of greater than 1.41 is considered as active. Table III records the results of this test at the in-dicated dose level of a typical compound of the present inven-tion and demonstrates the anti-inflammatory effect of this compound in comparison with known anti-inflammatory agents.
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, This invention will be described in greater detail in conjunction with the following specific examples.
EXAMP;LE 1 Benzoylacetonitrile, thallium (I) salt A suspension of 10 g. of benzoylacetonitrile in 200 ml. of dry diethyl ether is stirred at room temperature while 17.2 g. of neat thallium (I) ethoxide is slowly added.
The resulting reaction mixture is stirred for one hour at room temperature and then filtered. The collected precipitate is washed with diethyl ether and air dried whereby there is obtained 23.7 g. (99% yield) of the thallium (I) salt of ben-zoylacetonitrile which may be stored indefinitely at room temperature.
Cis-2-benzoyl-3-hydroxycrotononitrile -To a suspension of 2.2 g. of benzoylacetonitrile, thallium (I) salt in 20 ml. of tetrahydrofuran is added 2 ml.
of acetyl fluoride with stirring at room temperature. After one hour, another 2 ml. of acetyl fluoride is added, followed by 2 ml. more after twleve hours. Twelve hours later, the precipitated thallium (I) fluoride is removed by filtration and the filtrate is evaporated to dryness. The off-white residue is recrystallized from ethanol to provide the c15-2--benzoyl-3-hydroxycrotononitrile which has been described by Musante, Gazz. Chim. Ital. 69, 523 (1939).
Cis-2-benzoyl-3-hydroxy-2-pentenonitrile To a suspension of 5 g. of benzoylacetonitrile, thallium (I) salt in 50 ml. of diethyl ether is added a solu-tion of 5 g. of propionyl fluoride in 10 ml. of diethyl ether ~i34~8 with stirring at room temperature. After 12 hours, the re-action mixture is filtered and the filtrate evaporated and then pumped dry on a vacuum pump for one hour. The residue is then treated with chloroform and filtered and the solid collected provides the title compound.
Cis-2-benzoyl-3-hydroxy-2-hexenonitrile The procedure of Example 2 is repeated substituting an equimolecular amount of butyryl fluoride for the acetyl fluoride employed in that example. There is thus obtained the cis-2-benzoyl-3-hydroxy-2-hexenonitrile after purification by column chromatography.
Cis-2-benzoyl-3-hydroxy-4-methyl-2-pentenonitrile By replacing the acetyl fluoride employed in Exam-ple 2 with an equimolar amount of _ butyryl fluoride, there is obtained the corresponding cis-2-benzoyl-3-hydroxy-4-meth-yl-2-pentenonitrile after purification by column chromatography.
Cis-2-benzoyl-3-hydroxy-2-heptenonitrile The general procedure of Example 2 is repeated but replacing the acetyl fluoride employed in that example with an equivalent amount of valeryl fluoride whereby there is obtained the cls-2-benzoyl-3-hydroxy-2-heptenonitrile after purification by column chromatography.
2-Methylbutyryl fluoride A sample of 2-methylbutyryl chloride in dimethyl-formamide is treated with a threefold excess of sodium fluo-ride. The temperature is raised and the pure acid fluoride is collected by distillation from the reaction mixture.
34 ~8 Cis-2-benzoyl-3-hydroxy-4-methyl-2-hexenonitrile Following the general procedure of Example 3, ben-zoylacetonitrile, thallium (I) salt is treated with 2-methyl-butyryl fluoride to give the cis-2-benzoyl-3-hydroxy-4-meth-yl-2-hexenonitrile after purification by column chromatography.
Cis-2-benzoyl-3-hydroxy-5-methyl-2-hexenonitrile _ Treatment of be~nzoylacetonitrile, thallium (I) salt with lsovaleryl fluoride by the procedure described in Exam-ple 3 is productive of the cis-2-benzoyl-3-hydroxy-5-methyl--2-hexenonitrile after purification by column chromatography.
Cis-2-benzoyl-3-hydroxy-4,~-dimethyl-2-pentenonitrile In the manner described in Example 3, reaction of benzoylacetonitrile, thallium (I) salt with pivalyl fluoride provides the corresponding cis-2-benzoyl-3-hydroxy-4,4-di-methyl-2-pentenonitrile after purification by column chromato-graphy. EXAMPLE ll Cis-~-benzoyl-3-hydroxycrotononitrile, sodium salt __ A calculated concentration of sodium hydroxide in water is prepared and an excess of c -2-benzoyl-3-hydroxy-crotononitrile is added and stirred for half an hour. The mixture is filtered and the filtrate is evaporated. The gummy residue is dissolved in dry acetone and again evaporated, pro-viding the title compound. -Cis-2-benzoyl-3-hydroxy-2-pentenonitrile, triethylammonium -salt A sample of cis-2-benzoyl-3-hydroxy-2-pentenonitrile 34 ~1~
is dissolved in dry diethyl ether and an equivalent amount of triethylamine is added dropwise. The mixture is cooled in ice and the precipitate is removed by filtration to pro-vide the title compound.
EX~MPLE 13 Cis-2-benzoyl-3-hydroxycrotononitrile, copper (II) salt A weighed sample of c1s-2-benzoyl-3-hydroxycrotono-nitrile is dissolved in a dilute solution of ammonium hydrox-ide and an equivalent quantity of cupric sulfate in water is added. The blue solution is heated on a steam bath for 3 hours and cooled. The precipitate is removed by filtration and washed with water to yield the title compound.
Preparation of 50 mg. Tablets Per Tablet Per 10,000 Tablets 0.050 gM. Cis-2-benzoyl-3-hydroxy-crotonitrile ~ O~500 gm.
0.080 gm. Lactose ...... ~...................... 800 gm~
0.010 gm. Corn Starch (for mix) ~ .O~. lO0 gm.
0.008 gm. Corn Starch (for paste) ~ O~ 75 gm.
0 148 gm 1475 gm.
0 002 gm Magnesium Stearate (1%) ..... ~ .. 15 gm.
0.150 gm. 1490 gm.
The cis-2-benzoyl-3-hydroxycrotonitrile, lactose and corn starch (for mix) are blended together. The corn starch (for paste) is suspended in 600 ml. of water and heated with stirring to form a paste. This paste is then used to granulate the mixed powders. Additional water is used if necessary. The wet granules are passed through a No. 8 hand screen and dried at 120F. The dry granules are then passed through a No. 16 screen. The mixture is lubricated with 1%
magnesium stearate and compressed into tablets in a suitable tableting machine.
Prepa _tion of Oral Suspension Ingredient Amount Cis-2-Benzoyl-3-hydroxy-2-pentenonitrile ................. 500 mg.
Sorbitol solution (70~ N.F.) .............................. 40 ml.
Sodium benzoate ..~.............................. 150 mg.
Saccharin ........................................ 10 mg.
Red dye .......................................... 10 mg.
Cherry flavor .................................... 50 mg.
Distilled water... qs... ad ....................... 100 ml.
The sorbitol solution is added to 40 ml. of dis-tilled water and the cis-2-benzoyl-3-hydroxy-2-pentenonitrile is suspended therein. The saccharin, sodium benzoate, flavor and dye are added and dissolved. The volume is adjusted to 100 ml. with distilled water. Each ml. of syrup contains 5 mg. of cis-2-benzoyl-3-hydroxy-2-pentenonitrile.
Preparation of Parenteral Solution In a solution of 700 ml. of propylene glycol and 200 ml. of water for injection is suspended 20.0 grams of cis-2-benzoyl-3-hydroxy-2-hexenonitrile with stirring. After suspension is complete, the pH is adjusted to 5.5 with hydro-chloric acid and the volume is made up to 1000 ml. with water for injection. The formulation is sterilized, filled into 5.0 ml. ampoules each containing 2.0 ml. (representing 40 mg.
of drug) and sealed under nitrogen.
Preparation of Topical Cream Ingred ent Amount Cis-2-benzoyl-3-hydroxy-4-methyl--2-pentenonitrile........................... 1.0%
Ethoxylated stearyl alcohol.................. 10.0%
Benzyl alcohol................................ 0.9%
Isopropyl palmitate........................... 5.0%
~lycerin...................................... 5.0~
Sorbitol solution (USP)....................... 5.0%
Lactic acid... qs... topH 4.0-5.0 Water......... qs... ad................................. 100.0 4 ~8 The ethoxylated stearyl alcohol and isopropyl pal-mitate are heated to liquifying temperature. About 95% of the total volume of water is placed in a separate container followed by the glycerin and sorbitol solution. This aqueous mixture is brought to a boil and then cooled to 60-75C.
The cls-2-benzoyl-3-hydroxy-4-methyl-2-pentenonitrile is added to the wax phase and the mixture is stirred until a clear solution is obtained. The benzyl alcohol is added and dissolved in the wax phase. The water phase is passed through a screen into the wax phase while maintaining agitation.
Both phases are kept at about the same temperature during transfer. The mixture is cooled while agitation is continued.
At a temperature of 50-55C. the balance of the water is added. The pH is adjusted to 4.0-5.0 with lactic acid. The batch is cooled with minimum agitation until the cream sets in its final form.
Pre aration of Intra-articular Product P
Ingredient Amount Cis-2-benzoyl-3-hydroxy-2-heptenonitrile .......... 2-20 mg.
NaCl (physiological saline) ........................... 0.9%
Benzyl alcohol N.F. .................................... 0.9 Sodium carboxymethylcellulose .......................... 1-5 pH adjusted to 5.0-7.5 Water for injection ........ qs ad ...................... 100 Preparation of Injectable Depo Suspension Ingredient % w/V
Cis-2-benzoyl-3-hydroxy-4,4-dimethyl--2-pentenonitrile ~ O~ O~OOOO~OO~ 0.05-5 Polysorbate 80 USP ............................. Ø2 Polyethylene glycol 4000 USP ~ O~ 3.0 Sodium chloride USP ...... ,~,................... .Ø8 Benzyl alcohol N.F. ................... ......... .Ø9 HCl to pH 6-8 ~ O~ qs Water for injection....... ~qs ad ............... 100.0 Example 20 Cyanoacetone, sodium salt A solution of 0.174 mole of sodium ethoxide is pre-pared by dissolving 4.0 g. of sodium in 200 ml. of absolute ethanol. A neat sample of 15 ml. (0.184 mole) of 5-methyl-isoxazole is then added dropwise as a colorless precipitate forms. When the addition is complete, the mixture is cooled in an ice bath and then filtered. The precipitate is collected, and washed with hexane, yielding 14.0 g. of colorless product.
Example 21 Cis-2-benzoyl-3-hydroxycrotononitrile A mixture of 1.0 g. (9.5 mmole) of cyanoacetone, sodium salt in 20 ml, of tetrahydrofuran is stirred at room temperature as a solution of 0.37 ml. (3.2 mmole) of benzoyl chloride in 5 ml. of tetrahydrofuran is added. The reaction is heated to reflux for 2 hours and the solvent is then eva-porated. The residue is acidified and extracted with diethyl ether. Evaporation of the organic phase provides 0.7 g. of a yellow oil which crystallizes on standing to provide the title compound.
4~8 Example 22 l-Cyano-2-butanone, sodium salt A solution of 0.174 moles of sodium ethoxide is pre-pared by dissolving 4.0 g. of sodium in 200 ml. of absolute ethanol. A neat sample of 5-ethylisoxazole (17.9 g., 0.185 mole) is then added. The reaction is stirred for one hour as a colorless precipitate forms. The mixture is cooled in an ice bath and filtered. The precipitate is washed with hexane and air dried, yielding the title compound.
Example 23 Cis-2-benzo~l-3-hydroxy-2-pentenonitrile A mixture of 3.0 g. (25 mmole) of 1-cyano-2-butanone, sodium salt in 20 ml. of tetrahydrofuran is stirred as a sol-ution of 0.9 g. (8.6 mmole) of benzoyl chloride in 6 ml. of tetrahydrofuran is added. The reaction is heated to reflux for 3 hours, then cooled and the solvent evaporated. T~e residue is acidified and extracted with chloroform. The organ-ic phase is extracted twice with aqueous sodium bicarbonate which in turn is acidified and extracted again with chloro-form. The organic phase is dried and evaporated to yield the title compound.
4~8 Several procedures exist for the attachment of the acyl fragment to a benzoylacetonitrile side chain. The first involves direct acylation of the benzoylacetonitrile anion (1) with an acyl halide (2) in an appropriate solvent. The enolate anions (1) are prepared OH
OM ll O
[~CN + RC ~3J~R
10(1) (2) (3) by the treatment of the benzoylacetonitrile with the appropriate base in an inert solvent. This enolate may be generated in situ and acylated with (2) in the same solvent or may be isolated and reacted in a different solvent system. When M represents sodium where (1) has been generated by treatment of the benzoylacetonitrile with sodium hydride, sodium amide, sodium methoxide, etc. and X
represents chlorine, yields of ( 3) are low with undesired side products sometimes predominating. Preferably, the benzoylacetoni-trile is dissolved in diethyl ether and one equivalent of neat thalluim (I) ethoxide is added. The stable enolate (1), where M
is thalluim, precipitates and may be collected by filtration, dried and stored indefinitely. Suspension of (1) in an inert solvent such as ether, tetrahydrofuran, dioxane, etc. at room temperature and the treatment of same with an acyl fluoride (2) where X=F causes precipitation of thalluim (I) fluoride. This is removed by filtration and the produc-t is extracted from the filtrate.
Another approach involves addition of the acyl frayment as a hydrolyzable portion to yield (4). This may be o o o CN ~ ~ ~HO I RCN
(4) ( 3) performed by condensation of the benzoylacetonitrile with a trialkyl ortho estcr in refluxing acetic anhydride. Evaporation Of by products and excess acetic anhydride in vaCuo and purification of the product under anhydrous conditions provides (4) where R/ is alkoxy. This intermediate (4), where R/ is alkoxy, may be hydrolyzed under acidic conditions to provide the desired product (3).
A different approach to (3) involves addition of the cyanoacyl fragment to a benzoyl chloride. This reaction may be CN OIH
J ~ ~ ONa > CN
,~7 R
~ / (5) (3) / \ NaH
\N ~
performed by gcneration Of the enolate anion (5) in situ With the 5-alkyl-isoxazole and base such as sodium hydride or sodium amide and subsequent addition Of the benzoylacetonitrile to affect con-_ 25 -,~A.
~184~3 densation to provide (3). Alternatively the ~-cyanoenolate (5) may be prepared separately in a similar manner as above and iso-lated. Addition of this enolate to the appropriate benzoyl chloride in ether, tetrahydrofuran, etc. at room temperature or at reflux provides (3).
A less desirable route to (3) involves that discribed below. The acylacetophenone (6) o (CH3)2N-CH (OC 3 2 R 1~ N
t6) (7) ~CH3 O OH - NH2OH~ 1 ~\ R ~ j~ ~o + [~ O N
CN NaOH N/ o R
_ _ O
/ \ ,0 ' 11 R-C N + C6H5-1C N 6 5 ll C - Cll IC - Cl-l HO - C - R
_ COC6~15 COR l (VII[) (IX) (III) whcrein R :is as hereinbefore defined.
ETAILED DESCRIPTION OF THE INVENTION
The cis-2-benzoyl-3-hydroxy-2-alkenonitriles and cationic salts -thercof of the present invention have been found to be higllly useful for mcliorilting, inEIalnmati.on and inhibiting joint deterioratioll in man~nals when a~ inistcrcd in an10urlts ranging from about one milligralll to about 250 mg.
2() per ki,logralll of body weight per day. A preferred dosagc rcgimen Eor optimum - 3a -<,, , i~l84413 results would be from about 5 mg. to about 100 mg. per kilogram of body weight per day, and such dosage units are employed that a total of from about 0.35 gram to about 7.0 grams of the active ingredient for a subject of about 70 kg. of body weight are administered in a 24 hour period. This dosage regimen may be adjusted to provide the optimum therapeutic response.
For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the thera-peu~ic situation. A decided practical advantage of this invention is that the active ingredient may be administered in any convenient manner such as by the oral, intravenous, intramuscular, topical or subcutaneous routes.
Compositions according to the present invention having the desired clarity, stability and adaptability for parenteral use are obtained by dissolving from 0.10% to . .,.~s ' 10.0% by weight of active compound in a vehicle consisting of a polyhydric aliphatic alcohol or mixtures thereof. Es-pecially satisfactory are glycerin, propylene glycol, and polyethylene glycols. The polyethylene glycols consist of a mixture of non-volatile, normally liquid, polyethylene glycols which are soluble in both water and organic liquids and which have molecular weights of from about 200 to 1500.
Although the amount of active compound dissolved in the above vehicle may vary from 0.10 to 10.0% by weight, it is pre-ferred that the amount of active compound employed be from about 3.0 to about 9.0% by weight. Although various mixtures of the aforementioned non-volatile polyethylene glycols may be employed, it is preferred to use a mixture having an aver-age molecular weight of from about 200 to about 400~
In addition to the active compound, the parenteral solutions may also contain various preservatives which may be used to prevent bacterial and fungal contamination. The preservatives which may be used for these purposes are, for example, myristyl-gamma-picolinium chloride, phenyl mercuric nitrate, benzalkonium chloride, phenethyl alcohol, p-chloro-phenyl-~-glycerol ether, methyl and propyl parabens, and thimerosal. As a practical matter it is also convenient to employ antioxidants. Suitable antioxidants include, for ex-ample, sodium bisulfite, sodium metabisulfite, and sodium formaldehyde sulfoxylate. Generally, from about 0~05 to about 0.2% concentrations of antioxidant are employed.
For intramuscular injection, the preferred con-centration of active compound is 0.25 to 0.50 mg./ml. of the finished compositions. The cls-2-benzoyl-3-hydroxy-2-alkeno-nitriles are equally adapted to intravenous administration ~ ~Lh~34'i8 when diluted with water or diluents employed in intravenous therapy such as isotonic glucose in appropriate quantities~
For intravenous use, initial concentrations down to about 0.05 to 0.25 mg./ml. of active compound are satisfactory.
The active compounds of the present invention may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsules, or they may be com-pressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administra-tion, the active compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active com-pound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2% to about 60% of the weight of the unit. The amount of active ingredient in such therapeutically useful composi-tions is such that a suitable dosage will be obtained. Pre-ferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form con-tains between about 50 and 250 milligrams of active compound.
The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum traga-canth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubri-cant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen, or cherry fla-4'~
voring. When the dosage unit form is a capsule, it may con-tain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or cap-sules may be coated with shellac, sugar or both~ A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor~ Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
The following test shows the activity of the ClS--2-benzoyl-3-hydroxy-2-alkenonitriles against chronic inflam-mation in adjuvant induced arthritis which is accompanied by joint destruction. Groups of three Royal Hart, Wistar strain rats weighing 200+10 grams each were injected intradermally in the right hind paw with Freund's adjuvant (dried human tuber-cle bacilli in a mineral oil vehicle) at a dose of 2 mg./kg.
of body weight. Test compound was administered orally in a 1.5% starch vehicle at various doses once daily on days 0 through 13 post challenge. Control rats were treated in a similar manner, but given only starch vehicle. On the 14th and 21st day post challenge the diameter of the injected paw (pr (primary lesion) was measured by micrometer caliper. The volume of inflamed paws were estimated from these measurements and the results are expressed as percent inhibition of swell-ing as compared to controls. At the same time, the other inflamed sites, such as ears, paws and tail (seconday lesions) were observed and each rat was graded as to degree of inflam-mation and swelling present. The grading is based on a scale of 0 to 24, where 0 represents a complete absence of induced arthritic nodules and 24 represents the maximum degree of in-flammation. The mean grade for each treated group is calcu-lated and the effects of each compound are expressed as per-cent inhibition of the control grade. Table I records the results of tests conducted with a typical compound of the pre-sent invention and known anti-inflammatory agents. The c~s--2-benzoyl-3-hydroxycrotononitrile appears to suppress the progression of the arthritis and associated joint deteriora-tion.
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_ g _ 34~8 Adjuvant induced experimental polyarthritis is a specific systemic desease of the rat which shares interesting similarities with rheumatoid arthritis. Specifically, the his-tology of the two diseases bears a remarkable resemblence as shown by C. M. Pearson et al., Am. J. Path. 42, 73 (1963).
E. M. Glenn, Am. J. Vet. Res. 27 (116), 339 (1966) has classi-fied adjuvant induced polyarthritis as a crippling and perm-anent deformity resulting from diffuse connective tissue in-volvement around certain susceptible joints in the rat. Zahiri et al, Can. Med. Ass. J. 101, 269 (1969) have shown that the fusiform swelling of the distal joints is associated with edema, congestion and synovitis including pannus formation, all of which precede the ultimate destruction of bone and cartilage.
Furthermore, Zahiri et al. indicate that the cartilage destruc-tion in the joint is due to an invasive pannus which originates in the marginal synovium and extends across the articular sur-face to erode it. When non-steroidal, anti-inflammatory agents such as indomethacin inhibit arthritic paw swelling, which is -composed of inflammatory cell infiltrates, they have also been shown to prevent joint and bone deterioration [see S. Wong et al., J. Pharm. & Exp. Ther. 185, 127 (1973) and G. R. Bobalick et al., Agents and Actions 4, 364 (1974)]. The most pertinent reference showing the relationship between arthritis and joint ; deterioration is an X-ray analysis of adjuvant arthritis in the rat by Blackham et al., Agents and Actions 7, 145 (1977).
In a similar manner, inhibition of the progress of arthritis in paws of rats treated with the compounds of this invention ~ also lessens associated joint deterioration.
4~
Another method of determining a drug effect on con-ditions which result in inflammation is by measuring the ef-fect on ultraviolet induced erythema in guinea pigs. Albino guinea pigs were depilitated on their flanks, the evening be-fore testing, with a standard mixture of barium sulfide and gum acacia. On the morning of the test, groups of four guinea pigs were dosed by gavage one hour prior (-l hour) to ultra-violet exposure. At 0 hour they were restrained in a plastic container which allows exposure of 3 circular spots. They were then exposed to ultraviolet irradiation from a "Hanovia"
Kromayer lamp, model 10, for 60 seconds. At one and four hours, the degree of erythema for each of the three sites was assessed according to the following scoring system: 0 = no erythema, 0.5 = incomplete circle or faint erythema, and 1.0 = complete circle of distinct erythema. Thus, the maximum score for each animal was 3Ø The following Table II summarizes the results of this test with a typical compound of the present invention and other drugs known to have a beneficial anti-inflammatory effect in suppressing ultra-violet induced erythema in warm blooded animals.
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34~8 In determining the acute anti-inflammatory acti-vity of the cls-2-benzoyl-3-hydroxy-2-alkenonitriles of the present invention, Royal Hart, Wistar strain rats, ranging in weight from 80 to 90 grams were used. The rats were fasted overnight prior to dosing but had free access to water. The test compounds were administered in aqueous suspension, by gavage, in a volume of 1.7 ml. per 50 grams of rat [corres-ponds to hydration volume used by Winter, et al., Proc. Soc.
Exp. Biol. & Med., 111, 544-547 (1962)]. The phlogistic agent used was carrageenin prepared as a sterile 1% suspension in 0.9~ aqueous sodium chloride for routine testing. A volume of 0.05 ml. was injected through a 26 gauge needle into the plantar tissue of the right hind paw. Measurements were made 5 hours after drug administration (4 hours after carrageenin challenge). Volumes of both the normal and carrageenin in-- flammed feet were determined. The difference between the two measurements is considered to be the increased edema due to the carrageenin administration. Results are expressed as a CtT efficacy ratio (edema of control animals/edema of treated animals) and a C/T ratio of greater than 1.41 is considered as active. Table III records the results of this test at the in-dicated dose level of a typical compound of the present inven-tion and demonstrates the anti-inflammatory effect of this compound in comparison with known anti-inflammatory agents.
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, This invention will be described in greater detail in conjunction with the following specific examples.
EXAMP;LE 1 Benzoylacetonitrile, thallium (I) salt A suspension of 10 g. of benzoylacetonitrile in 200 ml. of dry diethyl ether is stirred at room temperature while 17.2 g. of neat thallium (I) ethoxide is slowly added.
The resulting reaction mixture is stirred for one hour at room temperature and then filtered. The collected precipitate is washed with diethyl ether and air dried whereby there is obtained 23.7 g. (99% yield) of the thallium (I) salt of ben-zoylacetonitrile which may be stored indefinitely at room temperature.
Cis-2-benzoyl-3-hydroxycrotononitrile -To a suspension of 2.2 g. of benzoylacetonitrile, thallium (I) salt in 20 ml. of tetrahydrofuran is added 2 ml.
of acetyl fluoride with stirring at room temperature. After one hour, another 2 ml. of acetyl fluoride is added, followed by 2 ml. more after twleve hours. Twelve hours later, the precipitated thallium (I) fluoride is removed by filtration and the filtrate is evaporated to dryness. The off-white residue is recrystallized from ethanol to provide the c15-2--benzoyl-3-hydroxycrotononitrile which has been described by Musante, Gazz. Chim. Ital. 69, 523 (1939).
Cis-2-benzoyl-3-hydroxy-2-pentenonitrile To a suspension of 5 g. of benzoylacetonitrile, thallium (I) salt in 50 ml. of diethyl ether is added a solu-tion of 5 g. of propionyl fluoride in 10 ml. of diethyl ether ~i34~8 with stirring at room temperature. After 12 hours, the re-action mixture is filtered and the filtrate evaporated and then pumped dry on a vacuum pump for one hour. The residue is then treated with chloroform and filtered and the solid collected provides the title compound.
Cis-2-benzoyl-3-hydroxy-2-hexenonitrile The procedure of Example 2 is repeated substituting an equimolecular amount of butyryl fluoride for the acetyl fluoride employed in that example. There is thus obtained the cis-2-benzoyl-3-hydroxy-2-hexenonitrile after purification by column chromatography.
Cis-2-benzoyl-3-hydroxy-4-methyl-2-pentenonitrile By replacing the acetyl fluoride employed in Exam-ple 2 with an equimolar amount of _ butyryl fluoride, there is obtained the corresponding cis-2-benzoyl-3-hydroxy-4-meth-yl-2-pentenonitrile after purification by column chromatography.
Cis-2-benzoyl-3-hydroxy-2-heptenonitrile The general procedure of Example 2 is repeated but replacing the acetyl fluoride employed in that example with an equivalent amount of valeryl fluoride whereby there is obtained the cls-2-benzoyl-3-hydroxy-2-heptenonitrile after purification by column chromatography.
2-Methylbutyryl fluoride A sample of 2-methylbutyryl chloride in dimethyl-formamide is treated with a threefold excess of sodium fluo-ride. The temperature is raised and the pure acid fluoride is collected by distillation from the reaction mixture.
34 ~8 Cis-2-benzoyl-3-hydroxy-4-methyl-2-hexenonitrile Following the general procedure of Example 3, ben-zoylacetonitrile, thallium (I) salt is treated with 2-methyl-butyryl fluoride to give the cis-2-benzoyl-3-hydroxy-4-meth-yl-2-hexenonitrile after purification by column chromatography.
Cis-2-benzoyl-3-hydroxy-5-methyl-2-hexenonitrile _ Treatment of be~nzoylacetonitrile, thallium (I) salt with lsovaleryl fluoride by the procedure described in Exam-ple 3 is productive of the cis-2-benzoyl-3-hydroxy-5-methyl--2-hexenonitrile after purification by column chromatography.
Cis-2-benzoyl-3-hydroxy-4,~-dimethyl-2-pentenonitrile In the manner described in Example 3, reaction of benzoylacetonitrile, thallium (I) salt with pivalyl fluoride provides the corresponding cis-2-benzoyl-3-hydroxy-4,4-di-methyl-2-pentenonitrile after purification by column chromato-graphy. EXAMPLE ll Cis-~-benzoyl-3-hydroxycrotononitrile, sodium salt __ A calculated concentration of sodium hydroxide in water is prepared and an excess of c -2-benzoyl-3-hydroxy-crotononitrile is added and stirred for half an hour. The mixture is filtered and the filtrate is evaporated. The gummy residue is dissolved in dry acetone and again evaporated, pro-viding the title compound. -Cis-2-benzoyl-3-hydroxy-2-pentenonitrile, triethylammonium -salt A sample of cis-2-benzoyl-3-hydroxy-2-pentenonitrile 34 ~1~
is dissolved in dry diethyl ether and an equivalent amount of triethylamine is added dropwise. The mixture is cooled in ice and the precipitate is removed by filtration to pro-vide the title compound.
EX~MPLE 13 Cis-2-benzoyl-3-hydroxycrotononitrile, copper (II) salt A weighed sample of c1s-2-benzoyl-3-hydroxycrotono-nitrile is dissolved in a dilute solution of ammonium hydrox-ide and an equivalent quantity of cupric sulfate in water is added. The blue solution is heated on a steam bath for 3 hours and cooled. The precipitate is removed by filtration and washed with water to yield the title compound.
Preparation of 50 mg. Tablets Per Tablet Per 10,000 Tablets 0.050 gM. Cis-2-benzoyl-3-hydroxy-crotonitrile ~ O~500 gm.
0.080 gm. Lactose ...... ~...................... 800 gm~
0.010 gm. Corn Starch (for mix) ~ .O~. lO0 gm.
0.008 gm. Corn Starch (for paste) ~ O~ 75 gm.
0 148 gm 1475 gm.
0 002 gm Magnesium Stearate (1%) ..... ~ .. 15 gm.
0.150 gm. 1490 gm.
The cis-2-benzoyl-3-hydroxycrotonitrile, lactose and corn starch (for mix) are blended together. The corn starch (for paste) is suspended in 600 ml. of water and heated with stirring to form a paste. This paste is then used to granulate the mixed powders. Additional water is used if necessary. The wet granules are passed through a No. 8 hand screen and dried at 120F. The dry granules are then passed through a No. 16 screen. The mixture is lubricated with 1%
magnesium stearate and compressed into tablets in a suitable tableting machine.
Prepa _tion of Oral Suspension Ingredient Amount Cis-2-Benzoyl-3-hydroxy-2-pentenonitrile ................. 500 mg.
Sorbitol solution (70~ N.F.) .............................. 40 ml.
Sodium benzoate ..~.............................. 150 mg.
Saccharin ........................................ 10 mg.
Red dye .......................................... 10 mg.
Cherry flavor .................................... 50 mg.
Distilled water... qs... ad ....................... 100 ml.
The sorbitol solution is added to 40 ml. of dis-tilled water and the cis-2-benzoyl-3-hydroxy-2-pentenonitrile is suspended therein. The saccharin, sodium benzoate, flavor and dye are added and dissolved. The volume is adjusted to 100 ml. with distilled water. Each ml. of syrup contains 5 mg. of cis-2-benzoyl-3-hydroxy-2-pentenonitrile.
Preparation of Parenteral Solution In a solution of 700 ml. of propylene glycol and 200 ml. of water for injection is suspended 20.0 grams of cis-2-benzoyl-3-hydroxy-2-hexenonitrile with stirring. After suspension is complete, the pH is adjusted to 5.5 with hydro-chloric acid and the volume is made up to 1000 ml. with water for injection. The formulation is sterilized, filled into 5.0 ml. ampoules each containing 2.0 ml. (representing 40 mg.
of drug) and sealed under nitrogen.
Preparation of Topical Cream Ingred ent Amount Cis-2-benzoyl-3-hydroxy-4-methyl--2-pentenonitrile........................... 1.0%
Ethoxylated stearyl alcohol.................. 10.0%
Benzyl alcohol................................ 0.9%
Isopropyl palmitate........................... 5.0%
~lycerin...................................... 5.0~
Sorbitol solution (USP)....................... 5.0%
Lactic acid... qs... topH 4.0-5.0 Water......... qs... ad................................. 100.0 4 ~8 The ethoxylated stearyl alcohol and isopropyl pal-mitate are heated to liquifying temperature. About 95% of the total volume of water is placed in a separate container followed by the glycerin and sorbitol solution. This aqueous mixture is brought to a boil and then cooled to 60-75C.
The cls-2-benzoyl-3-hydroxy-4-methyl-2-pentenonitrile is added to the wax phase and the mixture is stirred until a clear solution is obtained. The benzyl alcohol is added and dissolved in the wax phase. The water phase is passed through a screen into the wax phase while maintaining agitation.
Both phases are kept at about the same temperature during transfer. The mixture is cooled while agitation is continued.
At a temperature of 50-55C. the balance of the water is added. The pH is adjusted to 4.0-5.0 with lactic acid. The batch is cooled with minimum agitation until the cream sets in its final form.
Pre aration of Intra-articular Product P
Ingredient Amount Cis-2-benzoyl-3-hydroxy-2-heptenonitrile .......... 2-20 mg.
NaCl (physiological saline) ........................... 0.9%
Benzyl alcohol N.F. .................................... 0.9 Sodium carboxymethylcellulose .......................... 1-5 pH adjusted to 5.0-7.5 Water for injection ........ qs ad ...................... 100 Preparation of Injectable Depo Suspension Ingredient % w/V
Cis-2-benzoyl-3-hydroxy-4,4-dimethyl--2-pentenonitrile ~ O~ O~OOOO~OO~ 0.05-5 Polysorbate 80 USP ............................. Ø2 Polyethylene glycol 4000 USP ~ O~ 3.0 Sodium chloride USP ...... ,~,................... .Ø8 Benzyl alcohol N.F. ................... ......... .Ø9 HCl to pH 6-8 ~ O~ qs Water for injection....... ~qs ad ............... 100.0 Example 20 Cyanoacetone, sodium salt A solution of 0.174 mole of sodium ethoxide is pre-pared by dissolving 4.0 g. of sodium in 200 ml. of absolute ethanol. A neat sample of 15 ml. (0.184 mole) of 5-methyl-isoxazole is then added dropwise as a colorless precipitate forms. When the addition is complete, the mixture is cooled in an ice bath and then filtered. The precipitate is collected, and washed with hexane, yielding 14.0 g. of colorless product.
Example 21 Cis-2-benzoyl-3-hydroxycrotononitrile A mixture of 1.0 g. (9.5 mmole) of cyanoacetone, sodium salt in 20 ml, of tetrahydrofuran is stirred at room temperature as a solution of 0.37 ml. (3.2 mmole) of benzoyl chloride in 5 ml. of tetrahydrofuran is added. The reaction is heated to reflux for 2 hours and the solvent is then eva-porated. The residue is acidified and extracted with diethyl ether. Evaporation of the organic phase provides 0.7 g. of a yellow oil which crystallizes on standing to provide the title compound.
4~8 Example 22 l-Cyano-2-butanone, sodium salt A solution of 0.174 moles of sodium ethoxide is pre-pared by dissolving 4.0 g. of sodium in 200 ml. of absolute ethanol. A neat sample of 5-ethylisoxazole (17.9 g., 0.185 mole) is then added. The reaction is stirred for one hour as a colorless precipitate forms. The mixture is cooled in an ice bath and filtered. The precipitate is washed with hexane and air dried, yielding the title compound.
Example 23 Cis-2-benzo~l-3-hydroxy-2-pentenonitrile A mixture of 3.0 g. (25 mmole) of 1-cyano-2-butanone, sodium salt in 20 ml. of tetrahydrofuran is stirred as a sol-ution of 0.9 g. (8.6 mmole) of benzoyl chloride in 6 ml. of tetrahydrofuran is added. The reaction is heated to reflux for 3 hours, then cooled and the solvent evaporated. T~e residue is acidified and extracted with chloroform. The organ-ic phase is extracted twice with aqueous sodium bicarbonate which in turn is acidified and extracted again with chloro-form. The organic phase is dried and evaporated to yield the title compound.
4~8 Several procedures exist for the attachment of the acyl fragment to a benzoylacetonitrile side chain. The first involves direct acylation of the benzoylacetonitrile anion (1) with an acyl halide (2) in an appropriate solvent. The enolate anions (1) are prepared OH
OM ll O
[~CN + RC ~3J~R
10(1) (2) (3) by the treatment of the benzoylacetonitrile with the appropriate base in an inert solvent. This enolate may be generated in situ and acylated with (2) in the same solvent or may be isolated and reacted in a different solvent system. When M represents sodium where (1) has been generated by treatment of the benzoylacetonitrile with sodium hydride, sodium amide, sodium methoxide, etc. and X
represents chlorine, yields of ( 3) are low with undesired side products sometimes predominating. Preferably, the benzoylacetoni-trile is dissolved in diethyl ether and one equivalent of neat thalluim (I) ethoxide is added. The stable enolate (1), where M
is thalluim, precipitates and may be collected by filtration, dried and stored indefinitely. Suspension of (1) in an inert solvent such as ether, tetrahydrofuran, dioxane, etc. at room temperature and the treatment of same with an acyl fluoride (2) where X=F causes precipitation of thalluim (I) fluoride. This is removed by filtration and the produc-t is extracted from the filtrate.
Another approach involves addition of the acyl frayment as a hydrolyzable portion to yield (4). This may be o o o CN ~ ~ ~HO I RCN
(4) ( 3) performed by condensation of the benzoylacetonitrile with a trialkyl ortho estcr in refluxing acetic anhydride. Evaporation Of by products and excess acetic anhydride in vaCuo and purification of the product under anhydrous conditions provides (4) where R/ is alkoxy. This intermediate (4), where R/ is alkoxy, may be hydrolyzed under acidic conditions to provide the desired product (3).
A different approach to (3) involves addition of the cyanoacyl fragment to a benzoyl chloride. This reaction may be CN OIH
J ~ ~ ONa > CN
,~7 R
~ / (5) (3) / \ NaH
\N ~
performed by gcneration Of the enolate anion (5) in situ With the 5-alkyl-isoxazole and base such as sodium hydride or sodium amide and subsequent addition Of the benzoylacetonitrile to affect con-_ 25 -,~A.
~184~3 densation to provide (3). Alternatively the ~-cyanoenolate (5) may be prepared separately in a similar manner as above and iso-lated. Addition of this enolate to the appropriate benzoyl chloride in ether, tetrahydrofuran, etc. at room temperature or at reflux provides (3).
A less desirable route to (3) involves that discribed below. The acylacetophenone (6) o (CH3)2N-CH (OC 3 2 R 1~ N
t6) (7) ~CH3 O OH - NH2OH~ 1 ~\ R ~ j~ ~o + [~ O N
CN NaOH N/ o R
(3) (8) (9) is condensed with N,N-dimethyl formamide dimethyl acetal at reflux either neat or in solution with an inert solvent such as chloro-foxm or carbon tetrachloride to provide the intermediate (7).
Treatment of this with hydroxyl amine hydrochloride in solvents such as alcohol, dioxane or dimethyl formamide or aqueous solu-tions of the same provides a mixture of products (8) and (9).
These are reacted as an unseparated mixture with a strong base such as sodium hydroxide or sodium alkoxide in alcohol and provides the desired product (3).
_26 _ 11~84 ~8 xamplc 2~
Cis-3-dimethylamino-2-(p-fluorobenzoyl)-crotononitrile To a solution of 1.6 g. of p-fluorobenzoylacetonitrile [Pihl _ al., Reakts. Sposobnost Org. Soedin. Tartu. Gos. Vniv., 5 (1), 27, (1968)] in 30 ml. of chloroform, cooled to -10C., is added 1.4 g. of N,N-dimethylacetamide dimethylacetal. The reaction mixture is stirred at -10C. for 2 hours and then evaporated in vacuo to an oil. This oil is dissolved in 150 ml. of benzene and filtered through magnesol. The filtrate is evaporated to 50 ml. and petroleum ether is added to effect crystallization. The product is collected by filtration and then recrystallized from benzene-petroleum ether with charcoal treatment giving the desired product.
Example 25 Benzoylacetonitrile, thallium (I~ salt A suspension of 10 g. of benzoylacetonitrile in 200 ml. of dry diethyl ether is stirred at room temperature while 17.2 g. of neat thallium (I) ethoxide is slowly added. The result-ing reaction mixture is stirred for one hour at room temperature and then filtered. The collected precipitate is washed with diethyl ether and air dried whereby there is obtained 23.7 g. (99~ yield) of the thallium (I) salt of benzoylacetonitrile which may be stored indefinitely at room temperature.
Example 26 Cis-2-benzoyl-3-hydroxycrotononitrile To a suspension of 2.2 g. of benzoylacetonitrile, thallium (I) salt in 20 ml. of tetrahydrofuran is added 2 ml. of acetyl fluoride with stirring at room temperature. After one hour, another 2 ml. of acetyl fluoride is added, followed by 2 ml.
more after twelve hours. Twelve hours later, the precipitated thallium (I) fluoride is removed by filtration and the filtrate is evaporated to dryness. The off-white residue is recrystallized from ethanol to provide the cis-2-benzoyl-3-hydroxycrotononitrile which has ~een described by Musante, Gazz. Chim. Ital. 69, (1939).
Example 27 1-Cyano-2-butanonel sodium salt A solution of 0.174 moles of sodium ethoxide is pre-pared by dissolving 4.0 g. of sodium in 200 ml. of absolute ethanol.
A neat sample of 5 ethylisoxazole (17.9 g., 0.185 mole) is then added. The reaction is stirred for one hour as a colorless pre-cipitate forms. The mixture is cooled in an ice bath and filtered.
The precipitate is washed with hexane and air dried, yielding the title compound.
xample 28 Cis-2-benzoyl-3-hydroxy-2-pentenonitrile A mixture of 3.0 g. (25mmole) of 1-cyano-2-butanone, sodium salt in 20 ml. of tetrahydrofuran is stirred as a solution of 0.9 g. (8.~ mmole) of benzoyl chloride in 6 ml. of tetrahydro-furan is added. The reaction is heated to reflux for 3 hours, then cooled and the solvent evaporated. The residue is acidified and extracted with chloroform. The organic phase is extracted twice with aqueous sodium bicarbonate which in turn is acidified and extracted again with chloroform. The organic phase is dried and evaporated to yield the title compound.
Example 29 -Cyanoacetone, sodium salt A solution of 0.174 mole of sodium ethoxide is pre-pared by dissolving 4.0 g. of sodium in 200 ml. of absolute ethanol. A neat sample of 15 ml. (0.184 mole) of 5-methyl-isoxazole is then added dropwise as a colorless precipitate forms.
1~84~8 When the addition is completc, the mixture i.s cooled in an lce bath and then filtered. The precipitate is collected, and washed - with hexane, yielding 14.0 g. of colorless product.
Example 30 Cis-2-benzoyl-3-hydroxycrotononitrile A mixture of 1.0 g. (9.5 mmole) of cyanoacetone, sodium salt in 20 ml. of tetrahydrofuran is stirred at room tem-perature as a solution of 0.37 ml. (3.2 mmole) of benzoyl chloride in 5 ml. of tetrahydrofuran is added. The reaction is heated to reflux for 2 hours and the solvent is then evaporated. The residue is acidified and extracted with diethyl ether. Evaporation of the organic phase provides 0.7 g. of a yellow oil which crystallizes on standing to provide the title compound.
~ e 31 Cis-2-benzoyl-3-methoxycrotononitrile A solution containing 50 g. (0.34 mole3 of benzoylace-tonitrile, 41 g. (0.34 mole) of trimethyl orthoacetate, and 90 g.
(0.88 mole) of acetec anhydride is heated to reflux for 5 hours.
The excess solvent and volatile by-products are then removed by vacuum distillation and the residue is recrystallized from diethyl ether. Alternatively, the distillation residue may be distilled over on a Kugelrohr apparatus at 160C./0.25 mm,to provide a vi~cous oil which may be crystallized from diethyl ether to provide the pure title compound.
_xample 32 Cis-2-benzoyl 3-hydroxycrotononitrile A solution of 5 g. of cis-2-benzoyl-3-methoxycroton-onitrile in 50 ml. of ethanol is treated with 25 ml. of 3N aqueous hydrochloric acid at room temperature for one hour. The solvent i8 evaporated, the residue diluted with water, and the product is 11184~8 extracted with chloroform. The organic phase is separated, dried, filtered and evaporated to provide the title compound.
_xample 33 2-(Dimethylaminomethylene)-l-phenyl-butane-1,3-dione A solution of 15 g. of benzoylacetone in 35 ml. of N,N-dimethylformamide dimethylacetal is heated on a steam bath and the volatile by-product (methanol) is distilled out. When the theoretical amount of methanol has been collected, the reaction mixture is pumped dry, then the product is collected by distillation from the reaction pot at 150C./0.025 mm. Crystalline product (19.5 g., 97% yield) is thus obtained upon cooling of the distillate.
Example 34
Treatment of this with hydroxyl amine hydrochloride in solvents such as alcohol, dioxane or dimethyl formamide or aqueous solu-tions of the same provides a mixture of products (8) and (9).
These are reacted as an unseparated mixture with a strong base such as sodium hydroxide or sodium alkoxide in alcohol and provides the desired product (3).
_26 _ 11~84 ~8 xamplc 2~
Cis-3-dimethylamino-2-(p-fluorobenzoyl)-crotononitrile To a solution of 1.6 g. of p-fluorobenzoylacetonitrile [Pihl _ al., Reakts. Sposobnost Org. Soedin. Tartu. Gos. Vniv., 5 (1), 27, (1968)] in 30 ml. of chloroform, cooled to -10C., is added 1.4 g. of N,N-dimethylacetamide dimethylacetal. The reaction mixture is stirred at -10C. for 2 hours and then evaporated in vacuo to an oil. This oil is dissolved in 150 ml. of benzene and filtered through magnesol. The filtrate is evaporated to 50 ml. and petroleum ether is added to effect crystallization. The product is collected by filtration and then recrystallized from benzene-petroleum ether with charcoal treatment giving the desired product.
Example 25 Benzoylacetonitrile, thallium (I~ salt A suspension of 10 g. of benzoylacetonitrile in 200 ml. of dry diethyl ether is stirred at room temperature while 17.2 g. of neat thallium (I) ethoxide is slowly added. The result-ing reaction mixture is stirred for one hour at room temperature and then filtered. The collected precipitate is washed with diethyl ether and air dried whereby there is obtained 23.7 g. (99~ yield) of the thallium (I) salt of benzoylacetonitrile which may be stored indefinitely at room temperature.
Example 26 Cis-2-benzoyl-3-hydroxycrotononitrile To a suspension of 2.2 g. of benzoylacetonitrile, thallium (I) salt in 20 ml. of tetrahydrofuran is added 2 ml. of acetyl fluoride with stirring at room temperature. After one hour, another 2 ml. of acetyl fluoride is added, followed by 2 ml.
more after twelve hours. Twelve hours later, the precipitated thallium (I) fluoride is removed by filtration and the filtrate is evaporated to dryness. The off-white residue is recrystallized from ethanol to provide the cis-2-benzoyl-3-hydroxycrotononitrile which has ~een described by Musante, Gazz. Chim. Ital. 69, (1939).
Example 27 1-Cyano-2-butanonel sodium salt A solution of 0.174 moles of sodium ethoxide is pre-pared by dissolving 4.0 g. of sodium in 200 ml. of absolute ethanol.
A neat sample of 5 ethylisoxazole (17.9 g., 0.185 mole) is then added. The reaction is stirred for one hour as a colorless pre-cipitate forms. The mixture is cooled in an ice bath and filtered.
The precipitate is washed with hexane and air dried, yielding the title compound.
xample 28 Cis-2-benzoyl-3-hydroxy-2-pentenonitrile A mixture of 3.0 g. (25mmole) of 1-cyano-2-butanone, sodium salt in 20 ml. of tetrahydrofuran is stirred as a solution of 0.9 g. (8.~ mmole) of benzoyl chloride in 6 ml. of tetrahydro-furan is added. The reaction is heated to reflux for 3 hours, then cooled and the solvent evaporated. The residue is acidified and extracted with chloroform. The organic phase is extracted twice with aqueous sodium bicarbonate which in turn is acidified and extracted again with chloroform. The organic phase is dried and evaporated to yield the title compound.
Example 29 -Cyanoacetone, sodium salt A solution of 0.174 mole of sodium ethoxide is pre-pared by dissolving 4.0 g. of sodium in 200 ml. of absolute ethanol. A neat sample of 15 ml. (0.184 mole) of 5-methyl-isoxazole is then added dropwise as a colorless precipitate forms.
1~84~8 When the addition is completc, the mixture i.s cooled in an lce bath and then filtered. The precipitate is collected, and washed - with hexane, yielding 14.0 g. of colorless product.
Example 30 Cis-2-benzoyl-3-hydroxycrotononitrile A mixture of 1.0 g. (9.5 mmole) of cyanoacetone, sodium salt in 20 ml. of tetrahydrofuran is stirred at room tem-perature as a solution of 0.37 ml. (3.2 mmole) of benzoyl chloride in 5 ml. of tetrahydrofuran is added. The reaction is heated to reflux for 2 hours and the solvent is then evaporated. The residue is acidified and extracted with diethyl ether. Evaporation of the organic phase provides 0.7 g. of a yellow oil which crystallizes on standing to provide the title compound.
~ e 31 Cis-2-benzoyl-3-methoxycrotononitrile A solution containing 50 g. (0.34 mole3 of benzoylace-tonitrile, 41 g. (0.34 mole) of trimethyl orthoacetate, and 90 g.
(0.88 mole) of acetec anhydride is heated to reflux for 5 hours.
The excess solvent and volatile by-products are then removed by vacuum distillation and the residue is recrystallized from diethyl ether. Alternatively, the distillation residue may be distilled over on a Kugelrohr apparatus at 160C./0.25 mm,to provide a vi~cous oil which may be crystallized from diethyl ether to provide the pure title compound.
_xample 32 Cis-2-benzoyl 3-hydroxycrotononitrile A solution of 5 g. of cis-2-benzoyl-3-methoxycroton-onitrile in 50 ml. of ethanol is treated with 25 ml. of 3N aqueous hydrochloric acid at room temperature for one hour. The solvent i8 evaporated, the residue diluted with water, and the product is 11184~8 extracted with chloroform. The organic phase is separated, dried, filtered and evaporated to provide the title compound.
_xample 33 2-(Dimethylaminomethylene)-l-phenyl-butane-1,3-dione A solution of 15 g. of benzoylacetone in 35 ml. of N,N-dimethylformamide dimethylacetal is heated on a steam bath and the volatile by-product (methanol) is distilled out. When the theoretical amount of methanol has been collected, the reaction mixture is pumped dry, then the product is collected by distillation from the reaction pot at 150C./0.025 mm. Crystalline product (19.5 g., 97% yield) is thus obtained upon cooling of the distillate.
Example 34
4-Acetyl-5-phenylisoxazole and 4-benzoyl-5-methylisoxazo _ To a solution of 12.8 g. of 2-(dimethylaminomethylene)--1-phenylbutane-1,3-dione in 130 ml. of THF is added 4.10 g. of hydroxylamine hydrochloride, followed by 40 ml. of water. The reaction is heated to reflux for 2 hours, then cooled and the sol-vent is evaporated. The residue is partitioned between ether and water and the organic layer is separated and evaporated. The regidue i8 distilled at 100-110C./0.25 mm. to provide 9.0 g. of an oily mixture of approximated equal amounts of 4-benzoyl-5--methylisoxazole and 4-acetyl-5-phenylisoxazole.
Example 35 Cis-2-benzoyl-3-hydroxycrotononitrile A solution of 1.65 g. of a mixture of 4-acetyl-5--phenylisoxazole and 4-benzoyl-5-methylisoxazole in equal amounts is dissolved in 7 ml. of methanol and treated with 5 ml. of 10~
aqueous sodium hydroxide. The solution is heated on a steam bath for 15 minutes then cooled, acidified with lN aqueous HCl and extracted with ehter. Evaporation of the ether provides 1.55 g.
of product. Recrystallization from isopropanol provides 1.0 g.
(66%) of cls-2-benzoyl-3-hydroxycrotononitrile, mp. 74.5-76.5C.
-30 _
Example 35 Cis-2-benzoyl-3-hydroxycrotononitrile A solution of 1.65 g. of a mixture of 4-acetyl-5--phenylisoxazole and 4-benzoyl-5-methylisoxazole in equal amounts is dissolved in 7 ml. of methanol and treated with 5 ml. of 10~
aqueous sodium hydroxide. The solution is heated on a steam bath for 15 minutes then cooled, acidified with lN aqueous HCl and extracted with ehter. Evaporation of the ether provides 1.55 g.
of product. Recrystallization from isopropanol provides 1.0 g.
(66%) of cls-2-benzoyl-3-hydroxycrotononitrile, mp. 74.5-76.5C.
-30 _
Claims (17)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process of forming a cis-2-benzoyl-3-hydroxy-2-alkenonitrile having the following general formula wherein R is an alkyl group having from 2 to 4 carbon atoms and M is hydrogen or a pharmaceologically acceptable cation and the tautomers thereof, which comprises:
a) acylation of a benzoylacetonitrile anion (I) with an acyl halide (II) as follows:
(I) (II) (III) wherein M and R are as hereinbefore defined, and X is a halogen;
b) condensation of benzoylacetonitrile with a trialkyl ortho-ester as follows:
(III) (IV) wherein R is a hereinbefore defined and R' is alkoxy, and then hydrolyzing the compound (IV) under acidic conditions to provide (III); or c) addition of a cyanoenolate (V) to benzoyl chloride as follows:
(V) (III) wherein R is as hereinbefore defined;
d) condensation of an acylacetophenone (VI) with N,N-dimethyl formamide dimethyl acetal to give a compound of general formula (VII) as follows:
(VI) (VII) wherein R is as hereinbefore defined and then treating the compound VII with hydroxylamine to give a mixture of products of formulae VIII and IX which are then reacted with a strong base to give a cis-2-benzoyl-3-hydroxy-2-alkenonitrile of general formula III as follows:
(VIII) (IX) (III) wherein R is as hereinbefore defined.
a) acylation of a benzoylacetonitrile anion (I) with an acyl halide (II) as follows:
(I) (II) (III) wherein M and R are as hereinbefore defined, and X is a halogen;
b) condensation of benzoylacetonitrile with a trialkyl ortho-ester as follows:
(III) (IV) wherein R is a hereinbefore defined and R' is alkoxy, and then hydrolyzing the compound (IV) under acidic conditions to provide (III); or c) addition of a cyanoenolate (V) to benzoyl chloride as follows:
(V) (III) wherein R is as hereinbefore defined;
d) condensation of an acylacetophenone (VI) with N,N-dimethyl formamide dimethyl acetal to give a compound of general formula (VII) as follows:
(VI) (VII) wherein R is as hereinbefore defined and then treating the compound VII with hydroxylamine to give a mixture of products of formulae VIII and IX which are then reacted with a strong base to give a cis-2-benzoyl-3-hydroxy-2-alkenonitrile of general formula III as follows:
(VIII) (IX) (III) wherein R is as hereinbefore defined.
2. A compound selected from the group consisting of those of the formula:
wherein R is an alkyl group having from two to four carbon atoms and M is hydrogen or a pharmacologically acceptable cation, and the tautomers thereof whenever prepared by the process of claim 1, or an obvious chemical equivalent thereof.
wherein R is an alkyl group having from two to four carbon atoms and M is hydrogen or a pharmacologically acceptable cation, and the tautomers thereof whenever prepared by the process of claim 1, or an obvious chemical equivalent thereof.
3. A process according to claim 1 which comprises acylating benzoylacetonitrile, thallium (I) salt with propionyl fluoride to give cis-2-benzoyl-3-hydroxy-2-pentenonitrile.
4. A process according to claim 1 which comprises adding benzoyl chloride to 1-cyano-2-butanone, sodium salt to give cis-2-benzoyl-3-hydroxy-2-pentenonitrile.
5. The compound according to claim 2 wherein R is ethyl and M
is hydrogen; cis-2-benzoyl-3-hydroxy-2pentenonitrile, whenever prepared by the process of claim 3 or 4, or an obvious chemical equivaltent thereof.
is hydrogen; cis-2-benzoyl-3-hydroxy-2pentenonitrile, whenever prepared by the process of claim 3 or 4, or an obvious chemical equivaltent thereof.
6. A process according to claim 1 which comprises acylating benzolyacetonitrile, thallium (I) salt with butyryl fluoride to give cis-2-benzoyl-3-hydroxy-2-hexenonitrile.
7. The compound according to claim 2 wherein R is n-propyl and M
is hydrogen; cis-2-benzoyl-3-hydroxy-2-hexenonitrile, whenever prepared by the process of claim 6, or an obvious chemical equivalent thereof.
is hydrogen; cis-2-benzoyl-3-hydroxy-2-hexenonitrile, whenever prepared by the process of claim 6, or an obvious chemical equivalent thereof.
8. A process according to claim 1 which comprises acylating benzoylacetonitrile, thallium (I) salt with iso-butyryl fluoride to give cis-2-benzoyl-3-hydroxy-4-methyl-2-pentenonitrile.
9. The compound according to claim 2 wherein R is isopropyl and M
is hydrogen; cis-2-benzoyl-3-hydroxy-4-methyl-2-pentenonitrile whenever prepared by the process of claim 8, or an obvious chenmical equivalent thereof.
is hydrogen; cis-2-benzoyl-3-hydroxy-4-methyl-2-pentenonitrile whenever prepared by the process of claim 8, or an obvious chenmical equivalent thereof.
10. A process according to claim 1 which comprises acylating benzolyacetonitrile, thallium (I) salt with isovaleryl fluoride to give cis-2-benzoyl-3-hydroxy-5-methyl-2-hexenonitrile.
11. The compound according to claim 2 wherein R is isobutyl and M
is hydrogen; cis-2-benzoyl-3-hydroxy-5-methyl-2-hexenonitrile whenever prepared by the process of claim 10, or an obvious chemical equivalent thereof.
is hydrogen; cis-2-benzoyl-3-hydroxy-5-methyl-2-hexenonitrile whenever prepared by the process of claim 10, or an obvious chemical equivalent thereof.
12. A process according to claim 1 which comprises acylating benzoylacetonitrile, thallium(I)salt with 2-methyl-butyryl fluoride to give cis-2-benzoyl-3-hydroxy-4-methyl-2-hexenonitrile.
13. The compound according to claim 2 wherein R is sec-butyl and M is hydrogen; cis-2-benzoyl-3-hydroxy-4-methyl-2-hexenonitrile whenever prepared by the process of claim 12, or an obvious chemical equivalent thereof.
14. A process according to claim 1 which comprises acylating benzoylacetonitrile, thallium (I) salt with valeryl fluoride to give cis-2--benzoyl-3-hydroxy-2-heptenonitrile.
15. The compound according to claim 2 wherein R is n-butyl and M is hydrogen; cis-2-benzoyl-3-hydroxy-2-heptenonitrile, whenever prepared by the process of claim 14, or an obvious chemical equivalent thereof.
16. A process according to claim 1 which comprises acylating benzoylacetontrile, thallium (I) salt with pivalyl fluoride to give cis-2--benzoyl-3-hydroxy-4,4-dimethyl-2-pentenonitrile.
17. The compound according to claim 2 wherein R is tert-butyl and M is hydrogen; cis-2-benzoyl-3-hydroxy-4,4-dimethyl-2-pentenonitrile whenever prepared by the process of claim 16, or an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US892,002 | 1978-03-31 | ||
| US05/892,002 US4170656A (en) | 1977-05-31 | 1978-03-31 | Compositions containing cis-2-benzoyl-3-hydroxy-crotononitrile used to treat inflammation and joint deterioration |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1118448A true CA1118448A (en) | 1982-02-16 |
Family
ID=25399199
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000304830A Expired CA1118448A (en) | 1978-03-31 | 1978-06-06 | Compositions containing cis-2-benzoyl-3-hydroxy- crotononitrile and method of use to treat inflammation and joint deterioration |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1118448A (en) |
-
1978
- 1978-06-06 CA CA000304830A patent/CA1118448A/en not_active Expired
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