[go: up one dir, main page]

US3696111A - Benzocyclobutene-1-carboxylic acids - Google Patents

Benzocyclobutene-1-carboxylic acids Download PDF

Info

Publication number
US3696111A
US3696111A US57755A US3696111DA US3696111A US 3696111 A US3696111 A US 3696111A US 57755 A US57755 A US 57755A US 3696111D A US3696111D A US 3696111DA US 3696111 A US3696111 A US 3696111A
Authority
US
United States
Prior art keywords
compound
carboxylic acid
salt
acid
cyclohexylbenzocyclobutene
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US57755A
Inventor
Peter Frederick Juby
Thomas William Hudyma
Richard Anthony Partyka
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bristol Myers Co
Original Assignee
Bristol Myers Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bristol Myers Co filed Critical Bristol Myers Co
Application granted granted Critical
Publication of US3696111A publication Critical patent/US3696111A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/46—Friedel-Crafts reactions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/657—Unsaturated compounds containing a keto groups being part of a ring containing six-membered aromatic rings
    • C07C49/665—Unsaturated compounds containing a keto groups being part of a ring containing six-membered aromatic rings a keto group being part of a condensed ring system
    • C07C49/67—Unsaturated compounds containing a keto groups being part of a ring containing six-membered aromatic rings a keto group being part of a condensed ring system having two rings, e.g. tetralones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
    • C07C49/813—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen polycyclic

Definitions

  • the compounds of the present invention relate to 4- cyclohexyl-or 4-phenylbenzocyclobutene-1-carboxylic acids, which compounds are useful non-steroidal antiinflammatory agents.
  • the 4-cyclohexylor 4-phenylbenzocyclobutene-1- carboxylic acids of the present invention are compounds having the formula wherein R is cyclohexyl or phenyl, and Y is hydrogen, (lower) alkyl, (lower) alkoxy, hydroxy, F, Br, Cl, I, OH, cyano, mercapto, amino, nitro or (lower) alkylthio; or a pharmaceutically acceptable, nontoxic salt thereof.
  • This invention relates to non-steroidal anti-inflammatory agents useful in animals, including man, which compounds are characterized by the formula It is an object of the instant invention to prepare nonsteroidal anti-inflammatory agents that would be useful in the treatment of a variety of inflammatory diseases such as Rheumatoid Arthritis, Rheumatoid Spondylitis, Osteoarthritis, Gout and other similar afflictions.
  • Y is H, Cl, Br, I, F, mercapto, CF OH, (lower) alkoxy; nitro, amino, cyano, (lower) alkyl or (lower) alkylthio; or a nontoxic, pharmaceutically acceptable salt thereof.
  • Another more preferred embodiment is a compound of formula 111 wherein Y is hydrogen, chloro, fluoro, hydroxy; (lower)alkyl, (lower)alkoxy, nitro or amino; or a pharmaceutically acceptable nontoxic salt thereof.
  • Still another more preferred embodiment is a compound of formula III wherein Y is hydrogen, chloro, (lower) alkyl or (lower)-alkoxy; or a pharmaceutically acceptable nontoxic salt thereof.
  • a most preferred embodiment is the compound of formula "1 wherein Y is hydrogen; or a pharmaceutically acceptable nontoxic salt thereof.
  • Another most preferred embodiment is the essentially pure levorotatory isomer of the compound of formula 111 wherein Y is hydrogen; or a pharmaceutically acceptable salt thereof.
  • Still another most preferred embodiment is the essentially pure dextrorotatory isomer of the compound of formula 111 wherein Y is hydrogen; or a pharmaceutically acceptable salt thereof.
  • a preferred embodiment of the present invention is a compound having the formula CozH .l .n. in which Y is H, mercapto, -CF;,, OH, (lower) alkoxy, nitro, amino, cyano, (lower) alkyl or (lower) alkylthio; or a nontoxic, pharmaceutically acceptable salt thereof.
  • Another preferred embodiment is a compound of formula IV in which Y is H, (lower) alkyl, (lower) alkoxy or OH: or a pharmaceutically acceptable salt thereof.
  • Still another preferred embodiment is a compound of formula IV in which Y is H, (lower) alkyl or (lower) alkoxy; or a pharmaceutically acceptable salt thereof.
  • a most preferred embodiment is the compound of formula IV in which Y is hydrogen; or a nontoxic, pharmaceutically acceptable salt thereof.
  • Another most preferred embodiment is the essentially pure levorotatory isomer of the compound of formula IV in which Y is hydrogen; or a nontoxic, pharmaceutically acceptable salt thereof.
  • Another most preferred embodiment is the essentially pure dextrorotatory isomer of the compound of formula IV in which Y is hydrogen; or a nontoxic, pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable nontoxic salts include those having metallic cations such as sodium, potassium, calcium, and aluminum and organic amine cations of trialkylamines, e.g., triethylamine, procaine,
  • dibenzylamine N-benzyl-B-phenethylamine, lephenamine, N ,N '-dibenzylethylenediamine, dehydroabietylamine, N,N-bisdehydroabietylethylenediamine, N-(lower)alkylpiperidines, e.g., N-ethylpiperidine, and other amines which have been used to form salts with medicinally active carboxylic acids.
  • (lower) alkyl as used herein means both straight and branched chain aliphatic hydrocarbon radicals having from one to six carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.
  • (lower)alkoxy it refers to the alkyl portion of such group which is therefore as described above in connection with (lower) alkyl and thus includes such radicals as methoxy, ethoxy, isopropoxy, etc.
  • the compounds of the instant invention can be prepared by the following synthesis:
  • the purified S-nitrosubstituted-benzocyclobutenel carboxylic acids obtained in part (b) above are reduced by the use of hydrogen and catalyst (Pd/C, PtO etc.) to produce the 5-aminosubstituted-benzocyclobutenel-carboxylic acids of the present invention.
  • the aminosubstituted compound prepared in step above is placed in a strong mineral acid, i.e., HCl, H 80 I-lBr, etc., at 0 C. Nitrous acid is generated in situ by the addition of sodium nitrite to produce the diazonium salt of the amine.
  • the 5-diazonium salt prepared as in step (d) from the 5-aminosubstitutedbenzocyclobutenel -carboxylic acid obtained in step (c) is treated with either copperbronze (Gattermann Reaction) or cuprous halide (Cl, Br, I) to produce the S-halo-substituted compound.
  • step (d) which is prepared in H 80 is treated with base to neutralize the salt solution, followed by the addition of a solution of cuprous cyanide-sodium cyanide complex to produce a precipitate. Heating of the precipitate decomposes it to the cyano-substituted acid.
  • the S-diazonium salt, as in step (d) is treated with fluoroboric acid.
  • the fluoroborate precipitates and is collected. After washing and drying, the precipitate is heated and it decomposes to the desired S-fluorosubstituted compound.
  • the 5 salt prepared in step (d) is treated with potassium ethyl xanthate which produces an ethyl dithiocarbonate. Saponification of the dithiocarbonate produces the desired S-mercaptosubstituted compound.
  • step (3') Treatment of the S-mercaptosubstituted compound obtained in step (3') with dimethylsulfate in the presence of a base, followed by mild hydrolysis, produces the S-methylthio-substituted acid.
  • step (g) The 5-bromoor iodo-4-cyclohexylbenzocyclobutene-l-carboxylic acid obtained in step (g) is treated with lithium dimethylcopper to produce S-methyl-4- cyclohexylbenzocyclobutene-l-carboxylic acid [E. J. Corey and G. H. Posner, J. Am. Chem. Soc., 89, p. 3911 (1967)].
  • the compounds of the instant invention can be resolved into their substantially pure dextroand levorotatory isomers by methods commonly known in the art.
  • the compound 4- cyclohexylbenzocyclobutene-l-carboxylic acid was resolved into its respective isomers by the procedure of first treating the mixture with cinchonidine to produce the cinchonidine salt of ()-4-cyclohexylbenzocyclobutene-l-carboxylic acid.
  • the salt was recrystallized and the decomposed to the free acid to yield substantially pure (-)-4-cyclohexylbenzocyclobutene-lcarboxylic acid.
  • Hot Skellysolve B (petroleum ether essentially n-hexane) was added to a boiling solution of the acid and an equimolar quantity of ()-a-( l-napthyl)ethylamine in benzene to produce the naphthylethylamine salt of (+)-4-cyclohexylbenzocyclobutene-l-carboxylic acid as a crystalline material.
  • the salt was recrystallized from acetonitrile and decomposed by the addition of acid to produce pure (+)-4-cyclohexylbenzocyclobutenel -carboxylic acid.
  • racemic mixtures can be precipitated as eutecties instead of mixed crystals and can thus be quickly separated and in such cases can sometimes be selectively precipitated.
  • the more common method of chemical resolution may be used.
  • diastereoisomers are formed from the racemic mixture by reaction with an optically-active resolving agent.
  • an opticallyactive base can be reacted with the carboxyl group.
  • the difference in solubility between the diastereoisomers formed permits the selective crystallization of one form and regeneration of the opticallyactive acid from the mixture.
  • a third method of resolving which shows great promise. This is one of the other forms of biochemical procedures using selective enzymatic reaction.
  • racemic acid can be subjected to an asymmetric oxidase or decarboxylase which will, be oxidation or decarboxylation, destroy one form, leaving the other form unchanged. Even more attractive is the use of hydrolylase on a derivative of the racemic mixture to form preferentially one form of the acid.
  • esters or amides of the acids can be subjected to an esterase or amidase which will selectively saponify one enantiomorph and leave the other unchanged.
  • Amide or salt diastereoisomers of the free acid may be formed with opticallyactive amines, such as quinine, brucine, cinchonidine, cinchonine, dehydroabietylamine, hydroxy-hydrindamine, menthylamine, morphine, aphenylethylamine, phenyloxynaphthylmethylamine, quinidine, l-fenchylamine, strychnine, basic amino acids, such as lysine, arginine, amino acid esters, and the like.
  • ester diastereoisomers of the free acid may be formed with opticallyactive alcohols, such as borneo], menthol, 2-octanol and the like.
  • cinchonidine to give the readily decomposable diastereoisomer salt which may then be resolved by dissolving in a solvent, such as acetone, and distilling the solvent at atmospheric pressure until crystals begin to appear and further crystallization produced by allowing the mixture to cool to room temperature, thereby separating the two enantiomorphs.
  • the acid may then be recovered from the salt by extracting the salt between an organic solvent, such as petroleum ether and dilute hydrochloric acid or some other organic solvent-aqueous system. Workup of the remaining mother liquors and subsequent purification will usually provide the other isomer.
  • racemic mixtures themselves are potent anti-inflammatory agents.
  • the compounds of this invention have a high degree of antiinflammatory activity. They are useful in treating arthritis, rheumatism and other inflammatory diseases in mammals.
  • Anti-inflammatory tests of the compounds of the present invention were carried out on rats using the carrageenin-induced foot edema test of Charles A. Winter et al., Carrageenin-lnduced Edema in Hind Paw of the Rat as an Assay for Anti-Inflammatory Drugs, Proceedings of the Society for Experimental Biology and Medicine, 111, 544 (1962).
  • the compound under investigation was given orally to the rat, and one hour later carregeenin was injected subcutaneously into one paw. 3 hours later the degree of edema was measured volumetrically by fluid displacement, and compared to that of the control paw to give a result presented in terms of percentage inhibition of edema. Any result of more than 30 percent inhibition was greater than three times the standard deviation of the result in control animals, and thus clearly indicated anti-inflammatory activity.
  • the compounds of the instant invention exhibit anti-inflammatory activity deemed useful in the treatment of inflammatory diseases in mammals, including man.
  • the compounds of the invention are generally useful in the dosage range of about 0.1 mg./kg. to about 40 mg./kg. three to four times a day.
  • the compounds of the instant invention can be administered orally or parenterally, but preferably orally. More specifically, the compounds of the instant invention are preferentially administered in dosages in the range of about 0.2 mg./kg. to about 30 mg./kg. three to four times a day.
  • the dosage will vary with the particular compound of the invention.
  • (i)-4-cyclohexylbenzocyclobutene-l-carboxylic acid had an MED of 3.5 mgjkg. in rats (MED is defined as the dose which produces 30 percent inhibition of edema).
  • the oral dosage in humans of the compounds of the present invention is in the range of about 0.2 mg./kg. to about 25 mg./kg. administered three or four times a day.
  • the preferred human dosage is in the range of 0.2 mg./kg. to about 10 mg./kg. three to four times a day.
  • EXAMPLE l S-Cyclohexyll -indanone
  • the title compound was prepared by a procedure similar to that described by Hart and Tebbe for the preparation of l-indanone from benzene and B- chloropropionyl chloride.
  • a solution of B- chloropropionyl chloride (13.33 g., 0.105 mole) and cyclohexylbenzene (16.03 g., 0.1 mole) in carbon disulfide (25 ml.) was added dropwise with stirring over a period of 15 minutes to a cooled (ice-water) suspension of aluminum chloride (16.0 g., 0.12 mole) in carbon disulfide (60 ml.).
  • the combined ether solution was washed with water (250 ml.) followed by saturated aqueous sodium bicarbonate (200 ml.), and saturated aqueous sodium chloride (2 X 200 ml.).
  • the washed solution was dried over anhydrous sodium sulfate and concentrated in a rotary evaporator to give a yellow-brown solid (19.7 g.), m.p. 6473 C.
  • the product was recrystallized with charcoal treatment from n-pentane to give 5- cyclohexyl-l-indanone (14.7 g., 69 percent) as yellow crystals, m.p. 75-76.5 C. Recrystallization from npentane with charcoal treatment gave off-white crystals, m.p. 75.5-77 C.
  • the cinchonidine salt (4.4 g.) was partitioned between diethyl ether (50 ml.) and 0.5 N HCl (30 ml.). The ethereal layer was washed with water (20 ml.) followed by two washings with water saturated with sodium chloride and dried (sodium sulfate). Removal of the ether left colorless crystals (1.77 g.) of ()-4- cyclohexylbenzocyclobutene-l-carboxylic acid: m.p. 9193; [011 954 (0. 2.173, ethanol). The acid was recrystallized twice from n-pentane to give colorless crystals; m.p. 93-95; [aw -9.0 (c. 2.00, ethanol).
  • Boiling Skellysolve B ml. was added to a boiling solution of the ()-acid (1.19 g., 0.00516 mole) with m.p. 93-95 and (+)-a-( l-naphthyl)ethylamine (0.884 g., 0.00516 mole) in benzene (10 ml.).
  • the hot solution was allowed to stand at 25 for 2 hours with an occasional scratching of the inside of the beaker with a glass stirring rod.
  • the colorless crystals (1.87 g., m.p.
  • Hot Skellysolve B ml. was added to a boiling solution of the enriched acid (2.54 g., 0.011 mole) and ()-a-(l-naphthyl)-ethylamine (1.89 g., 0.011 mole) in benzene (19 ml.).
  • the hot solution was allowed to stand at C. for 2 hours with occasional scratching of the inside of the beaker with a glass stirring rod.
  • EXAMPLE 8 (i)-Methyl 4-Cyclohexylbenzocyclobutenel -carboxylate Excess diazomethane in diethyl ether is added to a suspension of (i)-5-cyclohexylbenzocyclobutene-lcarboxylic acid in diethyl ether. The resulting solution is concentrated to an oil which slowly crystallizes on standing. The product is recrystallized from methanol after treatment with activated charcoal to produce the title compound.
  • EXAMPLE 10 (i)-4-Phenylbenzocyclobutenel -carobxylic Acid A solution of 10 percent aqueous sodium hydroxide is added to a solution of (i)-methyl 4-phenylbenzocyclobutene-l-carboxylate in ethanol, and the mixture is heated under reflux for 5 minutes. The mixture is cooled and then poured into cold water. The resulting solution is acidified with ice-cooling to pH 2 with 10 percent hydrochloric acid. The precipitated solid is washed with cold water, dried, and recrystallized from methanol with charcoal treatment to give the title product.
  • a compound of claim 1 having the formula CO H in which R is cyclohexyl or phenyl, and Y is H, Cl, Br, I, F, mercapto, -CF OH, (lower)alkyl, (lower)alkoxy, nitro, amino, cyano or (lower)alkylthio; or a nontoxic, pharmaceuticallyacceptable salt thereof.
  • a compound of claim 2 having the formula 1.4 6.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

4-Cyclohexyl-or 4-phenylbenzocyclobutene-1-carboxylic acids or derivatives thereof are useful in the treatment of inflammatory diseases in animals, including man. An example of the disclosure is 4-cyclohexylbenzocyclobutene-1-carboxylic acid.

Description

United States Patent 15] 3,696,111 Juby et al. [4 1 Oct. 3, 1972 s41 BENZOCYCLOBUTENE-l- 58] mu ofSearch ..260/293.5l, 515 R, CARBOXYLIC Acms A! 5 .M1. .9. Z9 .5.1 K51 .5 P
[72] Inventors: Peter Frederick Juby; Thomas W11- liam Hudyma, both of Dewitt; Richard Anthony Partyka, Liverpool, all of N.Y.
Assignee: Bristol-Myers Company, New York,
Filed: July 23, 1970 Appl. No.: 57,755
US. Cl ..260/293.51, 204/158 R, 260/141, 260/284, 260/285, 260/287 R, 260/448 R, 260/465 D, 260/469, 260/472, 260/50l.1, 260/501.l1, 260/501.18, 260/501.2, 260/515 R, 260/515 A, 260/515 M, 260/516, 260/518 R, 260/520, 260/566 A, 260/590, 260/592, 424/267, 424/317 Int. Cl ..C07c 63/44 [5 6] References Cited UNITED STATES PATENTS 3,408,391 10/1968 Skorcz ..260/5l8 Primary Examiner-James A. Patten Attomey-Herbert W. Taylor, Jr., Robert E.
Havranek, Richard H. Brink and James Magee, Jr.
[ ABSTRACT BACKGROUND OF THE INVENTION 1. Field of the Invention The compounds of the present invention relate to 4- cyclohexyl-or 4-phenylbenzocyclobutene-1-carboxylic acids, which compounds are useful non-steroidal antiinflammatory agents.
2. Description of the Prior Art The compounds 4-isobutylphenylacetic acid [South African Pat. No. 62/294 (1962)], 4-isobutyl-a-methylphenylacetic acid [8. S. Adams, E. E. Cliffe, B. Lessel, and J. S. Nicholson, J. Pharm. Sci., 56, 1686 (1967)], 3-chloro-4-cyclohexyl-a-methylphenyl-acetic acid [T. Y. Sheri, Chim. Therap., I1, 459, (1967)], and 5-pmethoxyphenyl-2-indancarboxylic acid [M. Minssen- Guett, M. Dvolaitzky, and J. Jacques, Bull Soc. Chim. France, No .5, 2111 (1968)] have been described in the literature as being useful anti-inflammatory agents.
Two other pertinent references are those of Cava, Litle and Napier, J. Amer. Chem. Soc., 80, 2257-63 (1958) and Homer, Kirmse and Muth, Chem. Ber., 91, 430-437 (1958). Both of these articles report on the synthesis of unsubstituted and substituted benzocyclobutene carboxylic acids. However, neither of the references describes nor anticipates the compounds of the instant invention nor do these articles report these compounds as having anti-inflammatory activity.
SUMMARY OF THE INVENTION The 4-cyclohexylor 4-phenylbenzocyclobutene-1- carboxylic acids of the present invention are compounds having the formula wherein R is cyclohexyl or phenyl, and Y is hydrogen, (lower) alkyl, (lower) alkoxy, hydroxy, F, Br, Cl, I, OH, cyano, mercapto, amino, nitro or (lower) alkylthio; or a pharmaceutically acceptable, nontoxic salt thereof.
This invention relates to non-steroidal anti-inflammatory agents useful in animals, including man, which compounds are characterized by the formula It is an object of the instant invention to prepare nonsteroidal anti-inflammatory agents that would be useful in the treatment of a variety of inflammatory diseases such as Rheumatoid Arthritis, Rheumatoid Spondylitis, Osteoarthritis, Gout and other similar afflictions.
These objectives have been achieved by the provision, according to the present invention, of the compound having formula COzH in-which R is cyclohexyl or phenyl, and Y is H, Cl, Br, 1, F, mercapto, -CF OH, (lower) alkyl, (lower) alkoxy, nitro, amino, cyano or (lower) alk ylthio', or a nontoxic pharmaceutically acceptable salt thereof.
A more preferred embodiment is the compound having the formula COzH III
in which Y is H, Cl, Br, I, F, mercapto, CF OH, (lower) alkoxy; nitro, amino, cyano, (lower) alkyl or (lower) alkylthio; or a nontoxic, pharmaceutically acceptable salt thereof.
Another more preferred embodiment is a compound of formula 111 wherein Y is hydrogen, chloro, fluoro, hydroxy; (lower)alkyl, (lower)alkoxy, nitro or amino; or a pharmaceutically acceptable nontoxic salt thereof.
Still another more preferred embodiment is a compound of formula III wherein Y is hydrogen, chloro, (lower) alkyl or (lower)-alkoxy; or a pharmaceutically acceptable nontoxic salt thereof.
A most preferred embodiment is the compound of formula "1 wherein Y is hydrogen; or a pharmaceutically acceptable nontoxic salt thereof.
Another most preferred embodiment is the essentially pure levorotatory isomer of the compound of formula 111 wherein Y is hydrogen; or a pharmaceutically acceptable salt thereof.
Still another most preferred embodiment is the essentially pure dextrorotatory isomer of the compound of formula 111 wherein Y is hydrogen; or a pharmaceutically acceptable salt thereof.
A preferred embodiment of the present invention is a compound having the formula CozH .l .n. in which Y is H, mercapto, -CF;,, OH, (lower) alkoxy, nitro, amino, cyano, (lower) alkyl or (lower) alkylthio; or a nontoxic, pharmaceutically acceptable salt thereof.
Another preferred embodiment is a compound of formula IV in which Y is H, (lower) alkyl, (lower) alkoxy or OH: or a pharmaceutically acceptable salt thereof.
Still another preferred embodiment is a compound of formula IV in which Y is H, (lower) alkyl or (lower) alkoxy; or a pharmaceutically acceptable salt thereof.
A most preferred embodiment is the compound of formula IV in which Y is hydrogen; or a nontoxic, pharmaceutically acceptable salt thereof.
Another most preferred embodiment is the essentially pure levorotatory isomer of the compound of formula IV in which Y is hydrogen; or a nontoxic, pharmaceutically acceptable salt thereof.
Another most preferred embodiment is the essentially pure dextrorotatory isomer of the compound of formula IV in which Y is hydrogen; or a nontoxic, pharmaceutically acceptable salt thereof.
The pharmaceutically acceptable nontoxic salts include those having metallic cations such as sodium, potassium, calcium, and aluminum and organic amine cations of trialkylamines, e.g., triethylamine, procaine,
dibenzylamine, N-benzyl-B-phenethylamine, lephenamine, N ,N '-dibenzylethylenediamine, dehydroabietylamine, N,N-bisdehydroabietylethylenediamine, N-(lower)alkylpiperidines, e.g., N-ethylpiperidine, and other amines which have been used to form salts with medicinally active carboxylic acids.
The term (lower) alkyl as used herein means both straight and branched chain aliphatic hydrocarbon radicals having from one to six carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc. Similarly, where the term (lower) is used as part of the description of another group, e.g., (lower)alkoxy, it refers to the alkyl portion of such group which is therefore as described above in connection with (lower) alkyl and thus includes such radicals as methoxy, ethoxy, isopropoxy, etc.
The compounds of the instant invention can be prepared by the following synthesis:
Scheme 1:
AlCla C1 0 )0 & n-BuONO NHzCl 1..-
ultraviolet 1 light 5 :N, o m0 "01H CHIN, "0,011,
. 002E p-Cyrnene The optionally Y-substituted benzocyclobutene-lcarboxylic acids of the present invention can be prepared by one of the synthetic routes:
1 a. 5-Halosubstituted-benzocyclobutenel -carboxylic Acids: 4-Cyclohexylbenzocyclobutene-1-carboxylic acid is halogenated with N-halosuccinimide to produce 5- halo-4-cyclohexyl-benzocyclobutene- 1 -carboxylic acid.
b. 3 or 5-Nitrosubstituted-benzocyclobutene-l-carboxylic Acids: 4-Cyclohexylbenzocyclobutene-l-carboxylic acid is nitrated with one equivalent of nitric acid in the presence of sulfuric acid to produce a mixture of 3 and 5-nitro-4-cyclohexylbenzocyclobutenel -carboxylic acids. The mixture can be resolved into pure 3-nitro-4- cyclohexylbenzocyclobutene-l-carboxylic acid and 5- nitro-4-cyclohexylbenzocyclobutenel -carboxylic acid by methods known to the art. These resolved 5- nitrosubstituted compounds are most valuable as intermediates in the preparation of the other claimed compounds of the present invention.
0. 5-Aminosubstituted-benzocyclobutene- 1 -carboxylic Acids:
The purified S-nitrosubstituted-benzocyclobutenel carboxylic acids obtained in part (b) above are reduced by the use of hydrogen and catalyst (Pd/C, PtO etc.) to produce the 5-aminosubstituted-benzocyclobutenel-carboxylic acids of the present invention.
d. Benzocyclobutene-l-carboxylic Acid Diazonium Salts:
The aminosubstituted compound prepared in step above is placed in a strong mineral acid, i.e., HCl, H 80 I-lBr, etc., at 0 C. Nitrous acid is generated in situ by the addition of sodium nitrite to produce the diazonium salt of the amine. I
e. -Hydroxy-4-cyclohexylbenzocyclobutenel -carboxylic Acid:
Heating of the S-diazonium salt obtained in step (d) after the addition of water, will result in the formation of the 5-hydroxy-4-cyclohexylbenzocyclobutene- 1 -carboxylic acid.
f. 5-Alkoxy-4-cyclohexylbenzocyclobutene- 1 -carboxylic Acid:
Heating of the S-diazonium salt obtained in step (d) after the addition of the appropriate alcohol will result in the formation of the 5-alkoxy compound.
g. 5-Halo-4-cyclohexylbenzocyclobutene-1-carboxylic Acid:
The 5-diazonium salt prepared as in step (d) from the 5-aminosubstitutedbenzocyclobutenel -carboxylic acid obtained in step (c) is treated with either copperbronze (Gattermann Reaction) or cuprous halide (Cl, Br, I) to produce the S-halo-substituted compound.
h. 5-Cyano-4-cyclohexylbenzocyclobutene- 1 -carboxylic Acid:
The S-diazonium salt obtained by the procedure of step (d) which is prepared in H 80 is treated with base to neutralize the salt solution, followed by the addition of a solution of cuprous cyanide-sodium cyanide complex to produce a precipitate. Heating of the precipitate decomposes it to the cyano-substituted acid.
i. 5-Fluoro-4-cyclohexylbenzocyclobutenel -carboxylic Acid:
The S-diazonium salt, as in step (d) is treated with fluoroboric acid. The fluoroborate precipitates and is collected. After washing and drying, the precipitate is heated and it decomposes to the desired S-fluorosubstituted compound.
j. 5-Mercapto-4-cyclohexylbenzocyclobutene-l-carboxylic Acid:
The 5 salt prepared in step (d) is treated with potassium ethyl xanthate which produces an ethyl dithiocarbonate. Saponification of the dithiocarbonate produces the desired S-mercaptosubstituted compound.
carboxylic Acid:
Treatment of the S-mercaptosubstituted compound obtained in step (3') with dimethylsulfate in the presence of a base, followed by mild hydrolysis, produces the S-methylthio-substituted acid.
I. 5 -Methyl-4-cyclohexylbenzocyclobutenel-carboxylic Acid:
The 5-bromoor iodo-4-cyclohexylbenzocyclobutene-l-carboxylic acid obtained in step (g) is treated with lithium dimethylcopper to produce S-methyl-4- cyclohexylbenzocyclobutene-l-carboxylic acid [E. J. Corey and G. H. Posner, J. Am. Chem. Soc., 89, p. 3911 (1967)].
5-Methylthio-4-cyclohexylbenzocyclobutene-1- The compounds of the instant invention can be prepared by the utilization of one or more of the disclosed procedures above and they include among others:
5 -Chloro-4-cyclohexylbenzocyclobutene- 1 -carboxylic acid, 5-Bromo-4-cyclohexylbenzocyclobutenel -carboxylic acid, 5-Iodo-4-cyclohexylbenzocyclobutene-l-carboxylic acid, 5-Fluoro-4-cyclohexylbenzocyclobutenel -carboxylic acid, 5-l-lydroxy-4-cyclohexylbenzocyclobutene- 1 -carboxylic acid, 5-Methoxy-4-cyclohexylbenzocyclobutene- 1 -carboxylic acid, 5-Nitro-4-cyclohexylbenzocyclobutenel -carboxylic acid, 5-Amino-4-cyclohexylbenzocyclobutenel-carboxylic acid,
5 Cyano-4-cyclohexylbenzocyclobutenel -carboxylic acid,
5-Methyl-4-cyclohexylbenzocyclobutenel -carboxylic acid, 5-Mercapto-4-cyclohexylbenzocyclobutene-l -carboxylic acid, 5-Methylthio-4-cyclohexylbenzocyclobutene- 1 -carboxylic acid, 5-l-lydroxy-4-phenylbenzocyclobutene-l-carboxylic acid,
5-Methoxy-4-phenylbenzocyclobutene-l-carboxylic acid,
5-Nitro-4-phenylbenzocyclobutene-l-carboxylic acid,
5-Amino-4-phenylbenzocyclobutenel -carboxylic acid,
5-Cyano-4-phenylbenzocyclobutenel -carboxylic acid,
5-Methyl-4-phenylbenzocyclobutenel -carboxylic acid,
5-Mercapto-4-phenylbenzocyclobutenel -carboxylic acid, and
5-Methylthio-4-phenylbenzocyclobutenel carboxylic acid.
The compounds of the instant invention can be resolved into their substantially pure dextroand levorotatory isomers by methods commonly known in the art. For illustrative purposes, the compound 4- cyclohexylbenzocyclobutene-l-carboxylic acid was resolved into its respective isomers by the procedure of first treating the mixture with cinchonidine to produce the cinchonidine salt of ()-4-cyclohexylbenzocyclobutene-l-carboxylic acid. The salt was recrystallized and the decomposed to the free acid to yield substantially pure (-)-4-cyclohexylbenzocyclobutene-lcarboxylic acid.
The dextrorotatory acid enriched mother liquors remaining above, after the collection of the cinchonidine salt of the levo-rotatory acid was isolated from it, was concentrated to dryness. The residue was treated with ether and hydrochloric acid. A partially resolved mixture of the dextrorotatory and levorotatory isomers, enriched with the dextrorotary acid, was obtained. The acid was extracted into ether and the solution taken to dryness in vacuo. Hot Skellysolve B (petroleum ether essentially n-hexane) was added to a boiling solution of the acid and an equimolar quantity of ()-a-( l-napthyl)ethylamine in benzene to produce the naphthylethylamine salt of (+)-4-cyclohexylbenzocyclobutene-l-carboxylic acid as a crystalline material.
The salt was recrystallized from acetonitrile and decomposed by the addition of acid to produce pure (+)-4-cyclohexylbenzocyclobutenel -carboxylic acid.
All the compounds of the instant invention can be resolved into their component dextrorotatory and levorotatory isomers by a procedure similar, if not identical, to that described above. Examination of the chemical literature likewise provides many other methods for the resolution of racemic monocarboxylic acids.
Some racemic mixtures can be precipitated as eutecties instead of mixed crystals and can thus be quickly separated and in such cases can sometimes be selectively precipitated. The more common method of chemical resolution may be used. By this method diastereoisomers are formed from the racemic mixture by reaction with an optically-active resolving agent. Thus, an opticallyactive base can be reacted with the carboxyl group. The difference in solubility between the diastereoisomers formed permits the selective crystallization of one form and regeneration of the opticallyactive acid from the mixture. There is, however, a third method of resolving which shows great promise. This is one of the other forms of biochemical procedures using selective enzymatic reaction. Thus, the racemic acid can be subjected to an asymmetric oxidase or decarboxylase which will, be oxidation or decarboxylation, destroy one form, leaving the other form unchanged. Even more attractive is the use of hydrolylase on a derivative of the racemic mixture to form preferentially one form of the acid. Thus, esters or amides of the acids can be subjected to an esterase or amidase which will selectively saponify one enantiomorph and leave the other unchanged. Amide or salt diastereoisomers of the free acid may be formed with opticallyactive amines, such as quinine, brucine, cinchonidine, cinchonine, dehydroabietylamine, hydroxy-hydrindamine, menthylamine, morphine, aphenylethylamine, phenyloxynaphthylmethylamine, quinidine, l-fenchylamine, strychnine, basic amino acids, such as lysine, arginine, amino acid esters, and the like. Similarly, ester diastereoisomers of the free acid may be formed with opticallyactive alcohols, such as borneo], menthol, 2-octanol and the like. Especially preferred is the use of cinchonidine to give the readily decomposable diastereoisomer salt which may then be resolved by dissolving in a solvent, such as acetone, and distilling the solvent at atmospheric pressure until crystals begin to appear and further crystallization produced by allowing the mixture to cool to room temperature, thereby separating the two enantiomorphs. The acid may then be recovered from the salt by extracting the salt between an organic solvent, such as petroleum ether and dilute hydrochloric acid or some other organic solvent-aqueous system. Workup of the remaining mother liquors and subsequent purification will usually provide the other isomer.
It is noted, however, the racemic mixtures themselves are potent anti-inflammatory agents.
The compounds of this invention have a high degree of antiinflammatory activity. They are useful in treating arthritis, rheumatism and other inflammatory diseases in mammals.
Anti-inflammatory tests of the compounds of the present invention were carried out on rats using the carrageenin-induced foot edema test of Charles A. Winter et al., Carrageenin-lnduced Edema in Hind Paw of the Rat as an Assay for Anti-Inflammatory Drugs, Proceedings of the Society for Experimental Biology and Medicine, 111, 544 (1962). The compound under investigation was given orally to the rat, and one hour later carregeenin was injected subcutaneously into one paw. 3 hours later the degree of edema was measured volumetrically by fluid displacement, and compared to that of the control paw to give a result presented in terms of percentage inhibition of edema. Any result of more than 30 percent inhibition was greater than three times the standard deviation of the result in control animals, and thus clearly indicated anti-inflammatory activity.
In the rat paw edema test described above, the compounds of the instant invention exhibit anti-inflammatory activity deemed useful in the treatment of inflammatory diseases in mammals, including man. The compounds of the invention are generally useful in the dosage range of about 0.1 mg./kg. to about 40 mg./kg. three to four times a day.
They can be administered orally or parenterally, but preferably orally. More specifically, the compounds of the instant invention are preferentially administered in dosages in the range of about 0.2 mg./kg. to about 30 mg./kg. three to four times a day.
The dosage will vary with the particular compound of the invention. For example, (i)-4-cyclohexylbenzocyclobutene-l-carboxylic acid had an MED of 3.5 mgjkg. in rats (MED is defined as the dose which produces 30 percent inhibition of edema).
The resolved isomers, ()-4-cyclohexylbenzocyclobutene-l-carboxylic acid and (+)-4-cyclohexylbenzocyclobutene-l-carboxylic acid had MEDs of 8.0 mg./kg. and 3.6 mg./kg. respectively.
The oral dosage in humans of the compounds of the present invention is in the range of about 0.2 mg./kg. to about 25 mg./kg. administered three or four times a day. The preferred human dosage is in the range of 0.2 mg./kg. to about 10 mg./kg. three to four times a day.
EXAMPLES EXAMPLE l S-Cyclohexyll -indanone The title compound was prepared by a procedure similar to that described by Hart and Tebbe for the preparation of l-indanone from benzene and B- chloropropionyl chloride. A solution of B- chloropropionyl chloride (13.33 g., 0.105 mole) and cyclohexylbenzene (16.03 g., 0.1 mole) in carbon disulfide (25 ml.) was added dropwise with stirring over a period of 15 minutes to a cooled (ice-water) suspension of aluminum chloride (16.0 g., 0.12 mole) in carbon disulfide (60 ml.). The mixture was concentrated then stirred at room temperature for 3 hours. The mixture was concentrated in a rotary evaporator. Sulfuric acid (250 ml of sp. gr. 1.84) was added slowly with stirring and cooling (ice-water) to the residual oil. After the addition was complete the mixture was stirred at room temperature for minutes; The mixture was then heated by means of an oil bath, the temperature of which was slowly raised to 100 C. and maintained at this temperature for 2 hours. The mixture was then'allowed to stand at room temperature for 15 hours. The mixture was poured onto ice (1 kg. The resulting mixture was extracted with diethyl ether (3 X 500 ml.). The combined ether solution was washed with water (250 ml.) followed by saturated aqueous sodium bicarbonate (200 ml.), and saturated aqueous sodium chloride (2 X 200 ml.). The washed solution was dried over anhydrous sodium sulfate and concentrated in a rotary evaporator to give a yellow-brown solid (19.7 g.), m.p. 6473 C. The product was recrystallized with charcoal treatment from n-pentane to give 5- cyclohexyl-l-indanone (14.7 g., 69 percent) as yellow crystals, m.p. 75-76.5 C. Recrystallization from npentane with charcoal treatment gave off-white crystals, m.p. 75.5-77 C.
Anal. calcd. for C H O: C, 84.07; H, 8.47.
Found: C, 83.99; H, 8.43.
R. T. Hart and R. F. Tebbe, J. Am. Chem. Soc., 72, 3286 (1950).
EXAMPLE 2 5-Cyclohexyl-2-oximino-l-indanone n-Butyl nitrite (19.04 g., 0.185 mole) was added during 1.5 minutes to a stirred mixture of 5-cyclohexyl-1- indanone (34.0 g., 0.159 mole) in methyl cellosolve (180 ml.) and hydrochloric acid (42 ml. of sp. gr. 1.19) at an initial temperature of 25 C. The reaction mixture was stirred an additional 14 minutes, during which time it turned homogeneous and reached a maximum temperature of 41 C. The warm solution was poured onto cold water (1.5 l.) with stirring. Stirring was continued with external cooling (ice-water) until the gummy solid turned granular. The solid was collected, washed with cold water and dried to give 5-cyclohexyl-2-oximino-1- indanone (44 g.), m.p. 180185 C. with decomposition and prior softening. Recrystallization from benzene-Skellysolve B (ca. 3:1) gave pale yellow crystals (31.6 g., 82 percent), m.p. l92-193 C. with decomposition and prior softening.
EXAMPLE 3 5-Cyclohexyl-2-diazo-l-indanone Ammonium hydroxide (7.55 ml. of sp. gr. 0.90, 0.113 mole) was added to a stirred, cooled (ice-water) mixture of 5-cyclohexyl-2-oximo-l-indanone (6.19 g., 0.0252 mole) and 1.0 N sodium hydroxide (25.2 ml., 0.0252 mole) in ethanol (60 ml.). This was followed by the dropwise addition of 5.25 percent sodium hypochlorite solution (75.5 ml., 0.058 mole) during minutes. The mixture was then stirred with cooling for 3 hours followed by 1 hour at C. The mixture was extracted with ether (2 X 80 ml.) and the combined ethereal extracts were washed with water (2X) followed by water saturated with sodium chloride. The ethereal solution was dried (Na SO filtered and the filtrate reduced to dryness to leave a gummy solid (5.36 g.). A solution of this material in toluene was filtered through alumina (40 g.) and the filtrate reduced to dryness to leave an oily solid residue. Crystallization from Skellysolve B gave 5-cyclohexyl-2-diazo-l-indanone (2.81 g., 46 percent) as yellow needles, m.p. 1 l9-120 C.
EXAMPLE 4 (i)-4-Cyclohexylbenzocyclobutenel-carboxylic Acid A mixture of 5-cyclohexyl-2-diazo-l-indanone (9 g.) in tetrahydrofuran 1.5 l.) and water (270 m1.) containing sodium bicarbonate (9 g.) was irradiated for 7 hours at 30 C. with a Hanovia 8A36 ultraviolet lamp. The bulk of the tetrahydrofuran was removed in a rotary evaporator and additional water ml.) was added to the mixture. The mixture was extracted with ether (2X) and the combined ethereal extracts were saved.
The aqueous layer was acidified with concentrated hydrochloric acid and was then extracted with ether (3 X ml.). These ethereal extracts were combined and washed with saturated aqueous sodium chloride (2X) and reduced to dryness to leave an oil (1.4 g.) This material was chromatographed on silicic acid (25 g.) eluting with toluene-acetone (20:1) to give 1.1 g. of crystalline material which upon recrystallization from Skellysolve B gave pale yellow crystals (0.918 g.) of (1')-4-cyclohexylbenzocyclobutenel -carboxlic acid, m.p. 100-l02 C.
The ethereal extracts which were retained were reduced to dryness to leave an oil which still contained starting 5-cyclohexyl-2-diazo-l-indanone. This oil was recycled and the product purified as described to give an additional 0.55 g. of product, m.p. 99-100 C. The total product from this experiment (1.47 g.) was combined with similar material (0.2 g.) from two small scale runs and the lot was recrystallized from Skellysolve B with charcoal treatment to give pale yellow crystals of (i)-4-cyclohexylbenzocyclobutene-l-carboxylic acid, m.p. 99.5101.5 C.
Anal. calcd. for c.,n,,o,; C, 78.32; H, 7.88.
Found: C, 78.18; H, 7.94.
EXAMPLE 5 (i)-4-Cyclohexylbenzocyclobutene- 1 -carboxylic Acid A slow stream of nitrogen was bubbled through a mixture of 5-cyclohexyl-2-diazo-l-indanone (30 g.), sodium bicarbonate (30 g.), water ml.) and tetrahydrofuran (1.3 1.) contained in a quartz vessel for 12 hours. With continued nitrogen flow the mixture was then irradiated in a Rayonet RPR-100 photochemical reactor with 3,000 A lamps at 44 C. for 36 hours. The mixture was diluted with water and most of the tetrahydrofuran removed in a rotary evaporator. The mixture was made strongly basic with 5N NaOH and then washed with diethyl ether (2X). The aqueous solution was acidified (concd. HCl) and the precipitated product extracted with ether (2X). These combined ethereal extracts were washed with water saturated with sodium chloride (2X) and dried (Na SO Removal of the ether left an oil (12 g.) which crystallized. Recrystallization from Skellyvolve B (decolorizing carbon) gave pale yellow crystals 10.2 g., 35.6 percent) of (i)-4-cyclohexylbenzocyclobutene-l-carboxylic acid, m.p. 97-99.
EXAMPLE 6 ()-4-Cyclohexylbenzocyclobutene- 1 -carboxylic Acid A solution of (:t)-4-cyclohexylbenzocyclobutene-lcarboxylic acid (5.77 g., 0.025 mole) and cinchonidine (7.35 g., 0.025 mole) in ethanol (175 ml.) was boiled down to a volume of about 110 ml. The hot solution was allowed to stand three hours at 25. The colorless crystalline material was collected and washed with cold ethanol to give the cinchonidine salt (7.76 g.), m.p. l93-196 with prior softening. The salt was recrystallized twice from ethanol to give colorless crystals (4.4 g. m.p. 199-202 with slight prior softening.
The combined mother liquors from the cinchonidine salt formation and the first ethanol recrystallization were saved for eventual isolationof (+)-4-cyclohexylbenzocyclobutenel -carboxylic acid.
The cinchonidine salt (4.4 g.) was partitioned between diethyl ether (50 ml.) and 0.5 N HCl (30 ml.). The ethereal layer was washed with water (20 ml.) followed by two washings with water saturated with sodium chloride and dried (sodium sulfate). Removal of the ether left colorless crystals (1.77 g.) of ()-4- cyclohexylbenzocyclobutene-l-carboxylic acid: m.p. 9193; [011 954 (0. 2.173, ethanol). The acid was recrystallized twice from n-pentane to give colorless crystals; m.p. 93-95; [aw -9.0 (c. 2.00, ethanol).
Boiling Skellysolve B ml.) was added to a boiling solution of the ()-acid (1.19 g., 0.00516 mole) with m.p. 93-95 and (+)-a-( l-naphthyl)ethylamine (0.884 g., 0.00516 mole) in benzene (10 ml.). The hot solution was allowed to stand at 25 for 2 hours with an occasional scratching of the inside of the beaker with a glass stirring rod. The colorless crystals (1.87 g., m.p. l58-l60) were collected and recrystallized from acetonitrile to give the salt (1.69 g.) of (+)-a-( 1- naphthyl)ethylamine with ()-4-cyclohexylbenzocyclobutene-l-carboxylic acid, m.p. 161l63 with slight prior softening. The salt was decomposed with hydrochloric acid and the product extracted into ether as previously described. The ether was removed and the residue (0.908 g., m.p. l01-l02) recrystallized from n-pentane to give 0.775 g. of ()-4-cyclohexylbenzocyclobutene-l-carboxylic acid: m.p. l0l-l02; [a] ,,12.2 (c. 1.54, ethanol).
Anal. calcd. for C H O C, 78.23; H, 7.88.
Found: C, 78.03; H, 7.97.
EXAMPLE 7 (+)-4-Cyclohexylbenzocyclobutenel -carboxylic Acid The mother liquors which were retained in Example 6 were reduced to dryness and the resulting mixture of salt decomposed with hydrochloric acid and the liberated acids extracted into ether. Removal of the ether left a mixture of acids (2.54 g.) enriched in the (+)-isomer.
Hot Skellysolve B ml.) was added to a boiling solution of the enriched acid (2.54 g., 0.011 mole) and ()-a-(l-naphthyl)-ethylamine (1.89 g., 0.011 mole) in benzene (19 ml.). The hot solution was allowed to stand at C. for 2 hours with occasional scratching of the inside of the beaker with a glass stirring rod. The off white crystalline material was collected, washed with cold benzene-Skellysolve B and dried to give the salt (2.44 g.) of ()-a-l-naphthyl)ethylamine with (+)-4- cyclohexylbenzocyclobutene-l-carboxylic acid, m.p. l55-l57 with slight prior softening. The salt was recrystallized from acetonitrile to give off white needles (2.28 g.), m.p. l58.5-l6.5.
EXAMPLE 8 (i)-Methyl 4-Cyclohexylbenzocyclobutenel -carboxylate Excess diazomethane in diethyl ether is added to a suspension of (i)-5-cyclohexylbenzocyclobutene-lcarboxylic acid in diethyl ether. The resulting solution is concentrated to an oil which slowly crystallizes on standing. The product is recrystallized from methanol after treatment with activated charcoal to produce the title compound.
EXAMPLE 9 (:)-Methyl 4-Phenylbenzocyclobutenel -carboxylate A mixture of (:L)-methyl 4-cyclohexylbenzocyclobu tene-1carboxylate and 10 percent palladium on carbon in p-cymene is heated under reflux for 42 hours. The reaction mixture is cooled and filtered to remove the catalyst. The filtrate is concentrated in a rotary evaporator to leave an oil which is crystallized from petroleum ether (b.p. 30-60) to give (:t)-methyl 4- phenylbenzocyclobutenel -carboxylate crystals.
EXAMPLE 10 (i)-4-Phenylbenzocyclobutenel -carobxylic Acid A solution of 10 percent aqueous sodium hydroxide is added to a solution of (i)-methyl 4-phenylbenzocyclobutene-l-carboxylate in ethanol, and the mixture is heated under reflux for 5 minutes. The mixture is cooled and then poured into cold water. The resulting solution is acidified with ice-cooling to pH 2 with 10 percent hydrochloric acid. The precipitated solid is washed with cold water, dried, and recrystallized from methanol with charcoal treatment to give the title product.
e la m; .2.
l. A compound having the formula CO H in which R is cyclohexyl or phenyl, and Y is H, Cl, Br, I, F, mercapto, CF 0H, (lower)alkoxy, nitro, amino, cyano, (lower)-alkyl or (lower)alkylthio; or a nontoxic pharmaceuticallyacceptable salt thereof.
2. A compound of claim 1 having the formula CO H in which R is cyclohexyl or phenyl, and Y is H, Cl, Br, I, F, mercapto, -CF OH, (lower)alkyl, (lower)alkoxy, nitro, amino, cyano or (lower)alkylthio; or a nontoxic, pharmaceuticallyacceptable salt thereof.
3. A compound of claim 2 having the formula 1.4 6. A compound of claim 3 wherein Y is hydrogen; or a pharmaceutically-acceptable nontoxic salt thereof.
7. The essentially pure levorotatory isomer of the compound of claim 6.
8. The essentially pure dextrorotatory isomer of the compound of claim 6.
9. A compound of claim 2 having the formula COzH in which Y is H, mercapto, CF=,, OH, (lower)alkoxy, nitro, amino, cyano, (lower)alkyl or (lower)alkylthio: or a nontoxic, pharmaceutically acceptable salt thereof.
10. A compound of claim 9 in which Y is H, (lower)alkyl, (lower)-alkoxy or OH; or a pharmaceuticallyacceptable salt thereof.
11. A compound of claim 9 in which Y is H, (lower)alkyl or (lower)alkoxy; or a pharmaceuticallyacceptable salt thereof.

Claims (10)

  1. 2. A compound of claim 1 having the formula in which R is cyclohexyl or phenyl, and Y is H, Cl, Br, I, F, mercapto, -CF3, OH, (lower)alkyl, (lower)alkoxy, nitro, amino, cyano or (lower)alkylthio; or a nontoxic, pharmaceuticallyacceptable salt thereof.
  2. 3. A compound of claim 2 having the formula in which Y is H, Cl, Br, I, F, mercapto, -CF3, OH, (lower)-alkoxy, nitro, amino, cyano, (lower)alkyl or (lower)alkylthio; or a nontoxic, pharmaceutically-acceptable salt thereof.
  3. 4. A compound of claim 3 wherein Y is hydrogen, chloro, fluoro, hydroxy, (lower)alkyl, (lower)alkoxy, nitro or amino; or a pharmaceutically-acceptable nontoxic salt thereof.
  4. 5. A compound of claim 3 wherein Y is hydrogen, chloro, (lower)alkyl or (lower)alkoxy; or a pharmaceutically-acceptable nontoxic salt thereof.
  5. 6. A compound of claim 3 wherein Y is hydrogen; or a pharmaceutically-acceptable nontoxic salt thereof.
  6. 7. The essentially pure levorotatory isomer of the compound of claim 6.
  7. 8. The essentially pure dextrorotatory isomer of the compound of claim 6.
  8. 9. A compound of claim 2 having the formula in which Y is H, mercapto, -CF3, OH, (lower)alkoxy, nitro, amino, cyano, (lower)alkyl or (lower)alkylthio: or a nontoxic, pharmaceutically acceptable salt thereof.
  9. 10. A compound of claim 9 in which Y is H, (lower)alkyl, (lower)-alkoxy or OH; or a pharmaceuticallyacceptable salt thereof.
  10. 11. A compound of claim 9 in which Y is H, (lower)alkyl or (lower)alkoxy; or a pharmaceuticallyacceptable salt thereof.
US57755A 1970-07-23 1970-07-23 Benzocyclobutene-1-carboxylic acids Expired - Lifetime US3696111A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US5775570A 1970-07-23 1970-07-23

Publications (1)

Publication Number Publication Date
US3696111A true US3696111A (en) 1972-10-03

Family

ID=22012563

Family Applications (1)

Application Number Title Priority Date Filing Date
US57755A Expired - Lifetime US3696111A (en) 1970-07-23 1970-07-23 Benzocyclobutene-1-carboxylic acids

Country Status (1)

Country Link
US (1) US3696111A (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3940434A (en) * 1972-08-24 1976-02-24 Ciba-Geigy Corporation Dicarboxylic acids and derivatives
US4007225A (en) * 1973-08-11 1977-02-08 Takeda Chemical Industries, Ltd. 4-Benzoylindan-1-carboxamide and derivatives thereof
US4407823A (en) * 1978-01-27 1983-10-04 Schering Aktiengesellschaft Novel phenylacetic acid derivatives
US4954584A (en) * 1989-06-12 1990-09-04 Shell Oil Company Thermosetting resin compositions
US4954583A (en) * 1989-06-12 1990-09-04 Shell Oil Company Arylcyclobutene carboxylate esters
US6127189A (en) * 1996-11-08 2000-10-03 The Trustees Of The University Of Pennsylvania Compositions and methods for detection of an amine compound in a fingerprint

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3408391A (en) * 1965-04-19 1968-10-29 Colgate Palmolive Co 1-benzocyclobutenyl amino acids

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3408391A (en) * 1965-04-19 1968-10-29 Colgate Palmolive Co 1-benzocyclobutenyl amino acids

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3940434A (en) * 1972-08-24 1976-02-24 Ciba-Geigy Corporation Dicarboxylic acids and derivatives
US4007225A (en) * 1973-08-11 1977-02-08 Takeda Chemical Industries, Ltd. 4-Benzoylindan-1-carboxamide and derivatives thereof
US4407823A (en) * 1978-01-27 1983-10-04 Schering Aktiengesellschaft Novel phenylacetic acid derivatives
US4954584A (en) * 1989-06-12 1990-09-04 Shell Oil Company Thermosetting resin compositions
US4954583A (en) * 1989-06-12 1990-09-04 Shell Oil Company Arylcyclobutene carboxylate esters
US6127189A (en) * 1996-11-08 2000-10-03 The Trustees Of The University Of Pennsylvania Compositions and methods for detection of an amine compound in a fingerprint

Similar Documents

Publication Publication Date Title
US3641127A (en) (3-benzoylphenyl) alkanoic acids
EP0722434B1 (en) Nitric esters having anti-inflammatory and/or analgesic activity and process for their preparation
JPS582936B2 (en) 5↓-Production method of aroylpyrroleacetic acid and its salts
US3696111A (en) Benzocyclobutene-1-carboxylic acids
JPH05208978A (en) Method for aroylating 5-position of 1,2-dihydro-3H-pyrrolo [1,2-α] pyrrole-1-carboxylic acid ester
JPS6055506B2 (en) Novel ω-aminocarboxylic acid amide and its production method
US3565943A (en) 1-indancarboxylic acids and derivatives
US3468939A (en) 4- and 5-aryl-1-naphthaleneacetic acid compounds
JPS6178778A (en) 4,5-dihydro-4-oxo-2-[(2-trans-phenylcyclopropyl)amino]-3-furancarboxylic acid and its derivatives
US3663627A (en) 1-indanmethanols
JPH0222059B2 (en)
US3821289A (en) Tetrahydronaphthylalkanoic acids and their derivatives
US3466372A (en) Treatment of inflammation with 4-phenyl - alpha - methyl - phenyl acetic acid,its salts,esters or amide derivatives
US3565904A (en) 1,2,3,4-tetrahydro-1-naphthoic acids
DE2004038C3 (en) 5-Cyclohexyl-1-indanecarboxylic acids, their lower alkyl and tert-amino lower alkyl esters, non-toxic pharmacologically acceptable salts and processes for their preparation
US3895063A (en) Substituted Anilino Benzyl Alcohols
KR100224330B1 (en) N- 4,5-dihydroxy- and 4,5,8-trihydroxy-9,10-dihydro-9,10-dioxo-2-anthracene-yl)carbonyl)amino acids
US5321154A (en) Optical resolution of (±)-2-(4-isobutylphenyl)-propionic acid
US4542235A (en) Method for producing an optically active 2,2-dimethylcyclopropanecarboxylic acid
DE2909742A1 (en) NEW DERIVATIVES OF PHENYL-ALANINE, THEIR PRODUCTION AND THEIR THERAPEUTIC USE
US3898269A (en) Tetrahydronaphthylglyoxylic acids and esters
US3845215A (en) Phenylalkane derivatives in the treatment of inflammation
US3886207A (en) Process for producing indan-1-carboxylic acid derivatives
Feuer et al. The Chemistry of Trinitromethane. III. Preparation of (2, 2, 2-Trinitroethyl)-succinic Acid and Derivatives.
US3804877A (en) 2-anilinophenylacetonitriles