US3883551A - Thienobenzopyrans and thiopyranobenzopyrans - Google Patents

Thienobenzopyrans and thiopyranobenzopyrans Download PDF

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US3883551A
US3883551A US210170A US21017071A US3883551A US 3883551 A US3883551 A US 3883551A US 210170 A US210170 A US 210170A US 21017071 A US21017071 A US 21017071A US 3883551 A US3883551 A US 3883551A
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Raj K Razdan
Harry G Pars
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Arthur D Little Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • This application relates to novel thienobenzopyrans and thiopyranobenzopyrans, to intermediates useful in the preparation thereof and to methods of making and using the novel compounds.
  • the invention sought to be patented, in a first composition aspect, resides in the concept of a class of chemical compounds which includes more particularly those designated as 7-alkyl(and 7-cycloalkylloweralkyl)-9-hydroxy(and 9-O-esters and 9-O-ethers)-4,4- diloweralkyl-l ,2-dihydro-4H-thieno[ 2,3-c] [l] benzopyrans; 7-alkyl (and 7-cycloalkylloweralkyl)-9-hydroxy (and 9-O-esters and 9-O-ethers)-4,4-diloweralkyl-l,3- dihydro-4H-thieno [3,4,-c] [l]benzopyrans; 7-alkyl (and 7-cycloalkylloweralkyl)-9-hydroxy (and 9-0- esters and 9-O-ethers)-4,4-diloweralkyl-2,3-dihydro- 4H-thieno
  • the invention sought to be patented, in a second composition aspect, resides in the concept of a class of chemical compounds which includes more particularly those designated as 7-a
  • the invention sought to be patented in a second composition aspect resides in the concept of a class of chemical compounds which includes 5-(alkyl(and 5 cycloalkylloweralkyl)-2-(4,5-dihydro-2-(2-hydroxy-2- propyl)-thien-3-yl)resorcinols; 5-(alkyl(and 5- cycloalkylloweralkyl)-2-(2,5-dihydro-3-(2-hydroxy-2- propyl)-thien-4-yl)resorcinols; 5-(alkyl(and 5- 2 cycloalkylloweralkyl)-2-(4,5-dlhydro-3-(2-hydroxy-2- propyl)-thien-2-yl)resorcinols; 5-alkyl(and 5- cycloalkylloweralkyl)-2-( 4,5-dihydro-2-( 2-hydroxy-2- propylJ6H-thiopyran'S-yl)resorcinols;
  • the tangible embodiments of the first composition aspect of the invention possess the inherent use characteristics of having biological activity as determined by standard pharmacological test procedures for potential therapeutic drugs.
  • the tangible embodiments of the second and third composition aspects of the invention possess the use characteristics of being intermediates in the preparation of the first composition aspect embodiments.
  • the invention sought to be patented in its method aspects, resides in the reaction of the appropriate oxotetrahydrothiophene-carboxylate or oxo-tetrahydrothiopyrano-carboxylate with an appropriately alkyl (or cycloalkylloweralkyl)-substituted resorcinol to form the intermediates required to the preparation of the desired compounds having biological activity.
  • the invention accordingly comprises the several steps and the relation of one or more such steps with respect to each of the others and the composition of matter possessing the characteristics, properties and the relation of components which will be exemplified in the composition hereinafter described, and the scope of the invention will be indicated in the claims.
  • R is dialkylaminoalkyl
  • the thienobenzopyrans and thiopyranobenxopyrans of this invention may be represented by general formula IX CH R 2 m (cl'l i ll: 4 R
  • R is dialkylaminoalkanoyl
  • the compounds may be represented by general formula X and the respective acid addition salts of compounds of formulas IX and X may be represented by general formulas XI and XII 4 O-(CH N X ⁇ R (c11 s Acid and R R4 2 ll 4 (CH O-C(CH N Acid XII where R, and R, have the meanings given above, x is a whole number from 1 through 6 and R, and R are loweralkyl.
  • loweralkyl means saturated, monovalent aliphatic radicals, including straight and branched chain radicals of from one to six carbon atoms, as illustrated by, but not limited to methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, arnyl, hexyl and the like.
  • alkyl means saturated, monovalent aliphatic radicals, including straight and branched-chain radicals of from one to twenty carbon atoms, as illustrated by, but not limited to methyl, n-amyl, n-hexyl, 2-heptyl, n-heptyl, 3-methyl-2-octyl, n-octyl, 2-nony1, Z-tetradecyl, n-hexadecyl, 2-eicosanyl and the like.
  • the derivatives of the compounds of formulas I-VIII, where R is loweralkyl, loweralkanoyl, carbamyl, N-loweralkylcarbamyl, N,N-diloweralkylcarbamyl or phosphonyl are prepared by reacting the corresponding compound where R is hydrogen, preferably in the presence of a basic catalyst, with a loweralkyl halide, to produce the compounds where R;, is lower-alkyl; with a loweralkanoic anhydride (or mixed anhydride) to produce the compounds where R is loweralkanoyl; with a molar equivalent of phosgene followed by reaction of the resulting chloroformate with ammonia, a loweralkylamine, or a diloweralkyl amine, to produce the compounds where R, is, respectively, carbamyl, N-loweralkylcarbamyl or N,N-diloweralkylcarbamyl; or with one molar equivalent amount of phospho
  • R is dialkylaminoalkyl
  • the compounds, represented by formula IX may be formed by reacting the appropriate benzopyran with an alkali alkoxide in a solvent, such as ethanol, to give the alkali derivative, which upon treatment with a dialkylaminoalkyl halide in a solvent, such as benzene, results in the formation of the desired derivatives.
  • the acid addition salts of the dialkylaminoalkyl derivatives (formula XI) may be prepared by reacting the free base with an appropriate acid in a suitable organic solvent, in which case the acid salts may be separated directly or obtained by concentration of the solvent.
  • R is dialkylaminoalkanoyl (formula X)
  • the appropriate benzopyran is reacted with equimolar amounts of carbodiimide and the appropriate acid or acid salt of the amino group to give either the free base or the acid addition salt (formula XII) directly. If the free base form is obtained, then it may be converted to the acid addition salt in the same manner as described for preparing the acid addition salt of the dialkylaminoalkyl derivativev It is well known that it is possible to convert from one acid addition salt to another by regenerating the free base form and acidifying it.
  • Appropriate acid addition salts are those derived from such diverse acids as formic acid, acetic acid, isobutyric acid, alpha-mercaptopropionic acid, malic acid, fumaric acid, succinic acid, succinamic acid, tartaric acid, citric acid, lactic acid, benzoic acid, 4- methoxybenzoic acid, phthalic acid, anthranilic acid, l-naphthalenecarboxylic acid, cinnamic acid, cyclohexanecarboxylic acid, mandelic acid, tropic acid, crotonic acid, acetylene dicarboxylic acid, sorbic acid,
  • Suitable solvents are diethyl ether, diacid, Z-pyridinecarboxylic acid, 3-indoleacetic acid, butyl ether, tetrahydrofuran, anisole, pyridine and the guinic acid, sulfamic acid, methane sulfonic acid, iselike.
  • phosphinic acid p-aminophenylarsinic acid, phenyl- This triol is converted to the desired benzopyran by disstibnic acid, phenylphosphinous acid, methylphossolving it in a suitable solvent, such as benzene, and phinic acid, phenylphosphinic acid, hydrofluoric acid, heating to reflux with an acid catalyst, such as p-tolhydrochloric acid, hydrobromic acid, hydriodic acid, uenesuifonic acid, to give the compound of formula perchloric acid, nitric acid, sulfuric acid, phosphoric l0 XV (cu (C 2 in OH (CH OH (cn l 2 n solvent: acid catalyst R R R R XIV xv acid, y r y p ph g acid.
  • the intermediate takes the form S xIII O with a loweralkyl magnesium halide as represented by the following reaction XVII S Sq (CH tcn l XIII xIv wherein R and R have the meanings given hereinit is prepared by reacting an alkyl 3-oxo-2,3,4,5- above, and x is a halogen.
  • the Grignard reaction is cartetrahydrothiophene-2-carboxylate of formula XVIII ried out in an organic solvent inert under the conditions with a resorcinol of formula XIX.
  • the reaction is car- 9 10 ried out in the presence of an acid catalyst, such as HCI
  • an acid catalyst such as HCI
  • the intermediate compound to be formed is of dissolved in ethanol, and may be represented as the general formula XXII COOAlkyl XVIII
  • XXII H O OH 5 is a synthetic route similar to that used for compounds of formulas XVII and XX may be used. I 5 When the intermediate takes the form R no 2 0 0/ R OH XIX XVII s wherein R and the meaning previously given. 0: l R
  • reaction is carried out COOAlkyl under conditions similar to those used in forming the XXIV compounds of formula XVII by a reaction which may be represented as follows OH H K R COOAlkyl XIX XXI XXIII Where the intermediate takes the form 5/ OH I no R K/ XIX XX XXV it may be prepared from an alkyl 4-oxo-2,3,4,5- tetrahydro-4H-thiopyran'3-carboxylate as described above.
  • the intermediates -alkyl or S-cycloalkylloweralkyresorcinols of formula XIX are conveniently prepared by methods generally known in the art, such as by dehydration of a 3,5-diloweralkoxyphenylalkyl (or cycloalkylloweralkyl)carbinol, reduction of the resulting 3,4-diloweralkoxyphenylalkene (or diloweralkoxyphe nylcycloalkylloweralkene), and hydriodic acid cleavage of the ether groups to the corresponding S-alkyl (or S-cycloalkylloweralkyl)resorcinol.
  • the starting carbinols are in turn prepared by reaction of an appropriate Grignard reagent with a 3,5-diloweralkoxybenzoic acid ester, amide or 3,5'-dil0weralkoxyalkanophenone (or 3,5'-diloweralkoxycycoloalkyloweralkanophenone).
  • the compounds exhibit activity when administered either by the oral or intraperitoneal routes, however, the oral route is preferred.
  • the compounds can be prepared for use by dissolving under sterile conditions in water or in a physiologically compatible aqueous medium such as saline, and stored in ampoules for intramuscular injection.
  • a physiologically compatible aqueous medium such as saline
  • they can be incorporated in unit dosage form as tablets or capsules for oral administration either alone or in combination with suitable adjuvants such as calcium carbonate, starch, lactose, talc, magnesium stearate, gum acacia and the like.
  • the compounds can be formulated for oral administration in aqueous alcohol, glycol or oil solutions or oil-water emulsions in the same manner as conventional medicinal substances are prepared
  • IR infrared
  • UV ultraviolet
  • NMR nuclear magnetic 5 resonance
  • the intermediate alkyl 3-oxo-2,3,4,5-tetrahydr0-6H thiopyran-Z-carboxylate can be prepared by the procedure of Leonard and Figueras, J. Amer. Chem. Soc. 74, 917 (1952).
  • the compounds of formula I exhibit CNS activity and are useful as anti-anxiety agents at dosages of from 0.01 to 20 mg./kg. of body weight daily, and can be used in treating anxiety with or without associated psychoneu' rotic depressive symptoms.
  • the anti-depressant activity of the compounds was first established in mice in the modified dopa test described by Everett et al., Fed. Proc., 23, I98 (1964) and confirmed in dogs and monkeys.
  • the marked tranquilizing activity was established in a battery of standard tests described in Psychopharmacology, A Ten Year Review, Public Health Service Publication No. 1836, including overt behavior in mice, rats, dogs and monkeys, blocking fighting response in mice, blocking learning acquisition, etc.
  • EXAMPLE 6 7-( l -Cyclohexylcthyl l .2 dihydro-9-hydroxy-4-oxo- 4H-thienol 2.3-c l ]benzopyran Following a procedure similar to that described in Example 18 hereinabove. methyl 3UXU-2.3.4.5- tetrahydrothiophene-Z-earboxylate is reacted with 5- (l-cyclohexylethyl )resorcinol to give 7-( lcyelohexylethylld.Z-dihydro-9-hydroxy-4-oxo-4H- thieno[2.3-cll l lbenzopyran. an.
  • EXAMPLE 7 Following a procedure similar to that described in Example lB hercinabovc. methyl 3-oxo-2.3.4.5- tetrahydrothiophene-Z-carboxylate is reacted with 5- (2-eicosyl)resorcinol to give l.2-dihydro-7-(Z-eicosyl 9-hydroxy-4-oxo-4H-thieno-l2.3-c][ l lbenzopyran.
  • the material was shown to be pure by thinlayer chromatography (TLC) 1071 MeOH/CHCLi); and the [R and NMR spectra indicated the compound to be 5-(3-methyL2-octyl)-2-(4,5-dihydro-2-(2- propyl)-thien-2-propyl)-theien-3-yl)resorcinol (triol 2.0 g. of the triol was dissolved in benzene and refluxed for 3 hours in the presence ofa small amount of p-toluenesulfonic acid. The benzene solution was concentrated and the residue was chromatographed using Florisil column support. 60-100 mesh. and graded ether/petroleum ether solvent mixtures.
  • EXAMPLE 20 EXAMPLE 2] l,Z-Dihydro-4,4-dimethyl-9-( N-methylcarbamyloxy 7-( 3methyl-2-octyl)-4H-thieno [2,3-e]( l ]benzopyran
  • l,2-dihydro-4,4-dimethyl-9-hydroxy-7- (3-methyl-2-octyl)-4H-thieno [2,3-c][1]benzopyran 17 By reacting l,2-dihydro-4,4-dimethyl-9-hydroxy-7- (3-methyl-2-octyl)-4H-thieno [2,3-c][1]benzopyran 17 with an equimolar amount of phosgene in the presence of dimethylaniline in a procedure similar to that de scribed in Example and reacting the resulting chloroformate with methylamine.
  • EXAMPLE 22 1.2-Dihydro-4,4-dimethyl-9-tN.N dimethylcarban'lyloxy
  • the reaction mixture was decomposed with saturated ammonium chloride; the organic layer was separated and the aqueous layer was extracted twice with ether. The organic layers were combined. washed with water, dried and evapo rated to give a gummy residue.
  • the IR and NMR spectra indicated the compound to be 5-( 3-methyl-2-octyl)- 2-(4.5-dihydro-2-( Z-hyd roxy-Z-propyl )-6H-thiopyran- 3-yl )resorcinol.
  • a compound of the formula l l l O (CH n or acid addition salt thereof, or dialkylaminoalkanoyl of the structure or acid addition salt thereof, wherein .r is 1 through 6 and R and R are loweralkyl; the lowcralkyl groups containing from I through 6 carbon atoms. the alkyl groups containing from i through 20 carbon atoms and the cycloalkyl groups containing from 3 through 8 ring carbon atoms.
  • n is 0 and said compound is of the formula wherein R, is loweralkyl; R is alkyl or cycloalkylloweralkyl and R is hydrogen. loweralkyl. loweralkanoyl. carbamyl. N-loweralkylcarbamyl. N N-diloweralkylcarbamyl. phosphonyl. hemi-succinate. phosphate. dialkylaminoalkyl of the structure or acid addition salt thereof.
  • dialkylaminoalkanoyl of the structure or acid addition salt thereof wherein .r is I through 6 and R and R are loweralkyl; the loweralkyl groups containing from 1 through 6 carbon atoms. the alkyl groups containing from l through 20 carbon atoms and the cycloalkyl groups containing from 3 through 8 ring carbon atoms.
  • R is methyl.
  • R is 3-methyl-2-oetyl and R is diethylaminobutyryl and the compound is 9-[4- (diethylamino )butyryloxy l ,2-dihydro-4.4-dimethyl- 7-(3-methyl-2-octyl)-4H-thieno[2,3-c][ l lbenzopyran.
  • R is loweralkyl'.
  • R is alkyl or cycloalkylloweralkyl and R, is hydrogen. lowcralkyl. loweralkanoyl, carbamyl. N-loweralkylcarbamyl. N.N-diloweralkylcarbamyl. phosphonyl. hemi-succinate. phosphate. dialkylaniintmlkyl of the structure 1 4 -C (CH2) N or acid addition salt thereof. or dialkylaminoalkanoyl of the structure II R -C (CH or acid addition salt thereof.
  • R are lowcralkyl; the loweralkyl groups containing from 1 through 6 carbon atoms. the alkyl groups containing from 1 through carbon atoms and the cycloalkyl groups containing from 3 through 8 ring carbon atoms.
  • R is methyl
  • R is 3-methyl-2-octyl.
  • R, is hydrogen and the compound is l.3-dihydro-4,4-dimethyl-9- hydroxy-7-( 3-methyl-2-octyl )-4H-thieno[ 3,4-
  • R is methyl.
  • R is S-methyl-Z-octyl and R;, is dimethylaminoethyl and the compound is dimethyl-9-(dimethylaminoethoxy)-7(3-methyl-2- octyl )-4H-thienol 3,4-c][ l lbenzopyranv H.
  • m is O.
  • n is 2 and said compound is of the formula wherein R, is loweralkyl; R is alkyl or cycloalkyllowen alkyl and R is hydrogen, loweralkyl, loweralkanoyl. carbamyl. N-loweralkylcarbamyl.
  • n is 0 and the compound is of the formula wherein R, is loweralkyl; R is alkyl or cycloalkylloweralkyl and R,-, is hydrogen. loweralkyl, loweralkanoyl. carbamyl, N-loweralkylcarbamyl. N.N-diloweralkylcarbamyl. phosphonyl. hemi-succinate, phosphate. dialkylaminoalkyl of the structure or acid addition salt thereof. or dialkylaminoalkanoyl of the structure or acid addition salt thereof.
  • x is 1 through E and R, and R are loweralkyl; the loweralkyl group: containing from 1 through 6 carbon atoms. the alky groups containing from I through 20 carbon atoms anc the eyeloalkyl groups containing from 3 through 8 ring carbon atoms.
  • n is l and said compound is of the formula wherein R, is loweralkyl; R, is alkyl or cycloalkyllower alkyl and R is hydrogen, loweralkyl. loweralkanoyl carbamyl. N-loweralkylcarbamyl. N,N-diloweralkylcarbamyl. phosphonyl. hemi-succinate, phosphate. dialkylaminoalkyl of the structure IR4 -C 2 x 5 or acid addition salt thereof, or dialkylaminoalkano of the structure 25 or acid addition salt thereof.
  • R and R are loweralkyl; the loweralkyl groups containing from I through 6 carbon atoms. the alkyl groups containing from I through 20 carbon atoms and the cycloalkyl groups containing from 3 through 8 ring carbon atoms.
  • R is methyl.
  • R is 3-methyl-2-octyl and R is hydrogen and the compound is l.2-dihydro-5.5- dimethyll -hydroxy-8-( 3-methyl-2-octyl )-4H.5H- thiopyrano [3.4-cH l ]benzopyran.
  • dialkylaminoalkanoyl of the structure or acid addition salt thereof wherein .r is I through 6 and R, and R are loweralkyl; the loweralkyl groups containing from I through 6 carbon atoms, the alkyl groups containing from l through carbon atoms and the cycloalkyl groups containing from 3 through 8 ring carbon atoms.
  • dialkylaminoalkyl of the structure -C (CH or acid addition salt thereof, or dialkylaminoalkanoyl of the structure or acid addition salt thereof, wherein x is 1 through 6 and R and R are loweralkyl; the loweralkyl groups containing from 1 through 6 carbon atoms. the alkyl groups containing from I through 20 carbon atoms and the cycloalkyl groups containing from 3 through 8 ring carbon atoms.

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Abstract

Novel thienobenzopyrans and thiopyranobenzopyrans represented by the formula

WHEREIN M AND N ARE EACH 0, 1, 2 OR 3 AND M + N IS 2 OR 3; R1 is loweralkyl; R2 is alkyl or cycloalkylloweralkyl and R3 is hydrogen, loweralkyl, loweralkanoyl, carbamyl, N-loweralkylcarbamyl, N,N-diloweralkylcarbamyl, phosphonyl, hemisuccinate or an ester of another such acid, phosphate, dialkylaminoalkyl of the structure

OR ACID ADDITION SALT THEREOF, OR DIALKYLAMINOALKANOYL OF THE STRUCTURE

OR ACID ADDITION SALT THEREOF, WHEREIN X IS 1 THROUGH 6 AND R4 and R5 are loweralkyl; the loweralkyl groups containing from 1 through 6 carbon atoms, the alkyl groups containing from 1 through 20 carbon atoms and the cycloalkyl groups containing from 3 through 8 ring carbon atoms. Novel intermediates for the synthesis of these compounds are also disclosed as well as methods for making the compounds.

Description

United States Patent 1 Razdan et al.
[ 1 THIENOBENZOPYRANS AND THIOPYRANOBENZOPYRANS [75] Inventors: Raj K. Razdan, Belmont; Harry G.
Pars, Lexington. both of Mass.
[73] Assignee: Arthur D. Little. Inc., Cambridge Mass,
22 Filed: Dec. 20, 1971 2!] Appl. No.:210,l70
Related U.S. Application Data [63] Continuation-impart of Ser. No. 852928. Aug 25.
1969. abandoned.
[52] U.S. Cl ..260/327 TH; 260/294.8 B; 260/326.l2 R; 260/332.2 A: 260/3322 HI 260/3322 R: 260/3323 R; 260/3323 P;
Turner, Screening Mel/rods in Pharmacology (Academic Press. N.Y., l965), pp. 69-86.
Primary Examinerl-lenry R. Jiles Assistant E.\'uminerCMS .laisle Attorney, Agent, or Firm-Bessie A. Lepper [57] ABSTRACT Novel thienobenzopyrans and thiopyranobenzopyrans represented by the formula 1 May 13, 1975 wherein m and n are each 0, l, 2 or 3 and m n is 2 or 3; R, is loweralkyl; R is alkyl or cycloalkylloweralkyl and R is hydrogen, loweralkyl, loweralkanoyl, carbamyl, N-lower-alkylcarbamyl. N,N-dilowerulkylcarbamyl, phosphonyl, hemisuccinate or an ester of another such acid, phosphate, dialkylaminoalkyl of the structure or acid addition salt thereof. or dialkylaminoalkanoyl of the structure or acid addition salt thereof, wherein x is l through 6 and R and R are loweralkyk the loweralkyl groups containing from 1 through 6 carbon atoms, the alkyl groups containing from I through 20 carbon atoms and the cycloalkyl groups containing from 3 through 8 ring carbon atoms. Novel intermediates for the synthesis of these compounds are also disclosed as well as methods for making the compounds.
19 Claims, No Drawings THIENOBENZOPYRANS AND THIOPYRANOBENZOPYRANS CROSS-REFERENCE TO RELATED APPLICATION This application is a continuation-in-art of copending US. Ser. No. 852,928, filed Aug. 25, 1969, now abandoned.
DETAILED DESCRIPTION OF THE INVENTION This application relates to novel thienobenzopyrans and thiopyranobenzopyrans, to intermediates useful in the preparation thereof and to methods of making and using the novel compounds.
The invention sought to be patented, in a first composition aspect, resides in the concept of a class of chemical compounds which includes more particularly those designated as 7-alkyl(and 7-cycloalkylloweralkyl)-9-hydroxy(and 9-O-esters and 9-O-ethers)-4,4- diloweralkyl-l ,2-dihydro-4H-thieno[ 2,3-c] [l] benzopyrans; 7-alkyl (and 7-cycloalkylloweralkyl)-9-hydroxy (and 9-O-esters and 9-O-ethers)-4,4-diloweralkyl-l,3- dihydro-4H-thieno [3,4,-c] [l]benzopyrans; 7-alkyl (and 7-cycloalkylloweralkyl)-9-hydroxy (and 9-0- esters and 9-O-ethers)-4,4-diloweralkyl-2,3-dihydro- 4H-thieno[2,3-c] [l]benzopyrans; 8-alkyl (and 8- cycloalkylloweralkyl)-lO-hydroxy (and lO-O-esters and lO-O-ethers) 5,5-diloweralkyl-l ,2-dihydro-3H,5H- thiopyrano[2,3-c] [l]benzopyrans; 8-alkyl(and 8- cycloalkylloweralkyl)-lO-hydroxy (and lO-O-esters and lO-O-ethers)-5,5diloweralkyl-l ,2-dihydro-4l-I, SH-thiopyrano [3,4-c] [l]benzopyrans; S-alkyKand 8-cycloalkylloweralkyl)-l0-hydroxy (and lO-O-esters and lO-O-ethers)-5,5-diloweralkyl-3,4-dihydro-lH,5H- thiopyrano[3,4-c] [l]benzopyrans; and 8-alkyl (and 8-cycloalkylloweralkyl)-10-hydroxy(and IO-O-esters and lO-O-ethers)-5.5-diloweralkyl-3,4-dihydro-2H,5H- thiopyrano[2,3-c] [l]benzopyrans.
The invention sought to be patented, in a second composition aspect, resides in the concept of a class of chemical compounds which includes more particularly those designated as 7-a|kyl(and 7- cycloalkylloweralkyl l ,Z-dihydro-9-hydroXy-4-oxo- 4H-thieno[2.3-c] [l]benzopyrans; 7-alkyl(and 7- cycloalkylloweralkyl l ,3-dihydro-9-hydroxy-4-oxo- 4H-thieno[3,4-c] [l]benzopyrans; 7-alkyl(and 7- cycloalkylloweralkyl)-2,3-dihydro-9-hydroxy-4-oxo- 4H-thieno[2,3-c] [l]benzopyrans; 8-alkyl(and 8 cycloalkylloweralkyl)-l ,Z-dihydro-l-hydroxy-5-oxo- 3H,5H-thiopyrans[2,3-c] [1] benzopyrans; 8-a1kyl(and 8'cycloalkylloweralkyl )-l ,Z-dihydrol O-hydroxy-S- oxo-4H,5H-thiopyrano[3,4-c] [l]benzopyrans; 8- alkyl(and 8-cycloalkylloweralkyl)-3,4-dihydro-10- hydroxy oxol H,5H-thiopyrano[ 3,4-c] 1]benzopyrans; and 8-alkyl (and S-cycloalkylloweralkyl)-3,4- dihydro--hydroxy-5-oxo-2H,5H-thiopyrano[2,3-c] [1] benzopyrans.
The invention sought to be patented in a second composition aspect, resides in the concept of a class of chemical compounds which includes 5-(alkyl(and 5 cycloalkylloweralkyl)-2-(4,5-dihydro-2-(2-hydroxy-2- propyl)-thien-3-yl)resorcinols; 5-(alkyl(and 5- cycloalkylloweralkyl)-2-(2,5-dihydro-3-(2-hydroxy-2- propyl)-thien-4-yl)resorcinols; 5-(alkyl(and 5- 2 cycloalkylloweralkyl)-2-(4,5-dlhydro-3-(2-hydroxy-2- propyl)-thien-2-yl)resorcinols; 5-alkyl(and 5- cycloalkylloweralkyl)-2-( 4,5-dihydro-2-( 2-hydroxy-2- propylJ6H-thiopyran'S-yl)resorcinols; 5-(alkyl(and 5-cycloalkylloweralkyl)-2-(5,6-dihydro-3-(Z-hydroxy- 2-propyl)-2H-thiopyran-4-yl)resorcinols; 5-(alkyl(and S-cycloalkylloweralkyl)-2-(5,6'dihydro-4-(Z-hydroxy- 2-propyl)-2H-thiopyran-3-yl)resorcinols; and S-(alkyl (and 5-cycloalk'ylloweralkyl)-2-(4,5-dihydro-3-(2- hydroxy-Z-propyl)-6H-thiopyran-2-yl)resorcinols.
The tangible embodiments of the first composition aspect of the invention possess the inherent use characteristics of having biological activity as determined by standard pharmacological test procedures for potential therapeutic drugs. The tangible embodiments of the second and third composition aspects of the invention possess the use characteristics of being intermediates in the preparation of the first composition aspect embodiments.
The invention sought to be patented, in its method aspects, resides in the reaction of the appropriate oxotetrahydrothiophene-carboxylate or oxo-tetrahydrothiopyrano-carboxylate with an appropriately alkyl (or cycloalkylloweralkyl)-substituted resorcinol to form the intermediates required to the preparation of the desired compounds having biological activity.
It is therefore a primary object of this invention to provide novel chemical compositions of matter, novel intermediates for synthesizing them and methods of forming the chemical compositions and their intermediates. It is another object to provide chemical compositions which exhibit CNS properties. Other objects of the invention will in part be obvious and will in part be apparent hereinafter.
The invention accordingly comprises the several steps and the relation of one or more such steps with respect to each of the others and the composition of matter possessing the characteristics, properties and the relation of components which will be exemplified in the composition hereinafter described, and the scope of the invention will be indicated in the claims.
Without limiting the generality of the foregoing, illustrative and preferred embodiments of our 7-alkyl(and 7-cycloalkylloweralkyl)-9 hydroxy(and 9-O-esters and 9-O-ethers)-4,4-diloweralkyl-1,2-dihydro-4H- thieno[2,3-c] l lbenzopyrans; 7-alkylland 7- cycloalkylloweralkyl)-9-hydroxy(and 9-O-esters and 9-O-ethers)-4,4-diloweralkyl-1,3-dihydro-4l-I- thieno[3,4-c] [l]-benzopyrans; 7-alkyl(and 7- cycloalkylloweralkyl)-9-hydroxy (and 9-O-esters and 9-O-ethers)-4,4-diloweralkyl-2,3-dihydro-4H-thieno [2,3-c] [l]benzopyrans; 8-alkyl(and 8-cycloalkylloweralkyl)-lO-hydroxy (and 10-O-esters and lO-O- ethers)-5 ,S-diloweralkyll ,2-dihydro-3H,5 H- thiopyrano[2,3-c] [l]benzopyrans; 8-alkyl(and 8- cycloalkylloweralkyl)- l 0-hydroxy(and IO-O-esters and lO-O-ethers)-5 ,5-diloweralkyll ,2-dihydro-4H,5 H- thiopyrano{3,4-c] lllbenzopyrans; 8-alkyl(and 8- cycloalkylloweralkyl)-lO-hydroxy(and lO-O-esters and 10-O-ethers)-5,5-diloweralkyl-3 ,4-dihydro- 1 H ,5 H- thiopyrano [3,4-c] [l]benzopyrans; and 8-alkyl(and 8-cycloalkylloweralkyl l O-hydroxy(and lO-O-esters and 10-O-ethers)-5,Sdiloweralkyl-3,4-dihydro- 2H,5H-thiopyrano[2,3-c] [l]benzopyrans are represented by formula I R (cs wherein m and n are each 0, l, 2 or 3 and m n is 2 or 3', R is loweralkyl; R is alkyl or cycloalkylloweralkyl and R is hydrogen, loweralkyl, loweralkanoyl, carbamyl, N-loweralkylcarbamyl, N,N-diloweralkylcarbamyl, phosphonyl, hemisuccinate or an ester of another such acid, phosphate, dialkylaminoalkyl of the struc' ture C(CH N or acid addition salt thereof, or dialkylaminoalkanoyl Where m is l and n is l, the compounds are represented by general formula III III Where m is O and n is 2, the compounds are represented by general formula IV Where m is 3 and n is 0, the compounds are represented by general formula V Where m is 2 and n is l, the compounds are repre sented by general formula VI Where m is l and n is 2, the compounds are represented by general formula VII VII Where m is 0 and n is 3, the compounds are represented by general formula VII] In formulas ll-VIII, R R and R have the same meanings as given for formula I.
Where R is dialkylaminoalkyl, the thienobenzopyrans and thiopyranobenxopyrans of this invention may be represented by general formula IX CH R 2 m (cl'l i ll: 4 R
where R; is dialkylaminoalkanoyl, the compounds may be represented by general formula X and the respective acid addition salts of compounds of formulas IX and X may be represented by general formulas XI and XII 4 O-(CH N X \R (c11 s Acid and R R4 2 ll 4 (CH O-C(CH N Acid XII where R, and R, have the meanings given above, x is a whole number from 1 through 6 and R, and R are loweralkyl.
As used herein, the term loweralkyl" means saturated, monovalent aliphatic radicals, including straight and branched chain radicals of from one to six carbon atoms, as illustrated by, but not limited to methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, arnyl, hexyl and the like.
The term alkyl means saturated, monovalent aliphatic radicals, including straight and branched-chain radicals of from one to twenty carbon atoms, as illustrated by, but not limited to methyl, n-amyl, n-hexyl, 2-heptyl, n-heptyl, 3-methyl-2-octyl, n-octyl, 2-nony1, Z-tetradecyl, n-hexadecyl, 2-eicosanyl and the like.
The derivatives of the compounds of formulas I-VIII, where R is loweralkyl, loweralkanoyl, carbamyl, N-loweralkylcarbamyl, N,N-diloweralkylcarbamyl or phosphonyl are prepared by reacting the corresponding compound where R is hydrogen, preferably in the presence of a basic catalyst, with a loweralkyl halide, to produce the compounds where R;, is lower-alkyl; with a loweralkanoic anhydride (or mixed anhydride) to produce the compounds where R is loweralkanoyl; with a molar equivalent of phosgene followed by reaction of the resulting chloroformate with ammonia, a loweralkylamine, or a diloweralkyl amine, to produce the compounds where R, is, respectively, carbamyl, N-loweralkylcarbamyl or N,N-diloweralkylcarbamyl; or with one molar equivalent amount of phosphorus oxychloride followed by reaction of the resulting dichlorophosphinate with aqueous sodium or potassium carbonate, to produce the compounds where R; is phosphonyl. Suitable solvents in these synthesis are benzene, toluene, xylene and the like, and suitable basic catalysts are alkali metal carbonates, bicarbonates or hydroxides, dimethylaniline, pyridine and the like.
Where R is dialkylaminoalkyl the compounds, represented by formula IX, may be formed by reacting the appropriate benzopyran with an alkali alkoxide in a solvent, such as ethanol, to give the alkali derivative, which upon treatment with a dialkylaminoalkyl halide in a solvent, such as benzene, results in the formation of the desired derivatives. The acid addition salts of the dialkylaminoalkyl derivatives (formula XI) may be prepared by reacting the free base with an appropriate acid in a suitable organic solvent, in which case the acid salts may be separated directly or obtained by concentration of the solvent.
Where R is dialkylaminoalkanoyl (formula X), the appropriate benzopyran is reacted with equimolar amounts of carbodiimide and the appropriate acid or acid salt of the amino group to give either the free base or the acid addition salt (formula XII) directly. If the free base form is obtained, then it may be converted to the acid addition salt in the same manner as described for preparing the acid addition salt of the dialkylaminoalkyl derivativev It is well known that it is possible to convert from one acid addition salt to another by regenerating the free base form and acidifying it.
Appropriate acid addition salts are those derived from such diverse acids as formic acid, acetic acid, isobutyric acid, alpha-mercaptopropionic acid, malic acid, fumaric acid, succinic acid, succinamic acid, tartaric acid, citric acid, lactic acid, benzoic acid, 4- methoxybenzoic acid, phthalic acid, anthranilic acid, l-naphthalenecarboxylic acid, cinnamic acid, cyclohexanecarboxylic acid, mandelic acid, tropic acid, crotonic acid, acetylene dicarboxylic acid, sorbic acid,
Z-furancarboxylic acid, cholic acid, pyrenecarboxylic of the reaction. Suitable solvents are diethyl ether, diacid, Z-pyridinecarboxylic acid, 3-indoleacetic acid, butyl ether, tetrahydrofuran, anisole, pyridine and the guinic acid, sulfamic acid, methane sulfonic acid, iselike.
thionic acid, benzenesulfonic acid, p-toluene-sulfonic After workup following the Grignard reaction, most acid, benzenesulfinie acid, butylarsonic acid, diethylof the material is isolated as the trio] of formula XIV. phosphinic acid, p-aminophenylarsinic acid, phenyl- This triol is converted to the desired benzopyran by disstibnic acid, phenylphosphinous acid, methylphossolving it in a suitable solvent, such as benzene, and phinic acid, phenylphosphinic acid, hydrofluoric acid, heating to reflux with an acid catalyst, such as p-tolhydrochloric acid, hydrobromic acid, hydriodic acid, uenesuifonic acid, to give the compound of formula perchloric acid, nitric acid, sulfuric acid, phosphoric l0 XV (cu (C 2 in OH (CH OH (cn l 2 n solvent: acid catalyst R R R XIV xv acid, y r y p ph g acid. m ly The intermediate which is reacted with the Grignard i acid. ph p y acid. py p ph ri acid. reagent ma be formed by reacting a compound generarsenic acid, picric acid, picrolonic acid, barbituric ally defined as acid, boron trifluoride, and the like.
The compounds of formula I are prepared by reacting the corresponding oxo-compound of formula Xlll 3O 2); (CH =0 COOAlkyl XVI wherein m and n are each 0, 1, 2 or 3 and m n is 2 or 3, with a S-alkylresorcinol (or a S-cycloalkyl- 40 loweralkylresorcinol).
Where the intermediate takes the form S xIII O with a loweralkyl magnesium halide as represented by the following reaction XVII S Sq (CH tcn l XIII xIv wherein R and R have the meanings given hereinit is prepared by reacting an alkyl 3-oxo-2,3,4,5- above, and x is a halogen. The Grignard reaction is cartetrahydrothiophene-2-carboxylate of formula XVIII ried out in an organic solvent inert under the conditions with a resorcinol of formula XIX. The reaction is car- 9 10 ried out in the presence of an acid catalyst, such as HCI Where the intermediate compound to be formed is of dissolved in ethanol, and may be represented as the general formula XXII COOAlkyl XVIII XXII H O OH 5 is a synthetic route similar to that used for compounds of formulas XVII and XX may be used. I 5 When the intermediate takes the form R no 2 0 0/ R OH XIX XVII s wherein R and the meaning previously given. 0: l R
Where the intermediate takes the form 5 o 2 XXIII it can be prepared by reacting an alkyl 3-oxo-2,3,4,5- tetrahydr0-6H-thiopyran-2-carboxylate of formula XXIV with a 5-alkylresorcinol of formula XIX under similar conditions described for preparing compounds of formula XVII as illustrated by the reaction it is prepared by reacting an alkyl 4-oxo-2,3,4,5- 5 =0 tetrahydrothiophene-3-carboxylate of formula XXI with a S-alkylresorcinol (or a 5cycloalkylloweralkyl- I resorcinol) of formula XIX. The reaction is carried out COOAlkyl under conditions similar to those used in forming the XXIV compounds of formula XVII by a reaction which may be represented as follows OH H K R COOAlkyl XIX XXI XXIII Where the intermediate takes the form 5/ OH I no R K/ XIX XX XXV it may be prepared from an alkyl 4-oxo-2,3,4,5- tetrahydro-4H-thiopyran'3-carboxylate as described above.
Where the intermediate compounds to be formed are of the general formula XXVI and XXVII and XXVII a synthetic route similar to that used for compounds of formula XXIII may be used.
The intermediates -alkyl or S-cycloalkylloweralkyresorcinols of formula XIX are conveniently prepared by methods generally known in the art, such as by dehydration of a 3,5-diloweralkoxyphenylalkyl (or cycloalkylloweralkyl)carbinol, reduction of the resulting 3,4-diloweralkoxyphenylalkene (or diloweralkoxyphe nylcycloalkylloweralkene), and hydriodic acid cleavage of the ether groups to the corresponding S-alkyl (or S-cycloalkylloweralkyl)resorcinol. The starting carbinols are in turn prepared by reaction of an appropriate Grignard reagent with a 3,5-diloweralkoxybenzoic acid ester, amide or 3,5'-dil0weralkoxyalkanophenone (or 3,5'-diloweralkoxycycoloalkyloweralkanophenone).
The intermediate alkyl 3-oxo-2,3,4,5- tetrahydrothiophene-2-carboxylate of formula XVIII and the intermediate alkyl 4-oxo-2,3-4,5- tetrahydrothiophene-3-carboxylate of formula XXI The Valium-like profile of both mild anti-depressant and marked tranquilizing activity render the compounds particularly useful as anti-anxiety agents. Like valium, the compounds additionally show sedative hypnotic and anti-convulsant activity.
The compounds exhibit activity when administered either by the oral or intraperitoneal routes, however, the oral route is preferred.
The compounds can be prepared for use by dissolving under sterile conditions in water or in a physiologically compatible aqueous medium such as saline, and stored in ampoules for intramuscular injection. A]- ternatively, they can be incorporated in unit dosage form as tablets or capsules for oral administration either alone or in combination with suitable adjuvants such as calcium carbonate, starch, lactose, talc, magnesium stearate, gum acacia and the like. Still further the compounds can be formulated for oral administration in aqueous alcohol, glycol or oil solutions or oil-water emulsions in the same manner as conventional medicinal substances are prepared The molecular structures of the compounds of our invention were assigned on the basis of study of their infrared (IR), ultraviolet (UV) and nuclear magnetic 5 resonance (NMR) spectra and their transformation products, and confirmed by the correspondence of calculated and found values for the elementary analyses for representative examples.
The following examples will further illustrate the invention without, however, limiting it thereto.
EXAMPLE I I,2-Dihydro-9-hydroxy7-( 3-methyl-2-octyl )-4-oxo4H- thieno[2,3-c][ l lbenzopyran may be prepared by the procedure of Woodward and of 80% of the desired l Eastman, J. Amer. Chem. Soc 68, 2229 (1946); and the intermediate alkyl 4-oxo-2,3,4,6-tetrahydro-4H- thiopyran-3-carboxylate by the method ofG.M. Bennet and L.V.D. Scorah, J. Chem. Soc., I94 I927). The intermediate alkyl 3-oxo-2,3,4,5-tetrahydr0-6H thiopyran-Z-carboxylate can be prepared by the procedure of Leonard and Figueras, J. Amer. Chem. Soc. 74, 917 (1952).
The compounds of formula I exhibit CNS activity and are useful as anti-anxiety agents at dosages of from 0.01 to 20 mg./kg. of body weight daily, and can be used in treating anxiety with or without associated psychoneu' rotic depressive symptoms.
The anti-depressant activity of the compounds was first established in mice in the modified dopa test described by Everett et al., Fed. Proc., 23, I98 (1964) and confirmed in dogs and monkeys.
The marked tranquilizing activity was established in a battery of standard tests described in Psychopharmacology, A Ten Year Review, Public Health Service Publication No. 1836, including overt behavior in mice, rats, dogs and monkeys, blocking fighting response in mice, blocking learning acquisition, etc.
COOCI'I .XXVIII and 20% of methyl 4-oxo-2,3,4,5-tetrahydrothiophen- 3-carboxylate COOCH 3 3-oxo-2. 3.4.5-tetrahydrothiophene-Z-carboxylate in 50 ml. of absolute ethanol in a three-necked flask equipped with drying tube was cooled in an ice-water bath and saturated with dry hydrogen chloride. The (3-methyl-2-octyl)resorcinol was prepared according to the method of Adams. MacKenzie and Loewe (J. Amer. Chem. Soc. 70. 664-8 (1948)). The reaction mixture was allowed to stand for three days at room temperature. during which time a heavy yellow solid formed. The hydrogen chloride was evaporated. the mixture was concentrated and the solid was filtered and washed with ethanol. The yield of the crude benzopyrone thus obtained was 2.6 g. (59% m.p. UMP-205C.
Repeated crystallization from absolute ethanol gave an analytical sample. m.p. 2U92lZC. of the compound XXX (IIllCHC H CI-l XXX
Anal. Calcd. for C H O S: C. 69.36; H. 7.51; S. 9.25 Found: C. 6915; H. 7.4l; S. 9.30
EXAMPLE 2 1.2-Dihydro-9-hyd roxy-7-mcthyl-4oxo-4H- thieno[2.3.-c]l l ]benzopyran Following the procedure similar to that described in Example lB hereinabove. methyl 3-oxo-2.3,4.5- tetrahydrothiophene-2-carboxylate is reacted with 5- methylresorcinol to give 1.2-dihydro-9-hydroxy-7- methyl-4-oxo-4H-thieno[ 2.3.-c][ l ]benzopyran.
EXAMPLE 3 Following a procedure similar to that described in Example lB hereinabove, methyl 3-oxo-2.3.4.5- tetrahydrothiophene-2-carboxylate is reacted with 5-(2-heptyl)resorcinol to give 1.2-dihydro-7-(2- heptyl )-9-hydroxy-4-oxo-4H-thieno[ 2 .3-
c][ 1 lbenzopyran.
EXAMPLE 4 7-( 3-Cyclopropyl-2-propyl )-l .2-dihydro-9-hydroxy-4- oxo-4H-thieno[2,3-c][ l lbenzopyran Following a procedure similar to that described in Example lB hercinabove. methyl 3-oxo-2.3,4.5- tetrahydrothiophenc-2-carboxylate is reacted with 5- (3-cyclopropyl-2-propyl)resorcinol to give 7-(3- cyclopropyl-Z-propyl l ,2-dihydro-9-hydroxy-4-oxo- 4H-thieno[ 2.3-c][ l lbenzopyran.
5-( l-pcntyl)resorcinol to give l.Z-dihydro-9-hydroxy- 4-oxo-7-( l-pentyl )-4H-thieno[2.3-cl[ l ]-benzopyran.
EXAMPLE 6 7-( l -Cyclohexylcthyl l .2 dihydro-9-hydroxy-4-oxo- 4H-thienol 2.3-c l ]benzopyran Following a procedure similar to that described in Example 18 hereinabove. methyl 3UXU-2.3.4.5- tetrahydrothiophene-Z-earboxylate is reacted with 5- (l-cyclohexylethyl )resorcinol to give 7-( lcyelohexylethylld.Z-dihydro-9-hydroxy-4-oxo-4H- thieno[2.3-cll l lbenzopyran. an.
EXAMPLE 7 Following a procedure similar to that described in Example lB hercinabovc. methyl 3-oxo-2.3.4.5- tetrahydrothiophene-Z-carboxylate is reacted with 5- (2-eicosyl)resorcinol to give l.2-dihydro-7-(Z-eicosyl 9-hydroxy-4-oxo-4H-thieno-l2.3-c][ l lbenzopyran.
EXAMPLE 8 l.2-Dihydro-4.4-dimethyl-9-hydroxy-7-( 3-methyl-2- octyl )-4H-thieno[2.3-c l lbenzopyran The Grignard reagent was prepared by bubbling bromomethane into a mixture of 7.2 g. (0.3 mole) ol'magnesium turnings in ether. When all the magnesium had reacted. the solution was refluxed for a short time to remove the excess bromomethane. A solution of 9.0 g. (0.026 mole) of l.Z-dihydro-9-hydroxy-7-(3-methyl-2- octyl)-4-oxo-4H-thieno[2.3-c][ l ]benzopyran in 250 ml. of benzene was added to the methylmagnesium bromide and the reaction mixture was kept at 45C for 24 hours. After the addition of saturated ammonium chloride. the benzene/ether layer was separated. and the aqueous layer was extracted with ether. The combined organic layers were washed with water, dried over sodium sulfate and evaporated to give a greenish. gummy residue. The material was shown to be pure by thinlayer chromatography (TLC) 1071 MeOH/CHCLi); and the [R and NMR spectra indicated the compound to be 5-(3-methyL2-octyl)-2-(4,5-dihydro-2-(2- propyl)-thien-2-propyl)-theien-3-yl)resorcinol (triol 2.0 g. of the triol was dissolved in benzene and refluxed for 3 hours in the presence ofa small amount of p-toluenesulfonic acid. The benzene solution was concentrated and the residue was chromatographed using Florisil column support. 60-100 mesh. and graded ether/petroleum ether solvent mixtures. The IR. UV and NMR spectra confirmed the structure cacac a ca 0 l 5 ll xxxI Anal. Calcd. for C HMO S: C. 73.33; H, 8.9 l S. 8.9] Found: C. 73. 10; H. 9.l6; S. 8.75
The gum exhibited M f 320 (loge 3.95l). lR. UV and NMR spectra confirmed the pyran structure.
EXAMPLE 9 l.2-Dihydro-Q-hydroxy-4.4.7-trimethy|-4H-thieno[2.3- c]{ l ]benzopyran Following the procedure similar to that described in Example 8 herein-above. l.2-dihydro-9-hydroxy-7- nicthyl4-oxo-4H-thieno[2.3-c][l]benzopyran is reacted with methylmagnesium bromide to give [.2- dihydro-9-hydroxy-4.4.7-trimethyl-4H-thieno-[2.3- CH 1 ]benzopyran' EXAMPLE l l.2-Dihydro-4,4-dimcthyl-7-( Z-he tyIJ-9-hydrOXy-4H thieno[2.3-c] l ]benzopyran By reacting l,2-dihydro-7-(2-heptyl)-9-hydroxy-4- oxo-4H-thieno{2.3-c] [l]benzopyran with methylmagnesium bromide in a procedure similar to that described hereinabove in Example 8 there is obtained 1,- Z-dihydro-4 4 dimethyl-7-( Z-heptyl )-9hydroxy-4H- thieno[2.3-c] [l]benzopyran.
EXAMPLE ll 7-( 3-Cyclopropyl-2-propyl )-4.4-dimethyll ,Z-dihydro- 9-hydroxy-4H-thienol 2,3-c] [llbenzopyran 7-( 3-cyclopropyl-Z-propyl )-l .2-dihydro-9-hydroxy- 4-oxo-4H-thienoi2,3-cl llbenzopyran is reacted with methylmagnesium bromide in a procedure similar to that described herein-above in Example 8 to give 7-(3- cyclopropyl-Z-propyl )-4.4-dimethyll .2-dihydro-9- hydroxy-4H-thieno [2.3-c] lllbenzopyranr EXAMPLE l2 l.2-Dihydro-4.4-dimethyl-9-hydroxy-7-( l-pentyl )-4H- thieno[ 2,3-c] l )benzopyran l ,2-Dihydro-9-hydroxy-4-oxo-7-( 1-pentyl)-4H- thieno-{2,3-c] [l]benzopyran is reacted with methylmagnesium bromide in a procedure similar to that described hereinabove in Example 8 to give l,2-dihydr0- 4,4-dimethyl-9-hydroxy-7-( l -pentyl)-4H-thieno [2,3- c][ l ]benzopyran.
EXAMPLE l3 7-( l-Cyclohexylethyl )-l ,2-dihydro-4 4-dimethyl-9- hydroxy-4H-thieno [2,3-eH l ]benzopyran 7-( l-Cyclohexylethyl )-l ,2-dihydro-9-hydroxy-4oxo- 4H-thieno [2.3-c][ l ]benzopyran is reacted with methylmagnesium bromide according to the procedure described hcreinabove in Example 8 to give 7-( lcyclohexylethyl )-l 2-dihydro-4.4-dimethyl-9-hydroxy- 4-H-thieno [2.3-c][ l ]benzopyran.
EXAMPLE l4 l 2-Dihydro-4.4-dimethyl-7-( Z-eicosyl )-9-hydroxy4H- thieno[2,3-c}l l ]benzopyran l,2-Dihydro-7-( Z-eicosyl)-9-hydroxy-4-oxo-4H- thieno [2.3-clll1benzopyran is reacted with methylmagnesium bromide according to the procedure described hereinabove in Example 8 to give l,2-dihydro- 4.4-dimethyl-7-(Z-eicosyl)-9-hydroxy-4H-thieno [2.3- c][ l ]benzopyranv EXAMPLE l 4.4-Di( l-hexyU-l ,2-dihydro-9hydroxy-7-methyl4H thieno [2,3-c l ]benzopyran By reacting l,2-dihydro-9-hydroxy-7-methyl-4-oxo- 4H-thieno [2,3-c][l]benzopyran with n-hexyl meg- 16 nesium bromide using the manipulative procedure described in Example 8, there is obtained 4.4-di( l-hexylJ- l,Z-dihydro-9-hydroxy-7-methyl-4H-thieno [2.3- c][ l ]benzopyran,
EXAMPLE [6 7-( 3-Cyclopropyl-2-propyl)-4,4-di( l-hexyl)-l,2-dihydro9-hydroXy-4H-thieno [2 3-c][ l ]benzopyran By reacting 7-( 3-cyclopropyl-2-propyl)-l ,2-dihydro- 9-hydroxy-4-oxo-4H-thieno [2,3-c l ]benzopyran with n-hexylmagnesium bromide using the manipulative procedure described above in Example 8, there is obtained 7-(3-cyclopropyl-2-propyl)-4.4-di(l-hexyl)- l.2-dihydro-9-hydroxy-4H-thieno [2,3- c][ l ]benzopyran.
EXAMPLE l7 By reacting l,2-dihydro-9-hydroxy-7-(3-methyl-2- octyl )-4-oxo-4H-thieno [2.3-c}[ l ]benzopyran with n-hexylmagnesium bromide, using the manipulative procedure described in Example 8, there is obtained 4,4-di( l-hexyl)-l ,2-dihydro-9-hydroxy-7-(3-methyl-2- 0ctyl)-4Hthieno [2,3-c][ l ]benzopyran EXAMPLE l8 9-Acetoxyl .2-dihydro-4,4-dimethyl7-( 3-methyl-2- octyl)-4H-thieno [2,3-c1l 1 ]benzopyran By reacting l,2-dihydro-4,4-dimethyl-9-l1ydroxy-7- (3-methyl-2-octyl)-4H-thieno [2,3-c][1]benzopyran with acetic anhydride, there is obtained 9-acetoxy-l,2- dihydro-4,4-dimethyl7-( 3-methyl-2-octyl )-4H-thieno l2,3-c][ l ]benzopyran.
EXAMPLE l9 l,2-Dihydro-4,4-dimethyl-9-methoxy-7-( 3-methyl-2- octyl-4H-thieno[ 2,3-c][ l ]benzopyran By reacting l,2-dihydro-4,4-dimethyl-9-hydroxy'7- (3-methyl-2-octyl )-4H-thieno [2,3-c]{ l ]benzopyran with methyl iodide in the presence of sodium ethoxide, there is obtained l,2-dihydro-4,4-dimethyl-9-methoxy- 7-( 3-methyl-2-octyl)-4H-thieno [2,3-c][ l ]benzopyran.
EXAMPLE 20 EXAMPLE 2] l,Z-Dihydro-4,4-dimethyl-9-( N-methylcarbamyloxy 7-( 3methyl-2-octyl)-4H-thieno [2,3-e]( l ]benzopyran By reacting l,2-dihydro-4,4-dimethyl-9-hydroxy-7- (3-methyl-2-octyl)-4H-thieno [2,3-c][1]benzopyran 17 with an equimolar amount of phosgene in the presence of dimethylaniline in a procedure similar to that de scribed in Example and reacting the resulting chloroformate with methylamine. there is obtained 1.2- dihydro-4 -l-dimethyl-9-( N-mcthylcarbamyloxy )-7( 3- methyl-Z-octyl)--lH-thieno [2.3-ell l ]benzopyran.
EXAMPLE 22 1.2-Dihydro-4,4-dimethyl-9-tN.N dimethylcarban'lyloxy |-7-( 3-methyl-2-octyl )-4H thieno [2.3 c][ l]benzopyran By reacting l.Z-dihydro-4,4-dimethyl-Q-hydroxyJ- (3-mcthyl-2-octyl)-4Hthieno[2.3-c]l1]benzopyran wtih an equimolar amount of phosgene in the presence of dimethylaniline in a procedure similar to that described above in Example 20 and reacting the resulting chloroformate wtih dimethylaminc. there is obtained l.2-dihydro-4.4-dimethyl-9-( N.N- diemthylearbamyloxy )-7-( 3-methyl-2-octyl )-4H- thieno l2,3c][ l lbenzopyran.
EXAMPLE 23 l.2-Dihydro-4.4-dimethyl-7-( 3-methyl-2-octyl H)- phosphonyloxy-4H-thieno [2.3-c][ lbenzopyran By reacting l.2-dihydro-4.4-dimethyl-9-hydroxy-7- (3-mcthyL2-octyl )-4H-thieno [2.3-c][1]benzopyran with one molar equivalent of phosphorus oxychloride in an inert organic solvent such as toluene. and in the presence of a basic catalyst such as pyridine and react ing the resulting dichlorophosphinate with aqueous potassium carbonate. there is obtained 1.2-dihydro-4A- dimethyl-7-( 3-mcthyl-2-octyl )-9-phosphonyloxy-4-H- thieno [2.3-c][ l lbenzopyran.
EXAMPLE 24 9-( Z-Diethylaminoethoxy l ,2-dihydro-4.4-dimethyl- 7-( 3-methyl-2-octyl )-4H-thieno {2.3-c1l1 ]benzopyran EXAMPLE 25 9-[44 Diethylamino )butyryloxy ]-1 ,2-dihydro-4.4- dimethyl-7-( 3-methyl-2-octyl )-4H-thieno[ 2.3-
c] [l lbenzopyran hydrochloride 0.5 g. (1.39 mmole) of l.2-dihydro-4,4-dimethyl-9- hydroxy-7-( 3-methyl-2-octyl )-4H-thieno[ 2.3 c][ l lbcnzopyran, 0.31 g. (1.50 mmole; Aldrich Chemical Co.) of dicyclohexylcarbodiimide and 0.272 g. 1.39 mmole) of 4-diethylaminobutyric acid hydro chloride (F. F. Blieke, W. B. Wright. Jr., and MR. Zienty. J. Amerv Chem. Soc. 63 2488 1941 were comlll bined in 30 ml. of methylene chloride and stirred at room temperature for 4 hours. The insoluble byproduct of dicyelohexylurea was separated by filtration and the methylene chloride was removed on a rotary evaporator. Attempts to crystallize the material were unsuccessful and 400 mg. (539?) of dark brown residue was obtained. The structure was confirmed by the IR and NMR spectra; and TLC gave R, 0.5 in 5% MeOH/CHCl The acid addition salt may be converted to the free base form by methods well known in the art. and the resulting free base form may then be reacted with another suitable acid to form a different acid addition salt.
EXAMPLE 26 A. Methyl-4-oxo-2.3.4.5-tctrahydrothiophene-3- Carboxylatc The procedure of Woodward and Eastman (J. Amer. Chem. Soc. 68. 2229 1946) was followed for the cyclization of 48 g. (0.25 mole) of methyl 3- (mcthoxycarbonylmethylthio)propionate to give 19.8 g. (507:) of methyl-4-oxo-2.3,4.5- tetrahydrothiophene-3-carboxylate. The IR and NMR spectra indicated the product to be the desired isomer.
B. l.3-Dihydro-9-hydroxy-7-( 3-methyl-2-octyl )4- oxo-4H-thieno [3.4.-c l ]benzopyran A solution ot'20 g. (0.125 mole) of the methyl 4-oxo- 2,3.4.5-tetrahydrothiophene-3-carboxylate prepared in A and 32 g. (0.135 mole) of 5-( 3-methyl-2- octyl)resorcino1 in 200 ml. of absolute ethanol was cooled in an ice-salt bath and saturated with anhydrous hydrogen chloride. The reaction mixture was allowed to stand at room temperature for 72 hours and the solid which formed was removed by filtration. Recrystallization from ethanol gave 16 g. (37%) mp. l65166C. The structure was confirmed by the IR and NMR spec- (I'll.
EXAMPLE 27 1,3-Dihydro-4,4-dimethyl-9-hydroxy-7-( 3-methyl-2- octyl )-4H-thieno [3,4-c][ 1 lbenzopyran A suspension of 6.0 g. (0.017 mole) ofthe pyrone of Example 26. part B. in 150 ml. of benzene was added to a Grignard reagent prepared by adding bromomethane to 8.47 g. (0.36 mole) of magnesium turnings in ml. of ether. The mixture was heated at 45C for 24 hours and then decomposed by the addition of dilute hydrochloric acid. The organic layer was sepa rated. washed with water. dried over sodium sulfate and evaporated to give a gummy residue. This material, as the triol. was dissolved in benzene and refluxed for 3 hours with a few crystals of p-toluencsulfonic acid. The benzene solution was washed, dried and evapo rated to give a dark gum which was chromatographed using Florisil (60-100 mesh) and graded ether/petroleum ether solvent mixtures. 2.6 g. (42%) of colorless gum was obtained. The material was shown to be pure by TLC (207: ether/petroleum ether) and exhibited A,,,,,,' 284 mptflog 4.157). The IR and NMR spectra were in agreement with the proposed structure.
Anal. Calcd. for C H O S: C 73.33; H. 8.91 Found: C. 73.21; H 8.76
EXAMPLE 28 l.2-Dihydrol -hydroxy-8-t 3-methyl-2-octyl )--oxo- 4H.5H-thiop vrano{ 3.4-e][ l )benzopyran A solution of 6.4 g (0.027 mole) of 5-(3methyl-2- octyl)resorcinol of Example 1 and 5.0 g. (0.266 mole) of ethyl 4-oxo2.3.5.o-tetrahydro-4H-thiopyran-3- carboxylate (Bennett and Scorah. J. Chem. Soc.. l94 (1922)) in 35 ml. of absolute ethanol was cooled in an ice bath while it was saturated with hydrogen chloride. The resulting deep red solution was tightly stoppered and allowed to stand at room temperature for l20 hours. After one day yellow crystalline material had collected on the bottom ofthe flask. The reaction mixture was warmed gently on the steam bath for [5 minutes. cooled and poured onto a water-ice mixture. The gumlike material that precipitated was extracted with several portions of chloroform. The chloroform solution was washed with aqueous potassium bicarbonate and with water and dried over sodium sulfate. Evaporation of the solvent left 7.5 g. of a light-colored solid. This material was triturated several times with boiling petroleum ether to remove unreacted keto ester. The residue was recrystallized from an ethyl acetatepetroleum ether mixture to give 6.5 g. (68%) of the compound of formula XXXll. m.p. l53l55C.
XXXII The NMR spectrum of this material was consistent with the assigned structure. From another preparation the analytical sample. m.p. l50-l52C. was obtained after two rccrystallizations from ethyl acetate petroleum ether. It exhibited h 310 mp. (loge 3.996).
Anal. Calcd. for C H O s: C, 70.00; H. 7.78; S. 8.89 Found: C. 69.99; H. 7.99; S, 8.83
EXAMPLE 29 l.2-Dihydro-5,S-dimethyll 0-hydroxy-8-( 3-methyl-2- oetyl)-4H,5H-thiopyrano {3.4-c][ l ]benzopyran A Grignard reagent was prepared in preflamed apparatus under an atmosphere of nitrogen by bubbling bromomethane into a 250 ml. 3-necked, round-bottomed flask containing 2.03 g. (0.0833 mole) of magnesium in 50 ml. of dry ether. When the magnesium had all reacted, l0 ml. of ether was distilled from the reaction mixture to remove excess bromomethane. A solution of 3 g. (0.00733 mole) of the thiopyrone as prepared in Example 28 was suspended in 30 ml. of dry benzene and ml. of dry ether and was added dropwise to the Grignard solution during a period of 45 minutes. The reaction mixture was refluxed for 5 days, cooled and poured slowly into a mixture of 75 ml. of saturated am' monium chloride solution and 50 g. of ice. The benzene layer was separated and the aqueous layer was ex tracted several times with benzene. The combined ex- LII tracts were wascd with water. aqueous potassium biear bonatc solution. again with water. dried over sodium sulfate and then evaporated to give 3.5 g. ofbrown residue. This residue was dissolved in l50 ml. of dry itheptane and when the solution was heated to boiling. four drops of 48% hydrobromic acid was added. After heating for 40 minutes. the solution was allowed to stand overnight and was filtered to remove a small amount of precipitate. Evaporation of the filtrate gave 2.6 g. (84%) of crude thiopyran. One gram of this material. purified in two 0.5 g. batches by heating in a sublimation apparatus at l50C/0.l mm. gave 200 mg. of a yellow viscous oil of the formula XXXlll XXXIII The NMR spectrum of this oil was consistent with the structure of the desired product XXXIll. Thin-layer chromatography (ethyl acetate/hexane, 1:9) showed a major spot (R, 0.80) and a minor spot (R, 0.74). The UV spectrum showed h f 275 mu (loge3.6).
Anal. Caled. for C H O S: C. 73.73; H, 9.15; S, 8.54 Found: C. 73.57; H, 9.l4; S, 8.76
EXAMPLE 30 1.2-Dihydrol0-hydroxy-8-(3-methyl-2-octyl )-5-oxo- 3H.5H-thiopyrano [2,3-c][ l lbenzopyran A. Methyl 3-oxo-2,3,4.S-tetrahydro-6H-thiopyran-2- carboxylate The procedure of Leonard and Figueras (J. Amer. Chem. Soc. 74, 917 (1952)) was followed for the cyclization of 20 g. of carbomethoxymethyl y-carbomethoxypropyl sulfide to give ll.l g. of methyl 3-oxo- 2,3,4,5-tetrahydro-6H-thiopyran-2-carboxylate. The structure was confirmed by IR and NMR spectra.
B. l.Z-Dihydro-l0-hydroxy-8-(3methyl-2-octyl)-5- oxo-3H,5H-thiopyrano [2,3-e][1]benzopyran A solution of l4.2 g. (0.06 mole) of 5-(methyl-2- octyl)resorcinol and l l.l g. (0.063 mole) of methyl 3- oxo-2,3.4,5-tetrahydro-6H-thiopyran-Z-carboxylate in ml. of absolute ethanol was cooled in an ice-salt bath and saturated with anhydrous hydrogen chloride. After standing for 2 days at room temperature. the ethanol was removed on a rotary evaporator. The residue was dissolved in ether. washed with sodium bicarbonate solution and dried over sodium sulfate. Evaporation of the solvent gave 28.0 g. of residue which was chromatographed using Florisil (60-100 mesh) and graded methanol/chloroform solvent mixtures. A total of 10 g. of crude solid was obtained from the l7r methanol/- chloroform fractions. The material was recrystallized twice from ethyl acetate/hexane to give 8.5 g. (40%) colorless crystals, mp 13 l-l 33C. The proposed structure was confirmed by [R and NMR spectra.
EXAMPLE 31 1.2-Dihydro-5 ,S-dimethyll O-hydroxy-S-t 3-methyI-2- octyl )-3H.5H-thiopyrano [2.3-c] 1 lbenzopyran Methylmagnesium bromide was prepared by bubbling bromomethane into a mixture of 7.68 g. (0.32 mole) of magnesium turnings in ether. When all the magnesium had reacted. the solution was refluxed for a short time to remove the excess homomethanc. A solution of 6.96 g. (0.02 mole) of the pyrone (prepared as above) in benzene was added and the reaction mixture was kept at 45C for 24 hours. The reaction mixture was decomposed with saturated ammonium chloride; the organic layer was separated and the aqueous layer was extracted twice with ether. The organic layers were combined. washed with water, dried and evapo rated to give a gummy residue. The IR and NMR spectra indicated the compound to be 5-( 3-methyl-2-octyl)- 2-(4.5-dihydro-2-( Z-hyd roxy-Z-propyl )-6H-thiopyran- 3-yl )resorcinol.
A small quantity of p-tolucnesulfonic acid was added to a benzene solution of the above triol and the mixture was heated at reflux for 1 hours in the presence of nitrogen. The benzene solution was washed with sodium bicarbonate solution, dried over sodium sulfate and evaporated to give a greenish-brown residue.
Chromatography using Florisil (60-100 mesh) and graded ether/petroleum ether solvent mixtures gave 5.2 g. (60%) of a nearly colorless gum. The gum exhibited h f 305 a (loge 4.262) and the IR. NMR and UV spectra confirmed the structure as l 2-dihydro-5.5- dimethyll -hydroxy-8-( 3-methyl-2-octyl )-3H.5 H- thiopyrano [2.3-c][ l ]benzopyran.
Anal. Calcd. for C ,;H O S: C, 73.73; H. 9.15; S, 8.54 Found: C. 73.55; H. 9.12; S, 8.45
We claim:
1. A compound of the formula l l l O (CH n or acid addition salt thereof, or dialkylaminoalkanoyl of the structure or acid addition salt thereof, wherein .r is 1 through 6 and R and R are loweralkyl; the lowcralkyl groups containing from I through 6 carbon atoms. the alkyl groups containing from i through 20 carbon atoms and the cycloalkyl groups containing from 3 through 8 ring carbon atoms.
2. A compound in accordance with claim 1 wherein m is Z. n is 0 and said compound is of the formula wherein R, is loweralkyl; R is alkyl or cycloalkylloweralkyl and R is hydrogen. loweralkyl. loweralkanoyl. carbamyl. N-loweralkylcarbamyl. N N-diloweralkylcarbamyl. phosphonyl. hemi-succinate. phosphate. dialkylaminoalkyl of the structure or acid addition salt thereof. or dialkylaminoalkanoyl of the structure or acid addition salt thereof, wherein .r is I through 6 and R and R are loweralkyl; the loweralkyl groups containing from 1 through 6 carbon atoms. the alkyl groups containing from l through 20 carbon atoms and the cycloalkyl groups containing from 3 through 8 ring carbon atoms.
3. A compound in accordance with a claim 2 wherein R is methyl, R is 3-methyl-2-octyl and R is hydrogen and the compound is l,2-dihydro-4,4-dimethyl-9- hydroxy-7-(S-methyI-Z-octyl)-4H-thieno[2.3-
c][ l lbenzopyran.
4. A compound in accordance with claim 2 wherein R is methyl, R is 3-methyl-2-octyl and R is diethylaminoethyl and the compound is 9-(2- diethylaminoethoxy l .2-dihydro-4,4-dimethyl-7-( 3- methyl-Z-octyl)-4H-thieno[2.3-c][ l Ibcnzopyran.
5. A hydrochloric acid addition salt of the compound of claim 4.
6. A compound in accordance with claim 2 wherein R, is methyl. R is 3-methyl-2-oetyl and R is diethylaminobutyryl and the compound is 9-[4- (diethylamino )butyryloxy l ,2-dihydro-4.4-dimethyl- 7-(3-methyl-2-octyl)-4H-thieno[2,3-c][ l lbenzopyran.
7. The hydrochloric acid addition salt of the compound of claim 6.
8. A compound in accordance with claim I wherein m is l, n is l and said compound is of the formula wherein R, is loweralkyl'. R is alkyl or cycloalkylloweralkyl and R, is hydrogen. lowcralkyl. loweralkanoyl, carbamyl. N-loweralkylcarbamyl. N.N-diloweralkylcarbamyl. phosphonyl. hemi-succinate. phosphate. dialkylaniintmlkyl of the structure 1 4 -C (CH2) N or acid addition salt thereof. or dialkylaminoalkanoyl of the structure II R -C (CH or acid addition salt thereof. wherein is l through 6 and R, and R are lowcralkyl; the loweralkyl groups containing from 1 through 6 carbon atoms. the alkyl groups containing from 1 through carbon atoms and the cycloalkyl groups containing from 3 through 8 ring carbon atoms.
9. A compound in accordance with claim 8 wherein R, is methyl, R is 3-methyl-2-octyl. and R,, is hydrogen and the compound is l.3-dihydro-4,4-dimethyl-9- hydroxy-7-( 3-methyl-2-octyl )-4H-thieno[ 3,4-
c H l ]benzopyran.
10. A compound in accordance with claim 8 wherein R, is methyl. R is S-methyl-Z-octyl and R;, is dimethylaminoethyl and the compound is dimethyl-9-(dimethylaminoethoxy)-7(3-methyl-2- octyl )-4H-thienol 3,4-c][ l lbenzopyranv H. A compound in accordance with claim 1 wherein m is O. n is 2 and said compound is of the formula wherein R, is loweralkyl; R is alkyl or cycloalkyllowen alkyl and R is hydrogen, loweralkyl, loweralkanoyl. carbamyl. N-loweralkylcarbamyl. N.N-diloweralkylcarhamyl. phosphonyl. hemi-succinate. phosphate. dialkylaminoalkyl of the structure IR4 C 2 x or acid addition salt thereof. or dialkylaminoalkanoyl of the structure CH2) N 4 l.3-dihydro-4.4-
12. A compound in accordance with claim 1 wherein m is 3. n is 0 and the compound is of the formula wherein R, is loweralkyl; R is alkyl or cycloalkylloweralkyl and R,-, is hydrogen. loweralkyl, loweralkanoyl. carbamyl, N-loweralkylcarbamyl. N.N-diloweralkylcarbamyl. phosphonyl. hemi-succinate, phosphate. dialkylaminoalkyl of the structure or acid addition salt thereof. or dialkylaminoalkanoyl of the structure or acid addition salt thereof. wherein x is 1 through E and R, and R are loweralkyl; the loweralkyl group: containing from 1 through 6 carbon atoms. the alky groups containing from I through 20 carbon atoms anc the eyeloalkyl groups containing from 3 through 8 ring carbon atoms.
13. A compound in accordance with claim 12 wherein R, is methyl, R is 3-methyl-2-octyl and R is hydrogen and the compound is l.2-dihydro-5.5- dimethyll0-hydroxy-8-( 3-methyl-2-octyl )-3 H.5 H- thiopyrano[2.3-c l ]benzopyran.
14. A compound in accordance with claim 1 whereir m is 2. n is l and said compound is of the formula wherein R, is loweralkyl; R, is alkyl or cycloalkyllower alkyl and R is hydrogen, loweralkyl. loweralkanoyl carbamyl. N-loweralkylcarbamyl. N,N-diloweralkylcarbamyl. phosphonyl. hemi-succinate, phosphate. dialkylaminoalkyl of the structure IR4 -C 2 x 5 or acid addition salt thereof, or dialkylaminoalkano of the structure 25 or acid addition salt thereof. wherein is l through 6 and R and R are loweralkyl; the loweralkyl groups containing from I through 6 carbon atoms. the alkyl groups containing from I through 20 carbon atoms and the cycloalkyl groups containing from 3 through 8 ring carbon atoms.
15. A compound in accordance with claim 14 wherein R, is methyl. R is 3-methyl-2-octyl and R is hydrogen and the compound is l.2-dihydro-5.5- dimethyll -hydroxy-8-( 3-methyl-2-octyl )-4H.5H- thiopyrano [3.4-cH l ]benzopyran.
16. A compound in accordance with claim [4 wherein R, is methyl, R is 3'methyl-2-oetyl and R1, is dimethylaminocthyl and the compound is l,2-dihydro- .S-dimethyll 0-(dimethylaminoethoxy )-8-( 3-methyl- 2-octyl )-4H.5H-thiopyrano[ 3,4-c1l l lbenzopyran.
17. A compound in accordance with claim I wherein m is l. n is 2 and said compound is of the formula wherein R, is loweralkyl; R is alkyl or cycloalkylloweralkyl and R is hydrogen. loweralkyl. loweralkanoyl, carbamyl. N-loweralkylcarbamyl. N,N-diloweralkylearbamyl. phosphonylhemi-suecinate, phosphate, dialkylaminoalkyl of the structure or acid addition salt thereof. or dialkylaminoalkanoyl of the structure or acid addition salt thereof, wherein .r is I through 6 and R, and R are loweralkyl; the loweralkyl groups containing from I through 6 carbon atoms, the alkyl groups containing from l through carbon atoms and the cycloalkyl groups containing from 3 through 8 ring carbon atoms.
18. A compound in accordance with claim I wherein m is 0, n is 3 and said compound is of the formula or acid addition salt thereof. or dialkylaminoalkanoyl of the structure ll 4 C (CH N or acid addition salt thereof. wherein .r is 1 through 6 and R and R are loweralkyl. the loweralkyl groups containing from I through 6 carbon atoms, the alkyl groups containing from I through 20 carbon atoms and the cycloalkyl groups containing from 3 through 8 ring carbon atoms.
19. A compound of the formula wherein m is 1,2 or 3, n is O or I and m +11 is 2 or 3; R, is loweralkyl: R is alkyl or cycloalkylloweralkyl and R is hydrogen. loweralkyl. loweralkanoyl. carbamyl, N-lowcralkylcarbamyl. N,N-diloweralkylcarbamyl, phosphonyl, hemisuccinate. phosphate. dialkylaminoalkyl of the structure -C (CH or acid addition salt thereof, or dialkylaminoalkanoyl of the structure or acid addition salt thereof, wherein x is 1 through 6 and R and R are loweralkyl; the loweralkyl groups containing from 1 through 6 carbon atoms. the alkyl groups containing from I through 20 carbon atoms and the cycloalkyl groups containing from 3 through 8 ring carbon atoms.

Claims (19)

1. A COMPOUND OF THE FORMULA
2. A compound in accordance with claim 1 wherein m is 2, n is 0 and said compound is of the formula
3. A compound in accordance with a claim 2 wherein R1 is methyl, R2 is 3-methyl-2-octyl and R3 is hydrogen and the compound is 1, 2-dihydro-4,4-dimethyl-9-hydroxy-7-(3-methyl-2-octyl)-4H-thieno(2,3 -c)(1)benzopyran.
4. A compound in accordance with claim 2 wherein R1 is methyl, R2 is 3-methyl-2-octyl and R3 is diethylaminoethyl and the compound is 9-(2-diethylaminoethoxy)-1,2-dihydro-4,4-dimethyl-7-(3-methyl-2-octyl)-4H -thieno(2,3-c)(1)benzopyran.
5. A hydrochloric acid addition salt of the coMpound of claim 4.
6. A compound in accordance with claim 2 wherein R1 is methyl, R2 is 3-methyl-2-octyl and R3 is diethylaminobutyryl and the compound is 9-(4-(diethylamino)butyryloxy)-1,2-dihydro-4,4-dimethyl-7-(3-methyl-2-octyl)-4H-thieno(2,3-c)(1)benzopyran.
7. The hydrochloric acid addition salt of the compound of claim 6.
8. A compound in accordance with claim 1 wherein m is 1, n is 1 and said compound is of the formula
9. A compound in accordance with claim 8 wherein R1 is methyl, R2 is 3-methyl-2-octyl, and R3 is hydrogen and the compound is 1, 3-dihydro-4,4-dimethyl-9-hydroxy-7-(3-methyl-2-octyl)-4H-thieno(3,4 -c)(1)benzopyran.
10. A compound in accordance with claim 8 wherein R1 is methyl, R2 is 3-methyl-2-octyl and R3 is dimethylaminoethyl and the compound is 1,3-dihydro-4,4-dimethyl-9-(dimethylaminoethoxy)-7-(3-methyl-2-octyl)-4H -thieno(3,4-c)(1)benzopyran.
11. A compound in accordance with claim 1 wherein m is 0, n is 2 and said compound is of the formula
12. A compound in accordance with claim 1 wherein m is 3, n is 0 and the compound is of the formula
13. A compound in accordance with claim 12 wherein R1 is methyl, R2 is 3-methyl-2-octyl and R3 is hydrogen and the compound is 1, 2-dihydro-5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-3H,5H-thiopyrano(2,3 -c (1)benzopyran. Pg,43
14. A compound in accordance with claim 1 wherein m is 2, n is 1 and said compound is of the formula
15. A compound in accordance with claim 14 wherein R1 is methyl, R2 is 3-methyl-2-octyl and R3 is hydrogen and the compound is 1, 2-dihydro-5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-4H,5H-thiopyrano (3,4-c)(1)benzopyran.
16. A compound in accordance with claim 14 wherein R1 is methyl, R2 is 3-methyl-2-octyl and R3 is dimethylaminoethyl and the compound is 1,2-dihydro-5,5-dimethyl-10-(dimethylaminoethoxy)-8-(3-methyl-2-octyl)-4H,5H-thiopyrano(3,4-c)(1)benzopyran.
17. A compound in accordance with claim 1 wherein m is 1, n is 2 and said compound is of the formula
18. A compound in accordance with claim 1 wherein m is 0, n is 3 and said compound is of the formula
19. A compound of the formula
US210170A 1969-08-25 1971-12-20 Thienobenzopyrans and thiopyranobenzopyrans Expired - Lifetime US3883551A (en)

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US05/550,292 US3987190A (en) 1971-12-20 1975-02-18 Method of treating hypertension with, and compositions useful therein containing, a 4H-thieno[2,3-c][1]benzopyran or a 3H,5H-thiopyrano[2,3-c][1]
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4021451A (en) * 1972-05-16 1977-05-03 American Home Products Corporation Process for preparing polycyclic heterocycles having a pyran ring
US4025640A (en) * 1975-08-26 1977-05-24 American Hoechst Corporation Oxothienobenzoxepin-acetic acids, precursors and derivatives thereof
US4060619A (en) * 1976-01-14 1977-11-29 Ayerst Mckenna And Harrison Ltd. 1,4-Dihydro-4-oxo-benzothiopyrano (4,3-b)pyridine-2-carboxylates and derivatives
US4287192A (en) * 1978-10-02 1981-09-01 Abbott Laboratories Antiglaucoma agents

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3462458A (en) * 1967-04-24 1969-08-19 Dow Chemical Co 3 - (alpha - bromoacyl) - 4 - hydroxycoumarin products and corresponding condensation products
US3467675A (en) * 1965-03-18 1969-09-16 Kefalas As Antidepressant basic derivatives of phthalanes,iso-chromanes and iso-chromenes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3467675A (en) * 1965-03-18 1969-09-16 Kefalas As Antidepressant basic derivatives of phthalanes,iso-chromanes and iso-chromenes
US3462458A (en) * 1967-04-24 1969-08-19 Dow Chemical Co 3 - (alpha - bromoacyl) - 4 - hydroxycoumarin products and corresponding condensation products

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4021451A (en) * 1972-05-16 1977-05-03 American Home Products Corporation Process for preparing polycyclic heterocycles having a pyran ring
US4025640A (en) * 1975-08-26 1977-05-24 American Hoechst Corporation Oxothienobenzoxepin-acetic acids, precursors and derivatives thereof
US4060619A (en) * 1976-01-14 1977-11-29 Ayerst Mckenna And Harrison Ltd. 1,4-Dihydro-4-oxo-benzothiopyrano (4,3-b)pyridine-2-carboxylates and derivatives
US4287192A (en) * 1978-10-02 1981-09-01 Abbott Laboratories Antiglaucoma agents

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