Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
  • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/02—Preparation by ring-closure or hydrogenation
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
  • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
  • C07D213/20—Quaternary compounds thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
  • C07D213/30—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
  • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
  • C07D221/22—Bridged ring systems
  • C07D221/26—Benzomorphans

Definitions

• This invention relates to new benzomorphan derivatives, the processes for preparing the same and their method of treatment as medicinal agents.
• the disclosed class of compounds in this invention has pronounced analgesic activity that is effective in the relief of pain.
• This invention relates to a new group of chemical compounds which are 2,3,5,-trisubstituted-2'-hydroxy- 6,7-benzomorphans and relates further to the non-toxic pharmaceutically acceptable salts thereof. This invention further relates to the novel methods of preparation of the instant 2,3,5,-trisubstituted-2'-hydroxy-6,7- benzomorphans.
• the compounds of this invention can be represented by the following structure:
• R is hydrogen, CN, COR or -CH R wherein R is hydrogen, alkyl (preferably lower alkyl such as methyl, ethyl, propyl, isopropyl, etc.), alkenyl (preferably loweralkenyl such as vinyl, isopropenyl, allyl, methallyl, 3-butenyl, etc.), cycloalkyl (preferably cycloloweralkyl such as cyclopropyl, cyclobutyl, etc.), cycloalkyl alkyl (preferably cycloloweralkyl lower alkyl such as cyclopropylmethyl, cyclopropylethyl, etc.), cycloalkenyl (preferably cyclolowerlakenyl such as l-cyclobutenyl, 2-cyclobutenyl, 3-cyclopentenyl, etc.), cycloalkenylalkyl (preferably cyclolowerlakenyl such as l-cyclobutenyl
• R is alkyl (preferably loweralkyl such as methyl,
• R is alkyl (preferably loweralkyl such as methyl,
• aryl preferably phenyl
• substituted .aryl preferably substituted phenyl, provided the substituent will not react with a lithium reagent such as p-methoxyphenyl.
• R is hydrogen or -CH R wherein R is hydrogen, lower alkyl (such as methyl or ethyl) cycloloweralkyl (such as cyclopropyl) or loweralkenylcycloloweralkyl (such as methylenecyclopropyl); R is lower alkyl (such as methyl or ethyl); and, R is lower alkyl (such as methyl, ethyl, propyl or butyl).
• R is hydrogen, lower alkyl (such as methyl or ethyl) cycloloweralkyl (such as cyclopropyl) or loweralkenylcycloloweralkyl (such as methylenecyclopropyl); R is lower alkyl (such as methyl or ethyl); and, R is lower alkyl (such as methyl, ethyl, propyl or butyl).
• Representative compounds of :this invention are as follows:
• benzomorphan 2-cyclopropylmethyl-3-methyl-5-n-propyl-2- hydroxy-6,7-benzomorphan; 2-methyl-3-ethyl-5-n-propyl-2'-hydroxy-6,7- benzomorphan; 2-methyl-3-ethyl-5-n-butyl-2'-hydroxy-6,7-
• benzomorphan Z-methylenecyclopropylmethyl-S-methyl-S-npropyl-2'-hydroxy-6,7-benzomorphan; 2-cyclopropylmethyl-3-methyl-5-n-butyl-2'-hydroxy-6,7-benzomorphan; 2-methylenecyclopropylmethyb3-methyl-5-n-butyl- 2-hydroxy-6,7-benzomorphan; 3,5-dimethyl-2-(2-methylenecyclopropylmethyl)-2'- hydroxy-6,7-benzomorphan; 3,5-dimethyl-2-(2-methylenecyclopropylmethyl)-2'-hydroxy-6,7-benzomorphan; 2-(3-cyclopenten-1-yl methyl)-2-hydroxy-3,5-
• a further aspect of this invention embraces a method of treatment of the relief of pain by the administration of compounds having the structural formula:
• R is hydrogen, CN, COR, or Cl-l R wherein R is hydrogen, alkyl (preferably lower alkyl such as methyl, ethyl, propyl, isopropyl, etc.), alkenyl (preferably loweralkenyl such as vinyl, isopropenyl, allyl, methallyl, 3-butenyl, etc.), cycloalkyl (preferably cycloloweralkyl such as cyclopropyl, cyclobutyl, etc.), cycloalkyl alkyl (preferably cycloloweralkyl lower alkyl such as cyclopropylmethyl, cyclopropylethyl, etc.), cycloalkenyl (preferably cycloloweralkenyl such as l-cyclobutenyl, 2-cyclobutenyl, 3-cyclopentenyl, etc.), cycloalkenylalkyl (preferably cycloloweralkenyl lower alkyl such as l-cycl
• R5 is alkyl (preferably loweralkyl such as methyl,
• substituted aryl preferably provided the substituent will not react with a lithium reagent such as p-methoxyphe'nyl.
• Included in this invention is the method of treatment of the relief of pain by the administration of compounds of the above structure and their optical isomers.
• the more preferred aspects of this invention embraces a method of treatment of the relief of pain by the administration of compounds having the structural
• the lack of narcotic antagonist activity can be advantageous because of the observation that high antagonist activity has generally been associated with undesirable side effects.
• a further feature of this invention resides in the fact that the compounds of this invention can be produced by synthetic means more conveniently than are members of the morphine familyof naturally occurring alkaloidal analgesics.
• the compounds of this invention are administered orally or subcutaneously, preferably as an aqueous solution of the hydrochloride salt and in the range of about 0.110 mg./kg. to about 18 mgJkg. per day.
• the 2-methyl-3,5-disubstituted-2-hydroxy-6,7- benzomorphan III may also be prepared by sodium borohydride reduction of the 2,4-disubstituted-lmethylpyridium halide IV to the 2,4-disubstituted-lmethyl-l,2,3,6-tetrahydropyridine VI, which is converted to the p-methoxybenzyl chloride quaternary VII.
• the quaternary salt VII is then rearranged with phenyl lithium in the Stephens rearrangement in an invert solvent (such as ether) to give 6-p-rnethoxybenzyl-lmethyl-2 ,4-disubstitute d- 1 ,2,3,6-tetrahydropyridine VIII. This is then cyclized with 48 percent hydrobromic acid to the desired 2-methyl-3,5-disubstituted-2'- hydroxy-6,7-benzomorphan III.
• an invert solvent such as ether
• the preparation of a 3,5-disubstituted-2'-hydroxy- 6,7-benzomorphan II is preferably carried out by acylating the 3,5-disubstituted-2'-hydroxy-2-methyl- 6,7-benzomorphan III at the 2'-position with acetic anhydride, heating the acylated compound at elevated temperature with cyanogen bromide in an organic solvent, preferably a halogenated hydrocarbon such as chloroform, thereby replacing the Z-methyl group with a cyano group and then removing the cyano and acetyl groups by hydrolysis in a dilute acid solution.
• cyanogen bromide in an organic solvent, preferably a halogenated hydrocarbon such as chloroform
• the 2,3,5-trisubstituted-2'-hydroxy-6,7- benzomorphans I of this invention can be prepared by the following process.
• Reduction of these derivatives for instance with lithium aluminum hydride in diethyl ether or tetrahydr
• the desired end products are isolated from their particular reaction solutions or mixtures by methods known in the art.
• the 2,3,5-trisubstituted-2-hydroxy-6,7- benzomorphans of this invention can be used as such or in the form of their non-toxic pharmaceutically acceptable acid-addition salts.
• Suchsalts are prepared from suitable acids (such as inorganic acids as hydrochloric or sulfuric acid or organic acids such as acetic or maleic acid and the like).
• the acid-addition salts are prepared by reacting the appropriate benzomorphan base with approximately one equivalent of the suitable acid in an organic solvent (such as diethyl either or alcohol) or aqueous solution.
• the isomeric forms of 3,5-disubstituted-2-hydroxy- 6,7-benzomorphan II may also be employed in the preparation of compounds of Structure I. These isomeric compounds may be prepared by known methods, using a resolving agent such as carnphor sulfonic acid, tartaric acid, dibenzoyl tartaric acid and the like to form the levo and dextro isomers. Each optical isomer of 3,5-disubstituted-2-hydroxy-6,7- benzomorphan can then be used as the starting material in the various examples resulting in dextro or levo 2,3,5-trisubstituted-2'-hydroxy-6,7- benzomorphans.
• a resolving agent such as carnphor sulfonic acid, tartaric acid, dibenzoyl tartaric acid and the like
• racemic 2,3,5- trisubstituted-Z'-hydroxy-6,7-benzomorphan end products can themselves be resolved according to a procedure similar to that described above to yield the dextrorotatory and levorotatory isomers of 2,3,5-tn'substituted-2-hydroxy-6,7-benzomorphans.
• EXAMPLE 1 EXAMPLE la l,2-Dimethyl-4-n-butylpyridine iodide 4-N-butyl-pyridine To a stirred slurry of 40 g. of sodium arnide in 650 ml. of liquid ammonia is added at a fast drip 93 grams (1 mole) of gamma-picoline. Stirring is continued 20 minutes and then 78.5 g. (1 mole) of l-chloropropane is added at such a rate as to maintain gentle refluxing. The ammonia is allowed to evaporate and the residue treated with 200 ml. of water. The aqueous mixture is extracted three times with 200 ml. of ether.
• EXAMPLE 2 tetrahydropyridines (b.p. l05-118/125 mm.) This is then dissolved in ml. of acetone and treated with 25 grams of p-methoxybenzyl chloride. The solution is allowed to stand, and the crystalline mass which separates is collected by suction filtration and washed with acetone to yield 37.5 g. of 1.4-dimethyl-2-ethyl-1- (p-methoxybenzyD-1,2,3',6-tetrahydropyridinium chloride.
• EXAMPIEA w 1,4-Dimethyl-2-ethyl-6-(p-methoxybenzyl)-1,2,3,6- tetrahydropyridine
• 1,4-dimethyl-2-ethyl-1-(pmethoxybenzyl )-1 ,2,3,6-tetrahydropyridinium chloride is slurried with 400 ml. of ether and 170 ml. of 2.07 N phenyl lithium solution is added under N as rapidly as possible.
• the resulting mixture is stirred for 30 minutes at room temperature and then for 3 hours under reflux.
• the cooled reaction mixture is poured onto ice and the organic layer is separated and extracted twice with 200 ml. portions of percent hydrochloric acid.
• the combined acidic extracts are made basic with ammonia and extracted three times with 200 ml. portions of ether.
• the combined ether extracts are dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield 29 grams of oily product. Distillation of the concentrate gives 24 g. of 1,4-Dimethyl-2-ethyl-6- (p-methoxybenzyl)-1,2,3,6-tetrahydropyridine as a light yellow oil (b.p. 135140/0.06 mm.
• the organic layer is separated and extracted with aqueous hydrochloric acid.
• the acid extract is made basic with aqueous ammonia and extracted twice with 200 ml. portions of ether.
• the combined ethereal extracts are dried over MgSO filtered and concentrated under reduced pressure.
• the concentrate is distilled to yield 19 grams of 1,2-dimethyl-4-nbutyl-6-p-methoxybenzyl- 1 ,2 ,3,6-tetrahydropyridine, b.p l45-153C/0.4 mm.
• benzomorphan the corresponding benzomorphans of Table I or their optical isomers
• Example 8 2,3- dimethyI-S-n-butyI-Z-hydroxy-6,7-benzomorphan (Example 4a) or 2,3-dimethyl-5-n-propyl-2'-hydroxy- 6,7-benzomorphan (Example 4b) there is obtained in place of 3-ethyl-5-methyl-2'-hydroxy-6,7- benzomorphan the corresponding norbenzomorphans or their optical isomers of Table I below.
• EXAMPLE 14 When the procedure of Example 11 is followed but substituting for cyclopropylcarbonyl chloride each of the acid chlorides of Table l, Example 12, with each of the nor-3,5-disubstituted-2'-hydroxy-6,7- benzomorphans or their optical isomers of Table l, Example 10, in place of nor-3-ethyl-5-methyl-2'-hydroxy- 6,7-benzomorphan, then the corresponding 2,3,5- trisubstituted-2-hydroxy-6,7-benzo-morphans or their optical isomers are formed. Some of these are in Table I below.
• the organic solution is dried over magnesium sulfate, filtered and concentrated to dryness and the residue taken up in 50 ml. of ether.
• the ether solution is added dropwise ta stirred slurry of 1.1 g. lithium aluminum hydride in 250 ml. of ether.
• 2.2 ml. of water is added dropwise and the inorganic salts are separated by suction filtration and then thoroughly washed with fresh ether.
• the combined filtrates are concentrated to 100 ml. and extracted twice with 25 ml. of a mixture of 7 ml. concentrated hydrochloric acid dissolved in 143 ml. of water.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (1)

Publications (1)

Family

ID=25160225

Family Applications (1)

Country Status (7)

Cited By (16)

Families Citing this family (4)

Citations (9)

• 1969
  • 1969-01-23 US US793571*A patent/US3700734A/en not_active Expired - Lifetime
  • 1969-12-08 BR BR214877/69A patent/BR6914877D0/pt unknown
• 1970
  • 1970-01-07 NL NL7000166A patent/NL7000166A/xx not_active Application Discontinuation
  • 1970-01-19 GB GB2502/70A patent/GB1261693A/en not_active Expired
  • 1970-01-21 CH CH82970A patent/CH534165A/de not_active IP Right Cessation
  • 1970-01-22 DE DE2002840A patent/DE2002840C3/de not_active Expired
  • 1970-01-22 FR FR7002294A patent/FR2034485B1/fr not_active Expired

Patent Citations (9)

Non-Patent Citations (1)

Also Published As

Similar Documents