WO2002024630A1 - Composes pharmaceutiques utiles comme modulateurs de reponse dependant des endocannabinoides - Google Patents

Composes pharmaceutiques utiles comme modulateurs de reponse dependant des endocannabinoides Download PDF

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WO2002024630A1
WO2002024630A1 PCT/US2001/026016 US0126016W WO0224630A1 WO 2002024630 A1 WO2002024630 A1 WO 2002024630A1 US 0126016 W US0126016 W US 0126016W WO 0224630 A1 WO0224630 A1 WO 0224630A1
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tetrahydronaphthyl
amide
butyryl
compound
alkyl
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PCT/US2001/026016
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George Joseph Cullinan
Christian Chambers Felder
Beth Jennifer Hoffman
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Eli Lilly And Company
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    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
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    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/11—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
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    • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • C07C233/13—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
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    • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • C07C233/15—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
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    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/22—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/29—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/74—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/11—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same saturated acyclic carbon skeleton
    • C07C255/13—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same saturated acyclic carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
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    • C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
    • C07C255/29—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton containing cyano groups and acylated amino groups bound to the carbon skeleton
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
    • C07C69/616—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety polycyclic
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/12—One of the condensed rings being a six-membered aromatic ring the other ring being at least seven-membered

Definitions

  • the present invention relates to the fields of pharmacology, medicine, and medicinal chemistry, and provides compounds of formula I, compositions thereof, and methods of using the same for the treatment of various disorders related to endocannabinoid-mediated responses.
  • the present invention relates to processes for preparing the compounds of formula I and intermediates thereof .
  • Anandamide (arachidonylethanolamide) , an endocannabinoid, is one of the endogenous ligands which activates the receptors involved in the pharmacology- associated with the cannabinoid compounds, e.g., ⁇ 9 - tetrahydrocannabinol (THC) .
  • the pharmacology of the cannabinoids has been well documented and they exhibit both beneficial as well as detrimental activities.
  • beneficial activities are inhibition of pain, lowering of intra-ocular pressure, inhibition of nausea, increase in appetite, suppression of the immune system.
  • detrimental side effects such as, euphoria, hallucinations, lethargy, etc.
  • the highly lipophilic compounds such as THC
  • THC are super agonists, i.e., they act at the their receptors with greater activity than the endogenous or natural ligand.
  • a compound like THC has vastly different pharmacokinetics and metabolic regulation than the endogenous ligand, anandamide.
  • compounds possessing pharmacological profiles more favorably disposed toward the beneficial aspects are highly desired.
  • A is -O- or a direct bond
  • B is C ⁇ -C 8 alkyl , C 2 -C 8 alkenyl or C 4 -C 8 alkenylene ;
  • E is -COOZ , -CONR 1 Z , or
  • R 1 is -H, C ⁇ -C 4 alkyl , or C 2 -C 8 R 2 ;
  • R 2 each time taken, independently, is -H, -halo, -OR 4 ,
  • R 3 is -H, halo, or -OR 4 ;
  • R 4 each time taken, independently, is -H, -COC 1 -C 4 alkyl, or -COAr 1 wherein Ar 1 is phenyl or optionally substituted phenyl;
  • R 5 is -H, -C!-C 4 alkyl, -H, -COC-C ⁇ alkyl, or
  • Ar 2 is phenyl or optionally substituted phenyl ;
  • R 6 is -H, -C1-C 4 alkyl, -COC 1 -C 4 alkyl, or -COAr 3 wherein
  • Ar 3 is phenyl or optionally substituted phenyl; or R 5 taken together with R s and the nitrogen to which they are attached form a 4 to 7 membered ring;
  • G is -H, -OC ⁇ -C 8 alkyl, -OC 2 -C 8 alkenyl , C ⁇ -C 8 alkyl, or
  • the invention provides methods for the modulation of the endocannabinoid receptors with a compound of formula I.
  • the present invention provides methods for the treatment of the pathologic sequelae resulting from the inappropriate regulation or modulation of an endocannabinoid receptors comprising administering to a patient in need thereof an effective amount of a compound of formula I. That is, the present invention provides for the use of a compound of formula I or pharmaceutical composition thereof for treating pathologic sequelae resulting from the inappropriate regulation or modulation of an endocannabinoid receptors . '
  • a preferred endocannabinoid receptor to be modulated by a compound of formula I would be a receptor which has anandamide as its endogenous ligand. More particularly, anandamide receptors would be CB-1, CB-2, and the anandamide transporter.
  • Preferred types of modulation of anandamide receptors would be actions by compound of the current invention which antagonize, agonize, or have an allosteric effect.
  • Particularly preferred pathologic sequelae which can be treated according to the present invention include anxiety, pain, glaucoma, depression, feeding disorders, psychosis, and muscle spasms.
  • the present invention provides for pharmaceutical compositions comprising a compound of the formula I and a pharmaceutically acceptable diluent.
  • Such compositions are useful for treating the pathologic sequelae resulting from the inappropriate regulation or modulation of an endocannabinoid receptors.
  • the present invention provides for the use of a compound of formula I for the manufacture of a medicament for treating the pathologic sequelae resulting from the inappropriate regulation or modulation of an endocannabinoid receptors .
  • the present invention also provides intermediates for preparing the compounds of formula I .
  • These intermediates include the compounds of formula IV:
  • G and n are as described for the compound of formula I ;
  • B' is a C ⁇ -C 8 alkyl, C 2 -C 8 alkylene, or C 3 -C 7 alkenylene;
  • Y is halo, or -COOPg. wherein Pg is either a hydrogen, i.e., a carboxylic acid or a readly removable carboxylic acid protecting group.
  • the present invention also includes intermediates of the formula :
  • A is oxygen
  • G, B' , Y, and n are as described for the compound of formula I;
  • C ⁇ -C 8 alkyl refers to a straight or branched alkyl chain having from one to eight carbon atoms, and includes methyl, ethyl, propyl, iso-propyl, butyl, iso- butyl, sec-butyl, t-butyl, pentyl, hexyl, hetpyl, octyl, and the like.
  • ⁇ C ⁇ -C4 alkyl refers to a straight or branched alkyl chain having from one to four carbon atoms, and includes methyl, ethyl, propyl, iso-propyl, butyl, iso- butyl, sec-butyl, and t-butyl.
  • C 2 -C 8 alkylene refers to a straight or branched alkylene chain having from two to eight carbon atoms, and includes ethylene, propylene, iso-propylene, butylene, iso-butylene, sec-butylene, 1, 1-dimethylmethylene, 1, 1-dimethylethylene, 2, 2-dimethylethylene, pentylenes, hexylenes, hetpylenes, octylenes, and the like.
  • C 2 -C 8 alkenyl refers to a straight or branched alkene chain having from two to eight carbon atoms, and one or more double bonds and includes vinyl, propylene, iso-propylene, butylene, iso-butylene, sec-butylene, 1,1- dimethylmethylene, 1, 1-dimethylethylene, 2,2- dimethylethylene, pentylenes, hexylenes, hetpylenes, octylenes, and the like.
  • C 2 -C 8 R refers to C 2 -C 8 alkyl or branched alkyl, a C 2 -C 8 alkylene or a C 4 -C 8 alkenylene having an R substituent attached at its terminal carbon.
  • halo refers to a chloro, fluoro, bromo or iodo atom.
  • -COC ⁇ -C 4 alkyl refers to a carbonyl linked to a C -Ci alkyl.
  • R a is from 1 to 3 groups independently selected from the group consisting of hydrogen, C ⁇ -C 4 alkyl, C ⁇ -C 4 alkoxy, cyano, nitro, trifluoromethyl, and halogen.
  • C ! -C 4 alkoxy refers to straight or branched alkyl chain having from one to four on atoms attached to an oxygen atom, and includes methoxy, ethoxy, propoxy, iso- propoxy, butoxy, iso-butoxy, sec-butoxy, t-butoxy, and the like.
  • R s taken together with R 6 and the nitrogen to which they are attached form a 4 to 7 membered ring include the following:
  • pharmaceutically-acceptable addition salt refers to an acid addition salt .
  • the compound of formula I form pharmaceutically acceptable acid addition salts with a wide variety of organic and inorganic acids and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this invention.
  • a pharmaceutically-acceptable addition salt is formed from a pharmaceutically-acceptable acid as is well known in the art. Such salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2-19 (1977) which are known to the skilled artisan.
  • Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydriodic, nitric, sulfuric, phosphoric, hypophosphoric, metaphosphoric, pyrophosphoric, and the like.
  • Salts derived from organic acids such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used.
  • Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o- acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, ⁇ -hydroxybutyrate, butyne-1,4- dicarboxylate, hexyne-1, 4-dicarboxylate, caprate, caprylate, cinnamate, citrate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, teraphthalate, propiolate, propionate,
  • R 2 is halo
  • compounds in which R 2 is fluoro are especially preferred.
  • step 1 an appropriate compound of formula II is acylated with an appropriate compound of formula III to give a compound of formula IV.
  • An appropriate compound of formula II is one in which G and n are as desired in the final product of formula I .
  • An appropriate compound of formula III is one in which B' is a C 0 -C 7 alkyl, C 2 -C 8 alkenyl or C 2 -C 7 alkenylene and give or give rise to B as desired in the final product of formula I;
  • X is halo or taken with Y to form an anhydride, e.g., succinic or glutaric, etc.;
  • Y is halo, -CN, or -COOPg, wherein Pg is carboxyl protecting group.
  • protecting groups are well known and appreciated in the art. See for example, Protecting Groups in Organic Synthesis, Theodora Greene (Wiley-Interscience) .
  • the group Y is further elaborated to give E as desired in the final product of formula I.
  • an appropriate compound of formula II is contacted with an appropriate compound of formula III under Friedel-Crafts conditions.
  • the position of attachment can be influenced by other substituents present and the such groups as halogen and amino can be used to direct the position of attachment and removed later in the synthetic pathway by methods such as hydrogenation, substitution, diazitization, and the like.
  • Friedel-Crafts conditions include the use of a Lewis acid, a large variety of which are known in the art, e.g., ZnCl 2/
  • the reaction can be carried out in a variety of inert solvents such as halocarbons, ethers, and the like. Temperatures employed are usually between 0-100°C and the reaction is often complete in 2-24 hours.
  • the product of this step can be isolated and purified by techniques well known in the art, such as filtration, extraction, evaporation, trituration, chromatography, and recrystallization.
  • step 2 a compound of formula IV is reduced to give a compound of formula V.
  • Such reductions can be carried out by a variety of methods. These methods will take into account the substituent in Y.
  • the carbonyl of a compound of formula IV can be reduced by catalytic hydrogenation.
  • a catalyst which allows for the reduction of the carbonyl but does not substantially interfere with other functionality in the compound.
  • Suitable catalysts include those of palladium, platinum, nickel, and the like.
  • the catalyst may be bound to an inert medium, such as carbon.
  • the reaction can be carried out in a variety of inert solvents such as alcohols, acids, ethers, esters and aromatic solvent.
  • the reaction is typically carried at a pressures from atmospheric to about 150 psi. Temperatures employed are usually between ambient temperature and about 100°C.
  • the reaction is often complete in 2-24 hours.
  • the product of this step can be isolated and purified by techniques well known in the art, such as filtration, extraction, evaporation, trituration, chromatography, and recrystallization.
  • the compound of formula IV can be reduced to a hydroxyl followed by further reduction or elimination.
  • Reduction to a hydroxyl can be effected by metal hydrides, such as lithium aluminumhydride, sodium borohydride, and the like'.
  • metal hydrides such as lithium aluminumhydride, sodium borohydride, and the like'.
  • solvents such as, for lithium aluminumhydride, ethers and, for sodium borohydride, alcohols.
  • Temperatures employed are usually between ambient temperature and the refluxing temperature of the solvent. The reaction is often complete in 1-24 hours.
  • the hydroxyl product can be further reduced, either directly or after conversion to a halide.
  • the hydroxyl can be eliminated, either directly or after conversion to an group which is activated to elimination, such as halides or sulfonates ' .
  • the product of this step can be isolated and purified by techniques well known in the art, such as filtration, extraction, evaporation, trituration, chromatography, and recrystallization.
  • compounds of formula V can be prepared directly by Friedel-Crafts alkylation, under standard Friedel-Crafts conditions, using appropriate alkyl halides.
  • Such appropriate alkyl halides include compounds of the formula X-B'-Y as desired in the final product of formula I; X is halo and Y is as defined above.
  • Such alkylations are carried out, as is appreciated in the art, in a manner similar to the acylations described in Scheme 1, step 1, above.
  • Such alkylations give a compound of formula V directly, that is, without reduction of the intermediate acyl compound of formula IV.
  • step 3 a compound of formula V is converted to a compound of formula I .
  • step 3 a protected compound of formula V is modified or deprotected and modified, as needed, to give a compound of formula I.
  • a compound of formula I in which E is -C00Z and -CONR 1 Z are readily prepared from a compound of formula V in which Y is -COOPg by transesterification or by deprotection followed by ester or amide formation. Such ester and amide formation reactions can be carried out utilizing a variety of techniques. ⁇ '
  • suitable ester and amide formation reactions use of active ester leaving groups.
  • active ester leaving groups include but are not limited to anhydrides, mixed anhydrides, acid chlorides, acid bromides, 1-hydroxybenzotriazole esters, 1-hydroxysuccinimide esters, or the activated intermediates formed in the presence of coupling reagents, such as dicyclohexylcarbodiimide, 1- (3-dimethyaminopropyl) - 3-ethylcarbodiimide, and 2-ethoxy-l-ethoxycarbonyl-l, 2- dihydroquinolone .
  • One suitable ester formation involves the use of an acid chloride followed by reaction with an appropriate alcohol, HOZ .
  • An appropriate alcohol, HOZ is one in which Z is as desired in the final product of ormula I .
  • Acid chlorides are formed from acids by the action of thionyl chloride or oxalyl chloride, with or without a small amount of dimethylformamide, in an inert solvent such as, toluene, benzene, methylene chloride, or chloroform; at temperatures of from about 0-80°C.
  • the reaction is typically carried out for a period of time ranging from 1 hour to 24 hours.
  • the acid chloride can be isolated and purified or can often be used directly, that is, with or without isolation.
  • Ester formation is carried out by contacting the acid chloride and an and appropriate alcohol, HOZ.
  • the reaction is carried out in an inert solvent, such as toluene, methylene chloride, or chloroform and in the presence of a base, such as pyridine, triethylamine, N-methylmorpholine; and at temperatures of from about 0-80°C.
  • a base such as pyridine, triethylamine, N-methylmorpholine
  • the reaction is typically carried out for a period of time ranging from 1 hour to 12 hours.
  • the product can be isolated and purified by techniques well known in the art, such as quenching, extraction, evaporation, chromatography, and recrystallization.
  • NHR 1 Z An appropriate amine, NHR 1 Z, is one in which R 1 and Z is as desired in the final product of formula I.
  • the amide formation reaction is carried out using an active ester leaving groups, in an solvent suitable for the selected active ester, such as alcohols, water, toluene, methylene chloride, or chloroform.
  • the reaction is typically carried out in the presence of a base, such as pyridine, triethylamine, N-methylmorpholine, sodium carbonate, sodium bicarbonate, and sodium hydroxide and at temperatures of from about 0-100°C.
  • the reaction is typically carried out for a period of time ranging from 1 hour to 12 hours.
  • the product can be isolated and purified by techniques well known in the art, such as quenching, extraction, evaporation, chromatography, and recrystallization.
  • E is a tetrazole
  • compounds of formula I where E is a tetrazole may be synthesized from the corresponding nitrile by reaction with sodium azide and ammonium chloride at elevated temperature in an inert solvent such as DMF [See: Marshall et al . , J. Med. Chem., 30, (4), pp. 682-689 (1987)].
  • the tetrazoles may be prepared from the same nitriles by reaction with tributyltin azide.
  • the tetrazole intermediates may be converted to the compounds of formula I by alkylation of the tetrazole nitrogen with an appropriate halo-reagent, e.g., the ethylhydroxy analog may be prepared from bromoethanol , etc.
  • N-alkylation of this type are well known in the art and are usually carried out with a bromo, iodo, or chloro reagent in the presence of a base, such as potassium carbonate in an inert solvent such as methylethylketone at refluxing temperature .
  • an acid addition salt is formed using a pharmaceutically-acceptable acid.
  • the formation of acid addition salts is well known and appreciated in the art.
  • step 1 an appropriate compound of formula VI is acylated with an appropriate compound of formula VII to give a compound of formula VIII.
  • An appropriate compound of formula VI is one in which G and n are as desired in the final compound of formula I .
  • An appropriate compound of formula VII is one in which B and Y are as defined above.
  • a compound of formula VI is alkylated with a compound of formula VII to give a compound of formula VIII.
  • Such alkylations of phenolic hydroxyls are well known in the art and may be accomplished by using a organic or inorganic base such as sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, triethylamine, N- ethyldiisopropylamine, and the like.
  • a organic or inorganic base such as sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, triethylamine, N- ethyldiisopropylamine, and the like.
  • Such reactions may be carried out in an inert solvent such as alcohols, ethers, aromatic solvents, and dimethylformamide, dichloromethane and are carried out at temperatures from 0° to 100°C for a time period of 2-48 hours.
  • the product of this step can be isolated and purified by techniques well known in the art, such as filtration, extraction, evaporation, tritur
  • the compound of formula VIII can be modified as described in Scheme 1, step 3, to provide the group E as desired in the final product of formula I .
  • step 3 Once formed the compound of formula I prepared by Scheme 2 it can form an acid addition salt using a pharmaceutically-acceptable acid as described in Scheme 1, optional step 4, he formation of such acid addition salts is well known and appreciated in the art .
  • the title compound was prepared from the reaction of 13.2g (0.1 mole) of 1, 2, 3, 4-tetrahydronaphthalene with 12.4g (0.11 mole) of glutaric anhydride and 26g (0.2 mole) of aluminum chloride. This procedure yielded 11.7g of the title compound as a tan solid.
  • Preparation 5 4- [6- (1,2, 3,4-tetrahydronaphthyl)] butyric acid
  • 25.9g (0.11 mole) of the corresponding keto derivative was converted to the title compound by reduction with hydrogen at 60 psi, at 40°C, for eight hours with 6.5g of 5% Pd/C in a solvent of 500 mL of glacial acetic acid and 12 mL of cone, sulfuric acid. This yielded 13. lg of the title compound as a tan solid.
  • the methyl ester derivative was prepared by reaction of 1, 2 , 3, 4-tetrahydro-6-naphthol 3g (20 mmole) with methyl-5- bromopentanoate 7.7g (40 mmole) and 8.3g (60 mmole) of anhydrous K 2 C0 3 in 100 mL of methylethylketone. The mixture was refluxed for eighteen hours. The reaction was quenched by filtration followed by evaporation of the solvent, in vacuo. The residue was redissolved in EtOAc and extracted twice with brine, filtered through anhydrous Na 2 S0 4 followed by evaporation of the solvent. This yielded the methyl ester intermediate of the title compound.
  • Preparation 8 8- [6-oxy- (1, 2, 3 , 4-tetrahydronaphthyl) ] octanoic acid
  • Preparation 7 2.08g (14 mmole) of 1 , 2 , 3 , 4-tetrahydro-6-naphthol, 3.9g (16.5 mmole) of 8-bromo- methyloctanoate, and 4. lg (30 mmole) of K 2 C0 3 were converted to 3.12g of the methyl ester derivative of the title compound.
  • Example 1 The following Examples were made in a analogous manner as that provided in Example 1.
  • Example 8 [4- [6- (1,2,3,4 -tetrahydronaphthyl ) ] butyryl] amide
  • Example 9 [5- [6- (1, 2, 3, 4-tetrahydronaphthyl) ]pentanoyl] [N-2- fluoroethyl] amide
  • MS: M/e 278 (M+l) ES+
  • Example 21 [5- [6- (1,2, 3, 4-tetrahydronaphthyl)] pentanoyl] [N-3- hydroxypropyl] amide
  • 464mg (2mmole) of 5- [6- (1, 2 , 3 , 4-tetrahydronaphthyl) ] pentanoic acid 575mg (3.0 mmole) of 1- (3 -dimethylaminopropyi) -3- ethylcarbodiimide hydrochloride, and 300mg (4.0 mmole) of 3- hydroxypropylamine, were converted to 70mg of the title compound .
  • Example 23 [4- (5-indanyl) butyryl] [N-2 -hyrdoxyethyl] amide
  • MS: m/e 248 (M+l) ES+ EA: Calc; C 72.84, H 8.56, N 5.66: Found; C 72.65, H 8.54, N 5.67.
  • a solution was prepared with 6.6g (0.05 mole) of 1,2,3,4- tetrahydronaphthalene and 8. lg (0.06 mole) of n-hexanoyl chloride in 250 mL of methylene chloride.
  • the solution was cooled in an ice bath and 8g (0.06 mole) of A1C1 3 was slowly added.
  • the reaction mixture was stirred for sixteen hours, under a nitrogen atmosphere, slowly warming to ambient temperature.
  • the reaction mixture was poured into ice and separated.
  • the organic layer was washed sequentially with IN HC1, IN NaOH, and water.
  • the solution was dried by filtration through anhydrous sodium sulfate and evaporated to dryness. This yielded 8.5g of the title compound as a oily solid.
  • Example 1 The following Examples were made in a analogous manner as that provided in Example 1.
  • reaction was allowed proceed for sixteen hours at ambient temperature under a nitrogen atmosphere.
  • the reaction mixture was poured into ice-water and the organic layer isolated.
  • the organic was washed several times with water and dried with anhydrous sodium sulfate and evaporated to an oily solid. This yielded 6.61g of the title compounds.
  • Example 31 [4- [7- (6-hexyloxy-l, 2, 3, 4-tetrahydronaphthyl) butyryl] [N-2- hydroxyethyl] amide and [4- [5- (6-hexyloxy-l, 2, 3, 4- tetrahydronaphthyl) butyryl] [N-2-hydroxyethyl] mide
  • the title compounds were prepared as a tan oil (1.2g) and a mixture of isomers which were separated in the Examples, below.
  • PMR Consistent with the proposed structures
  • Example 31A [4- [5- (6-hexyloxy-l, 2, 3, 4-tetrahydronaphthyl) butyryl] [N-2- hydroxyethyl] amide
  • PMR Consistent with the proposed structure.
  • Example 3IB [4- [7- (6-hexyloxy-l, 2, 3, 4-tetrahydronaphthyl) butyryl] [N-2- hydroxyethyl] amide
  • PMR Consistent with the proposed structure.
  • Example 32A [4- [7- (6-hexyloxy-l ,2, 3, 4 -tetrahydronaphthyl) butyryl] [N-2- fluoroethyl] amide
  • the material from Example 32 was chromatographed on silica gel eluted with a solvent system of EtOAc-hexane (2:1, v/v) .
  • the highest R f compound isolated was the title compound, yielding 430 mg.
  • PMR Consistent with the proposed structure.
  • Example 32B [4- [7- (6-hexyloxy-l ,2, 3, 4 -tetrahydronaphthyl) butyryl] [N-2- fluoroethyl] amide
  • Preparation 34 4- [6- (1,2,3, 4-tetrahydronaphthyl) ] -2 , 2-dimethylbutyric acid
  • the mixture of isomers (8.73g (35 mmol) ) in Preparation 33 were reduced to the alkyl derivatives. Crystallization of the product from ether-hexane afforded the 2,2-dimethyl isomer. This yielded 4.26g (2 crops) of the title compound.
  • Preparation F 4- (6-1,2,3, 4-tetrahydronaphthyl) -2-methylbutric acid and 4- (6-1, 2, 3 , 4-tetrahydronaphthyl) -3 -methylbutric acid
  • isomeric keto-acids were reduced to the methylene bearing acids .
  • the crude product was chromatographed on silica gel eluted with EtOAc-hexane (1:2) (v/v) . This yielded 890 mg of the title compound as a tan oil and mixture of regio-isomers .
  • Preparation G 4- (6-1,2,3, 4-tetrahydronaphthyl) -2-methylbutric acid chloride and 4- (6-1,2, 3, 4-tetrahydronaphthyl) -3 -methylbutric acid chloride
  • the mixture of acids from Preparation F, supra was dissolved in 25 mL of anhydrous THF and 5 mL of thionyl chloride was added.
  • the reaction mixture was stirred at ambient temperature under an anhydrous atmosphere for several hours.
  • the reaction mixture was evaporated to a tan gum and used without further purification.
  • Example 35 [4- (6-1, 2, 3, 4-tetrahydronaphthyl) -3-methylbutyryl] [N-4- hydroxyphenyl] amide
  • PMR Clearly indicating the proposed structure.
  • Example 36 Clearly indicating the proposed structure.
  • Example 37 [4- [5- [1- (2-hydroxy) ethyl] tetrazoyl] butyloxy] -1,2,3,4- tetrahydronaphthalene 100 mg (0.37 mmol) of the tetrazole from Preparation A was condensed with lOOmg (0.83 mmol) of 2-bromoethanol catalyzed by 200 mg (1.45 mmol) of anhydrous potassium carbonate, in a manner analogous to Example XXI, supra . This yielded 100 mg of the title compound as an oil.
  • PMR Consistent with the proposed structure.
  • the invention provides methods for the modulation of the endocannabinoid receptors with a compound of formula I.
  • the present invention provides methods for the treatment of the pathologic sequelae resulting from the inappropriate regulation or modulation of an endocannabinoid receptors comprising administering to a patient in need thereof an effective amount of a compound of formula I .
  • Particularly preferred pathologic sequelae which can be treated according to the present invention include anxiety, pain, glaucoma, depression, feeding disorders, psychosis, and muscle spasms.
  • endocannabinoid denotes those endogenous biochemicals found in vivo, which are ligands for the receptors which are modulated by the exogenous cannabinoids, such as THC. Some examples of such compounds would be anandamide, 2-arachidonoyl glycerol, palmitoylethanolamine amide, any other fatty acid amides. Other compounds are may be found in the references cited herein.
  • Methods of the current invention are useful for modulating endocannabinoid receptors, the term, "modulate” means to effect a biological activity due to the interaction of a compound of formula I with a receptor which is the endogenous target for the endogenous ligand, an endocannabinoid.
  • Such effects may be either a functional agonistic response, i.e., the positive activation of the receptor, or a functional antagonistic response, i.e., the inactivation of the receptor or blockade of the receptor towards its endogenous ligand.
  • Such effects may be produced by interaction with endocannabinoid transporters.
  • the term "patient” refers to a warm blooded animal such as a mammal which is afflicted with one or more pathologic sequelae resulting from the inappropriate regulation or modulation of an endocannabinoid receptors.
  • I t is understood that guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep, and humans are examples of animals within the scope of the meaning of the term.
  • DSM- IVTM Diagnostic and Statistical Manual of Mental Disorders (1994, American Psychiatric Association, Washington, D.C.) provides a diagnostic tool for some of the disorders to be treated according to the present invention, including anxiety, mood disorders, such as depression, feeding disorders, such as bulimia and anorexia nervosa, and psychosis, such as schizophrenia.
  • DSM- IVTM Diagnostic and Statistical Manual of Mental Disorders (1994, American Psychiatric Association, Washington, D.C.
  • psychosis such as schizophrenia.
  • the skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for the disorders treated according to the present invention, and that these systems evolve with medical scientific progress.
  • the terms "treatment” and “treating” are intended to refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the sequel described herein, but does not necessarily indicate a total elimination of all symptoms, and is intended to include prophylactic treatment of such sequelae.
  • the term "effective amount" of a compound of formula I refers to an amount which is effective in treating pathologic sequelae resulting from the inappropriate regulation or modulation of an endocannabinoid receptors described herein.
  • an effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of conventional techniques and by observing results obtained under analogous circumstances .
  • the dose of a compound of formula I a number of factors are considered by the attending diagnostician, including, but not limited to: the compound of formula I to be administered; the co-administration of an mGlu agonist, if used; the species of mammal; its size, age, and general health; the specific disorder involved; the degree of involvement or the severity of the disorder; the response of the individual patient; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of other concomitant medication; and other relevant circumstances .
  • An effective amount of a compound of formula I is expected to vary from about 0.1 milligram per kilogram of body weight per day (mg/kg/day) to about 100 mg/kg/day. Preferred amounts are able to be determined by one skilled in the art .
  • CB-1 and CB-2 receptors include but are not limited to, CB-1 and CB-2 receptors, fatty acid aminohydrolase (FAAH) , an acid aminohydrolase and an anandamide transporter receptor.
  • FAH fatty acid aminohydrolase
  • anandamide transporter receptor See: DiMarzo et al , Trends Neurosci . , 21, pp.521-528 (1998) and references therein.
  • the CB-1 receptor is widely distributed in the central nervous system with highest concentrations in the hippocampus, striatum, and cerebellum, moderate levels in the cerebral cortex and thalamus, and low levels in the brainstem. [See: Matsuda et al . , Nature, 346, pp. 561-564 (1990); Westlake et al . , Neurosclence, 63, pp. 637-652 (1994); and Glass et al . , Neuroscience, 77, pp. 299-318 (1997) .] The CB-1 receptor is thought to be crucial to the cannabinoid pharmacology involving the central nervous system, especially as it relates to perception [See: Felder CC, et al .
  • the CB-2 receptor has been linked to the immune pharmacology associated with anandamide.
  • Agonism and antagonism of this receptor are known in the literature and methods for determining these properties likewise known [See: Rinaldi-Carmona M., et al . , JPET, 284(2), pp.644-650 (1998) , which is incorporated by reference herein and references cited] .
  • effects of anandamide and other endocannabinoids is noted at other receptors: the vanilloid receptor [Ross et al., FEBS Lett., 436, pp. 449-454 (1998); Melck et al . , BBRC, 262, pp.
  • Agonism, antagonism, or allosteric modulation of the anandamide transporter is also within the scope of the current invention. Methods of demonstration distinguishing between agonism, antagonism, or allosteric modulation are found in: Piomelli D., et al . , PNAS, 96, pp.5802-5807
  • anandamide transporter assays may be performed using mammalian cell lines, brain synaptosomes, primary neuronal and/or glial cultures, brain slices, or in vivo preparations. Such assays have been used to assess potency for inhibiting the uptake of H 3 -anandamide in the rat basophilic cell line, RBL2H3 cells using a physiological buffer solution as described by Beltramo et al . , ibid . , which is included by reference herein.
  • Example B IC 50 ⁇ g
  • the compounds of the present invention can be administered alone or in the form of a pharmaceutical composition, that is, combined with pharmaceutically acceptable carriers or excipients, the proportion and nature of which are determined by the solubility and chemical properties of the compound selected, the chosen route of administration, and standard pharmaceutical practice.
  • the compounds of the present invention while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable salts, for purposes of stability, convenience of crystallization, increased solubility, and the like.
  • the compounds of formula I are usually administered in the form of pharmaceutical compositions, that is, in admixture with pharmaceutically acceptable carriers or diluents, the proportion and nature of which are determined by the chemical properties of the selected compound of formula I, the chosen route of administration, and standard pharmaceutical practice.
  • the present invention provides pharmaceutical compositions comprising a compound of the formula I and a pharmaceutically acceptable diluent.
  • the compounds of formula I can be administered by a variety of routes.
  • a compound of formula I can be administered in any form or mode which makes the compound bioavailable in an effective amount, including oral and parenteral routes.
  • compounds of formula I can be administered orally, by inhalation, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, occularly, topically, sublingually, buccally, and the like.
  • Oral administration is generally preferred for treatment of pathologic sequelae described herein.
  • the pharmaceutical compositions are prepared in a manner well known in the pharmaceutical art.
  • the carrier or excipient may be a solid, semi-solid, or liquid material which can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art .
  • the pharmaceutical composition may be adapted for oral, inhalation, parenteral, or topical use and may be administered to the patient in the form of tablets, capsules, aerosols, inhalants, suppositories, solution, suspensions, or the like.
  • the compounds of the present invention may be administered orally, for example, with an inert diluent or capsules or compressed into tablets.
  • the compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like.
  • These preparations should contain at least 4% of the compound of the present invention, the active ingredient, but may be varied depending upon the particular form and may conveniently be between 4% to about 70% of the weight of the unit.
  • the amount of the compound present in compositions is such that a suitable dosage will be obtained.
  • Preferred compositions and preparations according to the present invention may be determined by a person skilled in the art.
  • the tablets, pills, capsules, troches, and the like may also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; and sweetening agents such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate or orange flavoring.
  • a liquid carrier such as polyethylene glycol or a fatty oil.
  • dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings.
  • tablets or pills may be coated with sugar, shellac, or other coating agents.
  • a syrup may contain, in addition to the present compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
  • the compounds of the present invention may be incorporated into a solution or suspension. These preparations typically contain at least 0.1% of a compound of the invention, but may be varied to be between 0.1 and about 90% of the weight thereof. The amount of the compound of formula I present in such compositions is such that a suitable dosage will be obtained.
  • the solutions or suspensions may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylene diaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • compositions and preparations are able to be determined by one skilled in the art . ..
  • the compounds of the present invention may also be administered topically, and when done so the carrier may suitably comprise a solution, ointment, or gel base.
  • the base may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bees wax, mineral oil, diluents such as water and alcohol, and emulsifiers, and stabilizers.
  • Topical formulations may contain a concentration of the formula I or its pharmaceutical salt from about 0.1 to about 10% w/v (weight per unit volume) .
  • typical pharmaceutical compositions are described below. The examples are illustrative only, and are not intended to limit the scope of the invention in any way.
  • Formulation 1 Gelatin Capsules
  • Hard gelatin capsules are prepared using the following:
  • a tablet formulation is prepared using the ingredients below:
  • the components are blended and compressed to form tablets .
  • Tablets each containing 0.1 - 1000 mg of active ingredient are made up as follows:
  • Polyvinylpyrrolidone 4 (as 10% solution in water)
  • the active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve.
  • the granules so produced are dried at 50°-60° C and passed through a No. 18 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 60 U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets.
  • Suspensions each containing 0.1 - 1000 mg of medicament per 5 ml dose are made as follows: Ingredient Quantity (mg/5 ml)
  • the medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste.
  • the benzoic acid solution, flavor, and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required vol ⁇ me .

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Abstract

L'invention concerne des composés représentés par la formule (I) qui servent à moduler les récepteurs endocannabinoïdes, des compositions pharmaceutiques les contenant, des procédés d'utilisation de ceux-ci, des procédés de préparation des composés représentés par la formule (I) et des produits intermédiaires associés.
PCT/US2001/026016 2000-09-22 2001-09-10 Composes pharmaceutiques utiles comme modulateurs de reponse dependant des endocannabinoides WO2002024630A1 (fr)

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EP1900365A3 (fr) * 2003-02-07 2008-07-23 Research & Innovation Soc. Coop. A R.L. Composés de type endocannabinoïde et leur utilisation

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US7057051B2 (en) 2001-07-20 2006-06-06 Merck & Co., Inc. Substituted imidazoles as cannabinoid receptor modulators
US7572785B2 (en) 2001-07-20 2009-08-11 Merck & Co., Inc. Substituted imidazoles as cannabinoid receptor modulators
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