EP0738144A1 - Hexanamides de phenylmethyle et leur utilisation - Google Patents

Hexanamides de phenylmethyle et leur utilisation

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Publication number
EP0738144A1
EP0738144A1 EP95906035A EP95906035A EP0738144A1 EP 0738144 A1 EP0738144 A1 EP 0738144A1 EP 95906035 A EP95906035 A EP 95906035A EP 95906035 A EP95906035 A EP 95906035A EP 0738144 A1 EP0738144 A1 EP 0738144A1
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EP
European Patent Office
Prior art keywords
hydrogen
methyl
phenyl
compound
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP95906035A
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German (de)
English (en)
Other versions
EP0738144A4 (fr
Inventor
Robert A. Daines
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
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SmithKline Beecham Corp
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Publication date
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Publication of EP0738144A1 publication Critical patent/EP0738144A1/fr
Publication of EP0738144A4 publication Critical patent/EP0738144A4/fr
Withdrawn legal-status Critical Current

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    • 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
    • C07D213/60—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 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/08—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/10—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • This invention relates to phenylmethyl hexanamides and pharmaceutical compositions containing them.
  • this invention relates to the use of phenylmethyl hexanamides as inhibitors of protein kinase C ("PKC").
  • PKC protein kinase C
  • this invention relates to the treatment of PKC mediated disease states, including, but not limited to, chronic inflammatory and proliferative diseases such as psoriasis, neurological disorders and cancer, all in mammals, preferably humans, with the phenylmethyl hexanamides of this invention.
  • PKC PKC
  • kinases that catalyze the transfer of a phosphate group from ATP to a substrate.
  • PKC catalyzes phosphorylation of the amino acids serine and threonine.
  • PKC is found in all tissue types and is believed to play a major role in cellular regulation, neurotransmission, tumor promotion, signal transduction, and cellular proliferation.
  • Physiological activity of the enzyme is regulated by Ca 2+ , diacylglycerol ("DAG”), and phosphotidylserine ("PS"). These modulators interact with the regulatory domain of the enzyme while substrate and ATP binding occur at the catalytic domain.
  • DAG diacylglycerol
  • PS phosphotidylserine
  • Activators of the enzyme such as phorbol esters, are known to cause intense inflammation and tumor promotion.
  • compounds that are able to regulate the enzyme would be expected to be useful therapeutic agents for the treatment of chronic inflammatory and proliferative diseases, including, but not limited to, psoriasis, neurological disorders and cancer.
  • An inhibitor ⁇ f PKC would be expected to serve as such a regulating agent.
  • the present invention is to compounds of formula (I) or formula (II) or pharmaceutically acceptable salts thereof:
  • Rl is hydrogen, lower alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;
  • R- is hydrogen or lower alkyl
  • R3 is hydrogen, C ⁇ CR 6 or -(CH2) R 6 .
  • R and R ⁇ independently from one another, are hydrogen or lower alkyl; or R ⁇ and R5, together with the nitrogen to which they are bound, form a saturated or unsaturated 5-, 6-, or 7-membered ring;
  • R 6 is aryl, -CO 2 R 7 , -NHC(O)R7, -NR7R8, or -C(O)NR7R 8 ;
  • R7 and R ⁇ independently from one another, are hydrogen, or alkyl, provided that when R 6 is -CO2R 7 .
  • R 7 is not hydrogen;
  • E is CH-R 9 , wherein R 9 is hydrogen, alkoxy, -OH or -NR ⁇ R 1 1 ;
  • RlO and R* * independently from one another, are hydrogen or lower alkyl, or wherein RlO and R ⁇ , together with the nitrogen to which they are bound, form a saturated or unsaturated 5-, 6-, or 7-membered ring;
  • X is CH or N
  • Y is -CH 2 , -O, -S, -N or C(O)NR 12 R 13 , wherein R 12 and R 13 are, independently from one another, hydrogen or alkyl, and further wherein Y is positioned on the central aromatic ring either ortho, meta or para relative to the amide containing side chain;
  • Z is -CH2, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl; k is an integer between 0 and 10; m is an integer between 0 and 10, provided that m is 0 only when Z is optionally substituted aryl or optionally substituted heteroaryl, and further, provided that when m is 0 and Z is optionally substituted aryl or optionally substituted heteroaryl, R ⁇ and R ⁇ are not hydrogen or lower alkyl; n is an integer between 6 and 20; and p is an integer between 0 and 1.
  • the present invention is to pharmaceutical compositions comprising a compound of formula (I) or formula (II), and a pharmaceutically acceptable carrier therefor.
  • the present invention is to a method of treating PKC mediated disease states, including, but not limited to, chronic inflammatory and proliferative diseases such as psoriasis, neurological disorders and cancer, all in mammals, preferably humans, comprising administering to such mammal in need thereof, an effective amount of a compound of formula (I) or formula (II), or pharmaceutically active salts thereof.
  • the present invention is in a method of inhibiting PKC in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof.
  • PKC inhibitors It has also now been discovered that selective inhibition of PKC mediated mechanisms by treatment with a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, represents a novel therapeutic and preventative approach to the treatment of a variety of disease states, including, but not limited to, chronic inflammatory and proliferative diseases such as psoriasis, neurological disorders and cancer, all in mammals, preferably humans.
  • lower alkyl is used herein at all occurrences to mean a straight or branched chain radical of 1 to 6 carbon atoms, unless the chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
  • alkyl is used herein at all occurrences to mean a straight or branched chain radical of 7 to 20 carbon atoms, unless the chain length is limited thereto, including, but not limited to heptyl, octyl, nonyl, decyl, dodecyl, and the like.
  • alkoxy is used herein at all occurrences to mean a straight or branched chain radical of 1 to 6 carbon atoms, unless the chain length is limited thereto, bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.
  • aryl or “heteroaryl” are used herein at all occurrences to mean 5- ⁇ 4- membered optionally substituted aromatic ring(s) or ring systems which may include bi- or tri-cyclic systems and, wherein one or more of the rings or ring systems may include one or more heteroatoms, which heteroatoms are selected from oxygen, nitrogen or sulfur.
  • Representative examples include, but are not limited to, phenyl, naphthyl, pyridyl, quinolinyl, thiazinyl, furanyl, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, benzimidazole, and the like.
  • halogen is used herein at all occurrences to mean chloro, fluoro, iodo and bromo.
  • 5-, 6-, or 7-membered ring is used at all occurrences to mean that substituents R ⁇ and R ⁇ and substituents R 7 and R%, together with the nitrogen to which they are bound, form a saturated or unsaturated cyclic ring structure optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur, including, but not limited to, morpholine, piperizine, piperidine, pyrrolidine, pyridine, and the like.
  • arylalkyl and “heteroarylalkyl” are used herein at all occurrences to mean an aryl or heteroaryl moiety, respectively as defined above, that is connected to a Cj_6 alkyl moiety as defined above, such as a benzyl group.
  • optionally substituted is used herein at all occurrences to mean that the moieties may or may not be substituted with, from one to three functional groups, including, but not limited to, alkyl, alkoxy, halogen, trifluoromethyl, nitro, cyano, amino, amido, hydroxy, aryl, heteroaryl, arylalkyl, and heteroarylalkyl.
  • optionally substituted aryl or “optionally substituted arylalkyl” are used herein at all occurrences to mean an aryl ring (or the aryl ring of an arylalkyl moiety as defined above) which is optionally substituted with alkyl, alkoxy, halogen, trifluoromethyl, nitro, cyano, amino, amido, hydroxy, aryl, heteroaryl, arylalkyl, and heteroarylalkyl, preferably alkoxy, halo or trifluoromethyl, more preferably methoxy, ethoxy, chloro, fluoro or trifluoromethyl.
  • optionally substituted heteroaryl or “optionally substituted heteroarylalkyl” is used herein at all occurrences to mean a heteroaryl ring (or the heteroaryl ring of a heteroarylalkyl moiety as defined above) which is optionally substituted with alkyl, alkoxy, halogen, trifluoromethyl, nitro, cyano, amino, amido, or hydroxy.
  • central aromatic ring is used herein at all occurrences to mean the aromatic ring of formula (I) or formula (II) which contains variable X.
  • salts include, but are not limited to, salts with organic acids such as hydrochloric, sulfate, phosphate, diphosphate, hydrobromide, and nitrate or salts with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methansulfonate, p- toluensulfonate or palmitate, salicylate and stearate.
  • organic acids such as hydrochloric, sulfate, phosphate, diphosphate, hydrobromide, and nitrate
  • salts with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methansulfonate, p- toluensulfonate or palmitate, salicylate and stearate.
  • Rl is suitably hydrogen, lower alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl.
  • Rl is preferably hydrogen, lower alkyl or unsubstituted aryl, more preferably, hydrogen, methyl, ethyl or phenyl, most preferably hydrogen, methyl or ethyl.
  • R 2 is suitably hydrogen or lower alkyl.
  • R 2 is hydrogen, methyl or ethyl. More preferably, R 2 is hydrogen or methyl.
  • R 3 is suitably hydrogen, C ⁇ CR ⁇ or -(CH2) ⁇ -
  • R 3 is hydrogen or -(CH2)kR .
  • R 3 is -(CH2)kR ⁇ k is preferably an integer from 0 to 5, more preferably, an integer from 0 to 3 and R 6 is preferably -NR 7 R 8 or -CO2R 7 .
  • R 6 is NR 7 R 8
  • R7 and R 8 are preferably hydrogen, or lower alkyl, more preferably hydrogen, methyl or ethyl, most preferably hydrogen.
  • R 7 is preferably lower alkyl, most preferably methyl.
  • R 3 is C ⁇ CR ⁇ R6 is aryl, preferably phenyl.
  • R4 and R ⁇ independently from one another, are suitably, hydrogen or lower alkyl; or R4 and R ⁇ , together with the nitrogen to which they are bound, form a saturated or unsaturated 5-, 6-, or 7-membered ring.
  • R ⁇ and R ⁇ independently from one another are hydrogen, methyl or ethyl.
  • the ring is preferably a piperazine ring or a morpholine ring.
  • R 6 is suitably aryl, -CO 2 R 7 , -NHC(O)R 7 , -NR 7 R 8 , or -C(O)NR 7 R 8 .
  • R 6 is -NR 7 R 8 or -CO2R 7 .
  • R 7 and R 8 independently from one another, are suitably hydrogen, or alkyl, provided that when R 6 is -CO2R 7 , R 7 is not hydrogen.
  • R 6 is -NR 7 R 8
  • R 7 and R 8 independently from one another are, preferably hydrogen or lower alkyl, more preferably, hydrogen or methyl, most preferably, R 7 and R 8 are each hydrogen.
  • R6 is -CO2R 7
  • R 7 is preferably lower alkyl, more preferably C] to C3 alkyl, most preferably methyl.
  • E is suitably CH-R 9 , wherein R 9 is hydrogen, alkoxy, -OH or -NR ⁇ R 1 1 . It will be clear to the skilled artisan that for a compound of formula (II), R 9 can not be -OH or -NRIORI 1 because the compounds are potentially unstable.
  • RIO and R 1 independently from one another, are hydrogen or lower alkyl, or wherein R 0 and R* , together with the nitrogen to which they are bound, form a saturated or unsaturated 5-, 6-, or 7-membered ring.
  • E is CH-R 9 , wherein R 9 is hydrogen or -NR ⁇ R 1 1, more preferably, R 9 is hydrogen.
  • R 9 is -NR ⁇ ORI ⁇ , preferably, R*0 and R ⁇ , independently from one another, are hydrogen, methyl or ethyl, most preferably R 1 ⁇ and R 1 1 are each hydrogen.
  • X is suitably CH or N. X is preferably CH.
  • Y is suitably -CH2, -O, -S, -N or -C(O)NR 12 R 13 , wherein R 12 and R 13 are, independently from one another, hydrogen or alkyl, and further wherein Y is positioned on the central aromatic ring either ortho, meta or para relative to the amide containing side chain.
  • Y is preferably -CH2, -O or -C(O)NR 12 R 13 , more preferably -CH2 or -O, most preferably -O.
  • Amide containing side chain refers to either the C(O)-N(R 2 )-CH2- moiety of formula (I) or to the -N(R 2 )-C(O)- moiety of formula (II).
  • Z is suitably -CH2, optionally substituted aryl, optionally substimted arylalkyl, optionally substimted heteroaryl or optionally substimted heteroarylalkyl.
  • Z is CH2 or optionally substimted aryl, more preferably, CH2 or unsubstituted aryl, most preferably CH2 or phenyl.
  • k is suitably an integer between 0 and 10; preferably k is an integer from 1 to 5.
  • n is an integer between 6 and 20; preferably n is an integer from 8 to 12.
  • p is an integer between 0 and 1.
  • a preferred embodiment of this invention is to a compound of formula (I) or formula (II), wherein: X is CH or N, more preferably, X is CH; Z is -CH2, or optionally substituted aryl; R 1 is hydrogen, lower alkyl or unsubstituted aryl, more preferably, R 1 is hydrogen or lower alkyl, most preferably, R 1 is hydrogen, methyl or ethyl; R 2 is hydrogen or unbranched lower alkyl, more preferably, R 2 is hydrogen, methyl or ethyl; R 3 is hydrogen or -(CH2)kR ⁇ .
  • R 4 and R ⁇ independently, from one another, are hydrogen, lower alkyl or R ⁇ and R ⁇ , together with the nitrogen to which they are bound, form a saturated or unsaturated 5-, 6- or 7-membered ring, more preferably, R 4 and R ⁇ , independently, from one another, are hydrogen, lower alkyl or R 4 and R ⁇ , together with the nitrogen to which they are bound, form a saturated six-membered ring, most preferably, R 4 and R ⁇ , independently, from one another, are hydrogen or lower alkyl; R ⁇ is -NR R 8 or -CO2R 7 , wherein R 7 and R 8 are, independently from one another, hydrogen or alkyl, provided that when R > is -CO2R 7 , R 7 is not hydrogen; more preferably, R 6 is NH 2 or CO2CH3.
  • R 7 and R 8 are most preferably hydrogen.
  • R 3 is -(CH2)kR 6 and R 6 is -NR 7 R 8
  • R 7 is preferably lower alkyl, more preferably methyl or ethyl, most preferably methyl.
  • E is CH-R 9 , wherein R 9 is hydrogen or -NR *0R * , wherein R 0 and R * , independently from one another, are hydrogen or lower alkyl, or wherein R ⁇ and R *, together with the nitrogen to which they are bound, form a saturated or unsaturated 5-, 6-, or 7-membered ring, more preferably, E is CH-R 9 , wherein R 9 is hydrogen or -NR ⁇ R ⁇ , wherein R 0 and Rl 1, independently from one another, are hydrogen, most preferably, E is CH-R 9 , wherein R 9 is hydrogen; k is an integer between 0 and 10; more preferably, k
  • the present compounds of formulae (I) and (II) can be prepared by art-recognized procedures from known or commercially available starting materials. Several different synthetic schemes can be used to prepare the compounds of this invention and are described in greater detail below.
  • an optionally substimted hydroxybenzaldehyde such as ortho salicylaldehyde, meta salicylaldehyde or 5-nitro salicylaldehyde all commercially available from Aldrich®, Milwaukee, WI
  • an appropriate commercially available or conventionally prepared alkylating agent such as 1-iodododecane, phenyloctylbromide, hexadecyliodide
  • an aprotic solvent such as dimethylformamide ["DMF”], dimethyl sulfoxide ["DMSO”] or acetone
  • the alkylating agent is chosen appropriately, depending upon the chain length desired for the substiment on the central aromatic ring.
  • Conversion of the aldehyde moiety on the intermediate prepared according to step (A) above to an N-alkyl amino moiety is accomplished by dissolving the intermediate in an appropriate solvent (such as methanol, ethanol or methylene chloride) and treating the solution with methylamine hydrochloride, sodium cyanoborohydride and sodium acetate at room temperamre, followed by work up with concentrated acid (such as HC1) and then basification with strong base (such as NaOH); and, if desired, subsequent purification.
  • an appropriate solvent such as methanol, ethanol or methylene chloride
  • step (B) Conversion of the amino intermediate prepared according to step (B) above to a protected amide of formula (I), is accomplished by adding to the amine, which is dissolved in an aprotic solvent (such as methylene chloride), a suitable base (such as 4- methylmorpholine or triethylamine); and a suitable activated ester or a suitable acid chloride or a suitable carboxylic acid which acid is in the presence of a peptide coupling reagent [such as N ⁇ , N ⁇ -di-tert-butoxycarbonyl-L-lysine N-hydroxysuccinimide ester or (tert- butoxycarbonyl)- ⁇ -aminocaproic acid; suitable peptide coupling reagents for use with the carboxylic acid are l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (“EDC”) or dicyclohexylcarbodiimide (“DCC”)], followed by addition of 1-hydroxy
  • step (C) The amide intermediate prepared according to step (C) is deprotected using standard procedures such as treatment with an acid (such as trifluoroacetic acid (“TFA”) or HC1) in an aprotic solvent (such as methylene chloride or dioxane).
  • a suitable base such as N,N-dimethylethylenediamine
  • D) The amide intermediate prepared according to step (C) is deprotected using standard procedures such as treatment with an acid (such as trifluoroacetic acid (“TFA”) or HC1) in an aprotic solvent (such as methylene chloride or dioxane).
  • TFA trifluoroacetic acid
  • aprotic solvent such as methylene chloride or dioxane
  • step (B) To prepare a compound of formula (I), wherein R 4 and R ⁇ , together with the nitrogen to which they are bound form a 6-membered morpholino ring, the above steps (A) and (B) are performed. Conversion of the amino intermediate prepared according to step (B) to an amide such as is depicted by 12-Scheme 3. is accomplished by acylating the amino group with a suitable acid halide (such as 6-bromo-hexanoyl chloride or octanoyl chloride) in an aprotic solvent (such as methylene chloride) at room temperamre or below.
  • a suitable acid halide such as 6-bromo-hexanoyl chloride or octanoyl chloride
  • aprotic solvent such as methylene chloride
  • step (E) Alkylation of the intermediate prepared according to step (E) is performed by adding a heterocyclic amine (such as morpholine, or a protected piperazine or a suitable tertiary amine such as trimethylamine) to a solution of the intermediate in an aprotic solvent (such as DMF or DMSO) in an inert atmosphere (such as argon). Standard work up and purification, if desired, follows.
  • a heterocyclic amine such as morpholine, or a protected piperazine or a suitable tertiary amine such as trimethylamine
  • an aprotic solvent such as DMF or DMSO
  • an inert atmosphere such as argon
  • step (B) and (C) are performed on a nitro hydroxybenzaldehyde (such as 5-nitro salicylaldehyde).
  • a nitro hydroxybenzaldehyde such as 5-nitro salicylaldehyde.
  • the protected nitro intermediate thus formed is reduced to the amino intermediate (see Scheme 5) using standard reduction conditions (such as palladium on carbon, in an H2 atmosphere).
  • standard reduction conditions such as palladium on carbon, in an H2 atmosphere.
  • the above ..mine-containing compound is deprotected according to step (D) discussed above.
  • step (H) To prepare compounds of formula (I), wherein R 3 is -NHC(O)R 7 , and R 7 is alkyl, the amino compound prepared according to step (H) is prepared and then acylated according to step (E), with subsequent deprotection according to step (D).
  • step (A) is performed on a hydroxypyridino compound such as 3-hydroxy-2- (hydroxymethyl)pyridine (Aldrich).
  • a suitable oxidizing agent such as manganese dioxide or pyridinium chlorochromate
  • an aprotic solvent such as methylene chloride
  • This intermediate is dissolved in a protic solvent (such as methanol or ethanol) and treated with an excess of base (such as potassium carbonate), after which the mixmre is poured into aqueous ammonium chloride and the desired Boc- protected hydroxyamide is extracted with an aprotic solvent (such as methylene chloride or ethyl acetate).
  • a protic solvent such as methanol or ethanol
  • base such as potassium carbonate
  • alkylation step (A) is performed as discussed above.
  • the aldehyde moiety of the intermediate prepared according to step (M) may be converted to a vinyl ester by dissolving it in an aprotic solvent (such as toluene) and treating it with methyl(triphenylphosphoranylidene)acetate and heated (to reflux, preferably, 50°C).
  • the vinyl ester is reduced according to step (H) above and deprotected according to step (D) above.
  • step (C) To prepare a compound of formula (II), wherein R 3 is -(CH2)kR 6 , wherein R6 is NR 7 R 8 , the method according to step (C) is performed by converting an acid (such as 5-iodosalicylic acid) into an amide by using N-Boc-1, 6-diaminohexane hydrochloride instead of (2-dodecyloxy)-N-benzylamine; which intermediate may be alkylated according to step (A) above.
  • an acid such as 5-iodosalicylic acid
  • step (R) Conversion of the iodo moiety into a protected amino moiety on the above alkylated intermediate prepared according to step (R), is accomplished by dissolving the alkylated intermediate in an amine base (such a triethylamine) under an inert atmosphere (such as argon) and adding bis(triphenylphosphine)palladium(II) chloride and copper(I) iodide, wherein said mixture is heated (to about 50°C), cooled, worked up by standard procedures and purified, if desired.
  • the protected amino moiety is reduced according to step (H) and deprotected according to step (D) above.
  • the palladium coupling may be accomplished by coupling to a boronate (Scheme 15) instead of an acetylene (Scheme 12)
  • Scheme 1 illustrates the preparation of a specific compound of formula (I) wherein -Y(CH2) n R 1 is -OC12H25; R 2 is methyl; R 3 is hydrogen; X is CH; E is -NH2; Z is -CH2; m is 3; and R 4 and R ⁇ are hydrogen.
  • Scheme 2 (Example 7.
  • Scheme 2 illustrates the preparation of a specific compound of formula (I) wherein -Y(CH2) n R 1 is -OC12H25; R 2 is methyl; R 3 is hydrogen; X is CH; E is -CH-R 9 , wherein R 9 is hydrogen; Z is -CH2; m is 3; and R 4 and R ⁇ are hydrogen.
  • Scheme 3 illustrates the preparation of a specific compound of formula (I) wherein -Y(CH2)nR 1 is -OC12H25; R 2 is methyl; R 3 is hydrogen; X is CH; E is -CH-R 9 , wherein R 9 is hydrogen; Z is -CH2; m is 3; and R 4 and R ⁇ independently from one another are hydrogen or, wherein R 4 and R ⁇ , together with the nitrogen to which they are bound, form a 6-membered ring.
  • Scheme 4 (Example 10)
  • Scheme 4 illustrates the preparation of a specific compound of formula (I) wherein -Y(CH2) n R 1 is -CH2(CH2)7Ph; R 2 is methyl; R 3 is hydrogen; X is CH; E is -CH-R 9 , wherein R 9 is hydrogen; Z is -CH2; m is 3; and R 4 and R ⁇ are hydrogen.
  • Scheme 5 illustrates the preparation of a specific compound of formula (I) wherein -Y(CH2)nR 1 is -OC12H25; R 2 is methyl; R 3 is -NR 7 R 8 , wherein R 7 and R 8 are each hydrogen; X is CH; E is -CH-R 9 , wherein R 9 is hydrogen; Z is -CH2; m is 3; and R 4 and R5 are hydrogen.
  • Scheme 6 illustrates the preparation of a specific compound of formula (I) wherein -Y(CH2) n R 1 is -OC12H25; R 2 is methyl; R 3 is -NHC(O)R 7 , wherein R 7 is alkyl; X is CH; E is -CH-R 9 , wherein R 9 is hydrogen; Z is -CH2; m is 3; and R 4 and R 5 are hydrogen.
  • Scheme 7 illustrates the preparation of a specific compound of formula (I) wherein -Y(CH2) n R 1 is -OC12H25; R 2 is hydrogen; R 3 is hydrogen, X is CH; E is -CH-R 9 , wherein R 9 is hydrogen; Z is -CH2; m is 3; and R 4 and R ⁇ are hydrogen.
  • Scheme 8 illustrates the preparation of a specific compound of formula (I) wherein -Y(CH2) n R 1 is -OC12H25 R 2 is methyl; R 3 is hydrogen; X is N; E is -CH-R 9 , wherein R 9 is hydrogen; Z is -CH2; m is 3; and R 4 and R 5 are hydrogen.
  • _K_ 41 a) HCI • H 2 N(CH 2 ) 6 NHBoc, pyridine, then K 2 C0 3 , MeOH; b) C 12 H 25 I, Cs 2 C0 3 , DMF, 85 °C; c) TFA, CH 2 C1 2 .
  • Scheme 9 illustrates the preparation of a specific compound of formula (II) wherein -Y(CH2) n R 1 is -OC12H25; R 2 is hydrogen; R 3 is hydrogen; X is CH; E is -CH-R 9 , wherein R 9 is hydrogen; Z is -CH2; m is 4; and R 4 and ⁇ are hydrogen.
  • HCI • H 2 N(CH 2 ) 6 NHBoc, EDC, HOBT, NMM, CH 2 C1 2 ; b) C 12 H 25 l, CS 2 CO 3 , DMF, 85 °C; c) Ph 3 P CHC0 2 Me, toluene, 50 °C; d) 10% Pd C, H 2 , MeOH-EtOAc; e) 4N HCI, dioxane.
  • Scheme 10 illustrates the preparation of a specific compound of formula (II) wherein -Y(CH2)nR 1 is -OC12H25; R 2 is hydrogen; R 3 is -(CH2)kR 6 . wherein k is 2 and R 6 is -CO2R 7 , wherein R 7 is methyl; X is CH; E is -CH-R 9 , wherein R 9 is hydrogen; Z is -CH2; m is 4; and R 4 and R ⁇ are hydrogen.
  • Scheme11 (Example 17 ⁇
  • Scheme 11 illustrates the preparation of a specific compound of formula (II) wherein -Y(CH2)nR 1 is -OC12H25; R 2 is hydrogen; R 3 is hydrogen; X is CH; Z is -CH2; m is 1; p is 0; and R 4 and R ⁇ are hydrogen.
  • Scheme 12 (Example 18.
  • Scheme 12 illustrates the preparation of a specific compound of formula (II) wherein -Y(CH2)nR 1 is -OC12H25; R 2 is hydrogen; R 3 is -(CH2)kR 6 , wherein k is 3 and R6 is -NR 7 R 8 , wherein R 7 and R 8 , independently from one another, are hydrogen; X is CH; E is -CH-R 9 , wherein R 9 is hydrogen; Z is -CH2; m is 4; and R 4 and R 5 are hydrogen.
  • Scheme 13 shows how to make other analogous compounds which are within the scope of this invention.
  • Scheme 13 illustrates the preparation of a specific compound of formula (II) wherein -Y(CH2)nR 1 is -OC12H25; R 2 is hydrogen; R 3 is hydrogen; X is CH; Z is phenyl; m is 3; p is 0; and R 4 and R ⁇ are hydrogen.
  • 3-iodoaniline may be substituted for 2- iodoaniline as a reagent in step a of Scheme 13, in order to give a compound of the invention with a varying substitution pattern.
  • Scheme 14 illustrates the preparation of a specific compound of formula (I) wherein -Y(CH2)nR 1 is -C(O)NHC ⁇ 1H22CH3; R 2 is hydrogen; R 3 is hydrogen; X is CH; Z is -CH2; m is 4; p is 0; and R 4 and R ⁇ are hydrogen.
  • Scheme 15 illustrates the preparation of a specific compound of formula (II) wherein -Y(CH2)nR 1 is -OC12H25; R 2 is hydrogen; R 3 is phenyl; X is CH; Z is -CH2; m is 5; p is 0; and R 4 and R ⁇ are hydrogen.
  • the compounds of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in a human, or other mammal, which is exacerbated or caused by excessive or unregulated Protein Kinase C production by such mammal's cells.
  • Compounds of formula (I) or formula (II) are capable of inhibiting Protein Kinase
  • the present invention provides a method of treating a PKC-mediated disease which comprises administering an effective PKC-inhibiting amount of a compound of formula (I) or formula(-__) or a pharmaceutically acceptable salt thereof.
  • compounds of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof are of use in the prophylaxis or therapy of any disease state in a human, or other mammal, which is exacerbated by or caused by excessive or unregulated PKC production by such mammal's cells.
  • this invention relates to a method of inhibiting the production of PKC in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof.
  • the compounds of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof may also be used topically in the treatment or prophylaxis of topical disease states mediated by or exacerbated by excessive PKC production, such as inflamed joints, psoriasis and other conditions associated with inflammation.
  • a pharmaceutical composition comprising an effective, non-toxic amount of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent
  • the pharmaceutically effective compounds of this invention are administered in conventional dosage forms prepared by combining a compound of formula (I) or (II) ("active ingredient") in an amount sufficient to produce inhibiting activity with standard pharmaceutical carriers or diluents according to conventional procedures. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • the pharmaceutical carrier employed may be, for example, either a solid or liquid.
  • solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers are syrup, peanut oil, olive oil, water and the like.
  • the carrier or diluent may include time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
  • the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but preferably will be from about 25 mg to about 1 g.
  • the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
  • the compounds of formula (I) or formula (II) may also be administered topically to a mammal in need of the inhibition of PKC.
  • the compounds of formula (I) or formula (II) may be administered topically in the treatment or prophylaxis of inflammation in a mammal, including humans, and may be used in the relief or prophylaxis of PKC mediated diseases.
  • a suitable anti-inflammatory dose of an active ingredient is 1.5 mg to 500 mg for topical administration, the most preferred dosage being 1 mg to 100 mg, for example 5 to 25 mg administered two or three times daily.
  • topical administration is meant non-systemic administration and includes the appUcation of a compound of formula (I) or formula (II) externally to the epidermis, to the buccal cavity and instillation of such a compound into the ear, eye and nose, and where the compound does not significantly enter the blood stream.
  • systemic administration is meant oral, intravenous, intraperitoneal and intramuscular administration. While it is possible for an active ingredient to be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation.
  • the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, e.g. from 1% to 2% by weight of the formulation although it may comprise as much as 10% w/w but preferably not in excess of 5% w/w and more preferably from 0.1% to 1% w/w of the formulation.
  • topical formulations of the present invention both for veterinary and for human medical use, comprise an active ingredient together with one or more acceptable carriers) therefor and optionally any other therapeutic ingredient(s).
  • the carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous or alcoholic solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent.
  • the resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100°C for half an hour.
  • the solution may be sterilized by filtration and transferred to the container by an aseptic technique.
  • bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).
  • Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
  • Lotions according to the present invention include those suitable for application to the skin or eye.
  • An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops.
  • Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
  • Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external appUcation.
  • the basis may comprise hydrocarbons such as hard, soft or Uquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or oUve oil; wool fat or its derivatives, or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol.
  • the formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as sorbitan esters or polyoxyethylene derivatives thereof.
  • Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as siUcaceous siUcas, and other ingredients such as lanoUn, may also be included.
  • the compounds of formula (I) or formula (II) may also be administered by inhalation.
  • inhalation is meant intranasal and oral inhalation administration.
  • Appropriate dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler may be prepared by conventional techniques.
  • the daily dosage amount of a compound of formula (I) or formula (H) administered by inhalation is from about 0.1 mg to about 100 mg per day, preferably about 1 mg to about 10 mg per day.
  • This invention relates to a method of treating a disease state which is mediated by PKC in a mammal in need thereof, including humans, which comprises administering to such mammal an effective, PKC inhibiting amount of a formula (I) or formula (II) compound.
  • treating is meant either prophylactic or therapeutic therapy.
  • mediated is meant caused by or exacerbated by.
  • Such formula (I) or formula (II) compound can be administered to such mammal in a conventional dosage form prepared by combining the formula (I) or formula (II) compound with a conventional pharmaceutically acceptable carrier or diluent according to known techniques. It wiU be recognized by one of skill in the art that the form and character of the pharmaceuticaUy acceptable carrier or dUuent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other weU-known variables.
  • the formula (I) or formula (II) compound is administered to a mammal in need of inhibition of PKC in an amount sufficient to inhibit PKC.
  • the route of administration may be oral, parenteral, by inhalation or topical.
  • parenteral as used herein includes intravenous, intramuscular, subcutaneous, intra-rectal, intravaginal or intraperitoneal administration.
  • the subcutaneous and intramuscular forms of parenteral administration are generaUy preferred.
  • the daily parenteral dosage regimen wiU preferably be from about 30 mg to about 300 mg per day.
  • the daUy oral dosage regimen wUl preferably be from about 100 mg to about 2000 mg per day for treatment of PKC mediated disease states.
  • the optimal quantity and spacing of individual dosages of a formula (I) or formula (H) compound wUl be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It wuT also be appreciated by one of skUl in the art that the optimal course of treatment, i.e., the number of doses of the formula (I) or formula (II) compound given per day for a defined number of days, can be ascertained by those skiUed in the art using conventional course of treatment determination tests.
  • Example 1(a) The compound of Example 1(a) (500 mg, 1.72 mmol) was dissolved in methanol (3.6 mL) and treated with methylamine hydrochloride ( 348 mg, 5.16 mmol), sodium cyanoborohydride (220 mg, 3.44 mmol), and sodium acetate (423 mg, 5.16 mmol). The reaction was stirred at room temperamre for 20 h by which time TLC showed complete reaction. Concentrated HCI (to pH 2) was added, and the solution was basified to pH 12 (soUd NaOH) after gas evolution stopped. After removing the methanol at reduced pressure, the basic aqueous layer was extracted with diethyl ether (2x).
  • Example 2(b) (133 mg, 0.32 mmol) for (R)-2,6-diamino-N-[[2-(dodecyloxy)phenyl]- methyl]-N-methylhexanamide, the title compound (153 mg, > 99%) was prepared as a milky oil.
  • Anal. (C26H47O2N2CI • 0.5 H2O) calcd: C, 67.28; H, 10.42; N, 6.04.
  • Example 4 Preparation of .RV2.6-diamino-N-methyl-N-. rr2-(8- phenvDoctyloxylphenyllmethyll hexanamide dihvdrochloride aHRV2.6-(Di-tert-butoxycarbonyl')diam-no-N-methyl-N-rrr2-(8-nhenyl .octyloxylphenyll methyllhexanamide
  • Example 3(c) FoUowing the procedure of Example 3(c), except substituting the compound of Example 4(a) (607 mg, 0.93 mmol) for 6-(tert-butoxyc__rbonyl)amino-N-methyl-N-[[[2- (8-phenyl)octyloxy]phenyl]methyl]hexanamide, the title compound (433 mg, 88%) was prepared as a white powder.
  • Anal. (C28H45O2N3CI2 • 0.25 H2O) calcd: C, 63.32; H, 8.63; N, 7.91. Found: C, 63.08; H, 8.65; N, 7.82.
  • Example 1(a) and 1(b) FoUowing the procedures of Example 1(a) and 1(b) respectively, except substituting 1-iodohexadecane for 1-iodododecane, the title compound was prepared as a white solid.
  • Example 5(a) (151 mg, 0.44 mmol) for (2-dodecyloxy)-N-methylbenzylamine, the title compound (216 mg, 86%) was prepared as a white solid. MS (ES) m/e 575.6 [M+H]+. c) 6- Amino-N-rr2-(hexadecyloxy.phenvnmethvn-N-methylhexanamide hydrochloride A solution of the compound of Example 5(b) (216 mg, 0.38 mmol) in 4N HCI in dioxane (0.93 mL) was stirred at room temperature for 1 h. The solvent was removed at reduced pressure and the resulting residue was triturated with acetonitrile (2x).
  • Example 6 Preparation of 4-amino-N-IT2-(dodecyloxy)phenv ⁇ methv ⁇ -N- methylbutanamide hydrochloride a) 4-(tert-Butoxycarbonyl)amino-N-rr2-(dodecyloxy.phenyllmethyll-N-methylbutanamide FoUowing the procedure of Example 2(a), except substituting (tert-butoxy- carbonyl)- ⁇ -aminobutyric acid (100 mg, 0.49 mmol) for (tert-butoxycarbonyl)- ⁇ - aminocaproic acid, the title compound (180 mg, 90%) was prepared as a colorless oU. MS (ES) m/e 491.2 [M+H]+. b. 4- Amino-N-rr2-(dodecyloxy.phenyllmethvn-N-methylhutanamide hydrochloride FoUowing the procedure of Example 5(c), except substituting the compound of
  • Example 6(a) (180 mg, 0.37 mmol) for 6-(tert-butoxycarbonyl)amino-N-[[2-(hexadecyl- oxy)phenyl]methyl]-N-methylhexanamide, the title compound (124 mg, 74%) was prepared as a white amorphous solid.
  • Example 2(a) FoUowing the procedure of Example 2(a), except substituting the compound of Example 7(a) (128 mg, 0.42 mmol) for (2-dodecyloxy)-N-methylbenzylamine, the title compound (174 mg, 80%) was prepared as a colorless oil.
  • MS (ES) m/e 519.2 [M+H] + , 463.2, 419.2.
  • Example 9 Preparation of N-IT2-(dodecyloxy)phenvnmethvn-N- rmethylhexanamido.-6-N'. IS'. N'-trimethylammonium bromide a) N-rr2-(Dodecyloxy)phenvnmethyll-N-rmethylhexanamidol-6-N'. N'. N"-trimethyl- ammonium bromide
  • Trimethyl amine gas was bubbled through a stirred solution of the compound of Example 8(a) (144 mg, 0.30 mmol) in N,N-dimethylforraamide (10 mL) under an argort atmosphere for 5 minutes. The reaction was stirred for 18 h at room temperamre and the solvent was removed at reduced pressure. The resulting residue was triturated with acetonitrile (2x) and lyophUized to provide 150 mg (93%) of the title compound as a hygroscopic white solid.
  • Anal. (C29H53 ⁇ 2N2Br • 0.33 H2O) calcd: C, 63.60; H, 9.88; N, 5.11. Found: C, 63.36; H, 9.83; N, 5.17.
  • Example 10 Preparation of 6-amino-N-methyl-N-riT2-(8- phenyl .octvPphenv ⁇ methvPhexanamide hydrochloride a) N-Methyl-r2-(8-phenyl.octyl]ben_-ylamine FoUowing the procedures of Example 1(a) and 1(b) respectively, except substituting 2-(8-phenyl)octylbenzaldehyde for 2-hydroxybenzaldehyde, the title compound was prepared as a pale yeUow oU. MS (ES) m/e 310.2 [M+H] + , 279. b') 6-.tert-Butoxycarbonyl')amino-N-methyl-N-rrr2-(8-phenyl ' )octvnphenyllmethyll hexanamide
  • Example 11 Preparation of N-IT(5-amino-2-dodecyloxy.phenvPn.ethvP-6- amino-N-methylhexanamide dihvdrochloride a) (2-Dodecyloxy-5-nitroVN-methylbenzylamine FoUowing the procedures of Example 1 (a) and 1 (b) respectively, except substituting 2-hydroxy-5-nitrobenzaldehyde for 2-hydroxybenzaldehyde, the title compound was prepared as a white sotid. MS (ES) m/e 351.2 [M+H] + .
  • Example 11(c) (127 mg, 0.24 mmol) for 6-(tert-butoxycarbonyl)amino-N-[[2-(hexadecyl- oxy)phenyl]methyl]-N-methylhexanamide and diethyl ether for acetonitrile as the trituration solvent, the title compound (141 mg, >99%) was prepared as a white amorphous soUd.
  • Anal. (C26H49O2N3CI2 • 0.25 H2O) calcd: C, 61.10; H, 9.76; N, 8.22. Found: C, 61.11; H, 9.70; N, 7.88.
  • Example 12 Preparation of 6-amino-N-lT2-dodecyloxy-5-IYl- oxooctvhaminolphenyPmethvP-N-methylhexanamide hydrochloride a) 6-(tert-Butoxycarbonyl.amino-N-rr2-dodecyloxy-5-r(l-oxooctyl)aminolphenvn- methyll-N-methylhexanamide
  • Example 11(c) (152 mg, 0.29 mmol) for (2-dodecyloxy)-N-methylbenzylamine and octanoyl chloride for 6-bromo-hexanoyl chloride, the title compound (144 mg, 81%) was prepared. MS (ES) m/e 660.4 [M+H]+, 560.4. b) 6-Amino-N-rr2-dodecyloxy-5-rfl-oxooctyl.aminolphenyllmethvn-N- methylhexanamide hydrochloride
  • Example 12(a) (145 mg, 0.27 mmol) for 6-(tert-butoxycarbonyl)amino-N-[[2-(hexadecyl- oxy)phenyl]methyl]-N-methylhexanamide, the title compound (113 mg, 87%) was prepared as a pale yeUow oU.
  • Anal. (C34H62O3N3CI • 0.125 H2O) calcd: C, 68.22; H,
  • Example 1(a) FoUowing the procedure of Example 1(a), except substituting 2-hydroxy- benzamide for 2-hydroxybenzaldehyde, the title compound was prepared as a white crystaUine sotid. MS (ES) m/e 306 [M+H]+. b) .2-Dodecyloxy.benzylamine To a stirred solution of the compound of Example 13(a) (100 mg, 0.33 mmol) in tetrahydrofuran (1.5 mL) at 0°C under an argon atmosphere was added a solution of 0.1 M Uthium aluminum hydride in tetrahydrofuran (0.66 mL, 0.66 mmol).
  • Example 5(c) FoUowing the procedure of Example 5(c), except substituting the compound of Example 13(c) (187 mg, 0.35 mmol) for 6-(tert-butoxycarbonyl)amino-N-[[2-(hexadecyl- oxy)phenyl]methyl]-N-methylhexanamide, the title compound (151 mg, 98%) was prepared as a white amorphous solid.
  • Anal. (C25H45O2N2CI • 0.125 H2O) calcd: C, 67.73; H, 10.29; N, 6.32. Found: C, 67.71; H, 10.31; N, 6.62.
  • Example 14 Preparation of 6-amino-N-r(3-dodecyloxy)-2- pyridinyllmethvP-N-methylhexanamide dihvdrochloride a) 3-Dodecyloxy-2-(hvdroxymethyl.pyridine
  • Example 1(a) FoUowing the procedure of Example 1(a), except substituting 3-hydroxy-2- (hydroxymethyl)pyridine hydrochloride (250 mg, 1.55 mmol) for 2- hydroxybenzaldehyde, the title compound (277 mg, 64%) was prepared as an off-white solid.
  • Example 14(d) (228 mg, 0.45 mmol) for 6-(tert-butoxycarbonyl)amino-N-[[2- (hexadecyloxy)phenyl]methyl]-N-methylhexanamide, the title compound (199 mg, 90%) was prepared as a hygroscopic pale yeUow soUd.
  • Anal. (C25H47O2N3CI2 • 0.67 H2O) calcd: C, 59.51; H, 9.65; N, 8.33. Found: C, 59.19; H, 9.68; N, 8.40.
  • N-Boc-1, 6-diaminohexane hydrochloride (255 mg, 1.01 mmol, Fluka) was dissolved in dry pyridine (2 mL) and treated with acetylsalicyloyl chloride (200 mg, 1.01 mmol). The reaction was stirred under an argon atmosphere at room temperature for 4 h. The reaction was dUuted with CH2CI2 and poured into 10% HCI. The product was extracted into CH2CI2 and the combined organic extracts were washed with NaHCO3 and brine and dried (MgSO4). Evaporation of the solvent gave crude product which was used directly in the next step.
  • Example 15(a) The compound from Example 15(a) (300 mg, 0.60 mmol) was dissolved in dry CH2CI2 (2.4 mL) and treated with trifluoroacetic acid (TFA, 0.60 mL). The reaction was stirred under Ar at 0 °C for 2 h followed by 30 minutes at room temperamre. The solvent and excess TFA were evaporated and the resulting oU was dissolved in H2O.
  • TFA trifluoroacetic acid
  • LyophiUzation provided the desired product as a Ught tan amorphous soUd (320 mg, 100%).
  • MS (DCI) m/e 405.5 [M+H]+, free base; 306.3 [M- (CH2)6NH2 +.H]+.
  • Example 16(a) (254 mg, 0.70 mmol) for 2-hydroxybenzaldehyde and cesium carbonate for potassium carbonate, the title compound (328 mg, 88%) was prepared as a white soUd.
  • Example 16(c) (327 mg, 0.56 mmol) for 6-(tert-butoxycarbonyl)amino-N-[[(2-dodecyl- oxy-5-nitro)phenyl]methyl]-N-methylhexanamide, the title compound (296 mg, 90%) was prepared as a white soUd.
  • MS (ES) m/e 591.4 [M+H] + . e .
  • N-( 6- Aminohexan- 1 -yl 2-dodecyloxy-5-(2-methoxycarbonyl)ethylben-_amide hydrochloride FoUowing the procedure of Example 5(c), except substituting the compound of
  • Example 16(d) (197 mg, 0.33 mmol) for 6-(tert-butoxycarbonyl)amino-N-[[2-(hexadecyl- oxy)phenyl]methyl]-N-methylhexanamide and diethyl ether for acetonitrile as the triturating solvent, the title compound (175 mg, 99%) was prepared as an amorphous white soUd.
  • Anal. (C29H51O4N2CI • 0.5 H 2 O) calcd: C, 64.96; H, 9.77; N, 5.22. Found: C, 65.11; H, 9.82; N, 5.06.
  • Example 17 Preparation of N-r4-(2-amino.ethvPphenyl-2- dodecyloxybenzamide hydrochloride a. N-(tert-Butoxycarbonv ⁇ -4-nitrophenethylamine A stirred, cooled (-78°C) solution of di-tert-butyl dicarbonate (539 mg, 2.47 mmol) in DMF (1 mL) under an argon atmosphere was treated witii a solution of 4-nitro- phenethylamine hydrochloride (500 mg, 2.47 mmol) in DMF (7 mL) and pyridine (0.2 mL, 2.47 mmol). The reaction was aUowed to warm slowly to room temperamre and stirred for 20 h.
  • Example 17(a) (176 mg, 0.66 mmol) for 6-(tert-butoxycarbonyl)amino-N-[[(2-dodecyl- oxy-5-nitro)phenyl]methyl]-N-methylhexanamide, the title compound (130 mg, 83%) was prepared as a pink crystalline soUd. MS (ES) m/e 237.0 [M+H] + .
  • Example 5(c) FoUowing the procedure of Example 5(c), except substituting the compound of Example 17(d) (89 mg, 0.17 mmol) for 6-(tert-butoxycarbonyl)amino-N-[[2-(hexadecyl- oxy)phenyl]methyl]-N-methylhexanamide and diethyl ether for acetonitrile as the triturating solvent, the title compound (77 mg, 98%) was prepared as a white amorphous sotid.
  • Anal. (C27H41O2N2CI • 0.25 H 2 O) calcd: C, 69.65; H, 8.98; N, 6.02. Found: C, 69.87; H, 9.05; N, 5.80.
  • Example 1(a) FoUowing the procedure of Example 1(a), except substituting the compound of Example 18(b) for 2-hydroxybenzaldehyde and cesium carbonate for potassium carbonate, the title compound was prepared as a white soUd.
  • MS (ES) m/e 631.2 [M+H] + . d . N-l " 6-( tert-Butoxycarbonyl .aminohexan- 1 -yll-5-r3-(tert-butoxycarbonyl .aminol- propvnvl-2-dodecvloxvbenzamide
  • Example 5(c) FoUowing the procedure of Example 5(c), except substituting the compound of Example 18(e) (87 mg, 0.13 mmol) for 6-(tert-butoxycarbonyl)amino-N-[[2-(hexadecyl- oxy)phenyl]methyl]-N-methylhexanamide and diethyl ether for acetonitrile as the triturating solvent, the title compound (67 mg, 97%) was prepared as a pale pink amorphous solid.
  • Anal. (C28H53O2N3CI2 • 1.25 H 2 O) calcd: C, 60.35; H, 10.04; N, 7.54. Found: C, 60.43; H, 10.07; N, 7.53.
  • Example 19 Preparation of N-(6-aminohexan-l-vP-2-dodecyloxy-5-(2- phenylethvnv benzamide hydrochloride a) N-r6-(tert-Butoxycarbonyl .aminohexan- 1 -yl .-2-dodecyloxy-5-(2-phenylethvnyl . benzamide
  • Example 20 Preparation of N-(6-aminohexan-l-yl)-2-dodecyloxy-5-(2- phenylethyl . benzamide hydrochloride a) N-r6-(tert-Butoxycarbonyl. aminohexan- l-yl.-2-dodecyloxy-5-.2-phenylethyl) benzamide FoUowing the procedure of Example 11 (c), except substituting the compound of
  • Example 19(b) FoUowing the procedure of Example 19(b), except substituting the compound of Example 20(a) (47 mg, 0.077 mmol) for N-[6-(tert-butoxycarbonyl)aminohexan-l-yl)-2- dodecyloxy-5-(2-phenylethynyl)benzamide and acetonitrile for diethyl ether as the triturating solvent, the title compound (37 mg, 88%) was prepared as an amorphous white sohd.
  • Anal. (C33H53O2N2CI • 0.5 H 2 O) calcd: C, 71.52; H, 9.82; N, 5.05. Found: C, 71.70; H, 9.76; N, 4.98.
  • Example 21 Preparation of 6-amino-N-!T3-I ⁇ N- dodecyl)aminocarbonvPphenvPmethv ⁇ hexanamide hydrochloride a. 6-(tert-Butoxycarbonyl.amino-N-. r(3-iodo.phenyl1methyl.hexanamide
  • Example 19(b) FoUowing the procedure of Example 19(b), except substituting the compound of Example 21(b) (15 mg, 0.028 mmol) for N-[6-(tert-butoxycarbonyl)aminohexan-l-yl)- 2-dodecyloxy-5-(2-phenylethynyl)benzamide, the title compound (13 mg, 92%) was prepared as an amorphous white solid.
  • Anal. (C 26 H4 6 O2N3CI • H2O) calcd: C, 64.24; H, 9.95; N, 8.64. Found: C, 63.88; H, 9.60; N, 8.33.
  • Example 22 Preparation of N-.6-aminohexan-l-vP-2-dodecyloxy-5- phenylbenzamide hydrochloride a) N-r6-(tert-Butoxycarbonyl)aminohexan- 1 -yl.-2-dodecyloxy-5-phenylhenzamide A mixture of paUadium acetate (4.5 mg, 5 mmol %) and l,4-bis(diphenyl- phosphino)butane (8.5 mg, 5 mmol %) in anhydrous DME (3.5 mL) under argon was heated at 70°C for 40 seconds and graduaUy cooled to room temperature.
  • Example 18(c) The compound of Example 18(c) (250 mg, 0.4 mmol) was added, foUowed by phenylboric acid (54 mg, 0.44 mmol), sodium carbonate (93 mg, 0.88 mmol) and water (0.15 mL). The reaction was heated at 70°C for 2 h and 100°C for 10 h. The reaction mixture was dUuted with ethyl acetate and washed witii water, 10% HCI, and brine, dried (Na2SO4), and concentrated in vacuo. The resulting crude mixture was purified by flash column chromatography (sUica, 15% and 20% ethyl acetate / hexane) to afford the title compound (97 mg, 42%) as a white solid.
  • Example 19(b) FoUowing the procedure of Example 19(b), except substituting the compound of Example 22(a) (66 mg, 0.11 mmol) for N-[6-(tert-butoxycarbonyl)aminohexan-l-yl)-2- dodecyloxy-5-(2-phenylethynyl)benzamide, the title compound (59 mg, 96%) was prepared as an amorphous white soUd.
  • Anal. (C31H49O2N2CI • H2O) calcd: C, 69.57; H, 9.61; N, 5.23. Found: C, 69.72; H, 9.35; N, 5.17.
  • Example 25 Preparation of N-.3-Piperazinyl-4-n_ethoxy)phenyl-2- benzvlbenzamide dihvdrochloride FoUowing the procedure described in Example 15, except substituting the compound of Example 24(a) (176 mg, 0.57 mmol) for N-BOC-l,6-diaminohexane hydrochloride, benzyl bromide for 1-iodododecane, and 4N HCl/dioxane for trifluoroacetic acid, die title compound (217 mg, 87%) was prepared as an amorphous white solid.
  • Anal. (C25H29O3N3CI2 • 2.25 H O) calcd: C, 56.55; H, 6.16; N, 7.91. Found: C, 56.90; H, 6.42; N, 7.81.
  • PROTEIN KINASE C INHIBITION ASSAY PKC is purified (>90 percent) from rat brain according to Walton et al. (Walton,
  • PKC activity is assayed as Ca ⁇ + / phosphoUpid-dependent transfer of 32p-iabeled phosphate from ATP to a synthesized peptide substrate (purchased from Bachem).
  • Reaction mixtures (50 mL) contain, in addition to purified PKC: 10 mM Tris, pH 7.5; 1.1 raM CaCl2; 10 mM MgC_2; 1.0 mM EGTA; 40 mg/raL phosphatidyl serine; 1 mg/mL Diolein; 100 mg mL Bachem peptide; 0.5 microcuries of g-32p-ATP (specific activity.
  • the compounds of this invention show activity as PKC inhibitors and have IC50 values in the range of 0.001 to 150 micromolar.
  • IC50 values in the range of 0.001 to 150 micromolar.
  • one of ordinary skiU in the art can utiUze the present assay in order to determine which compounds of formula (I) or (II) are inhibitors of PKC.
  • the above description fuUy discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specificaUy disclosed herein are within the scope of the f oUowing claims.

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Abstract

La présente invention se rapporte à des composés de la formule (I) ou de la formule (II) ou à des sels pharmaceutiquement acceptables de ceux-ci, composés utilisés dans le traitement d'états pathologiques induits par la protéine kinase C (PKC). Dans ces formules, entre autres, R1 représente hydrogène, alkyle inférieur ou aryle éventuellement substitué; R2 représente hydrogène ou alkyle inférieur; R3 représente hydrogène ou -(CH¿2?)kR?6 où R6¿ représente -CO¿2R?7, -NHC(O)R?7, -NR7R8¿ ou -C(O)NR?7R8, où R7 et R8¿ représentent, indépendamment l'un de l'autre, hydrogène ou alkyle à condition que, si R6 représente -CO¿2R?7, alors R7 ne représente pas hydrogène; R4 et R5 représentent, indépendamment l'un de l'autre, hydrogène ou alkyle inférieur, ou bien R4 et R5, avec l'azote auquel ils sont liés, forment un noyau pentagonal, hexagonal ou heptagonal saturé ou insaturé; E représente CH-R?9, où R9¿ représente hydrogène, alcoxy, -OH ou bien -NR?10R11, où R10 et R11¿ représentent, indépendamment l'un de l'autre, hydrogène ou alkyle inférieur, ou bien où R?10 et R11¿, avec l'azote auquel ils sont liés, forment un noyau pentagonal, hexagonal ou heptagonal saturé ou insaturé; X représente CH ou N; Y représente -CH¿2? ou -O, et Y est en outre situé sur le noyau aromatique central en position ortho, métha ou para par rapport à la chaîne latérale contenant l'amide; Z représente -CH2 ou aryle éventuellement substitué; k est un nombre entier compris entre 0 et 10; m est un nombre entier compris entre 0 et 10, à condition que m soit égal à 0 uniquement lorsque Z représente aryle éventuellement substitué ou hétéroaryle éventuellement substitué, et également, à condition que, lorsque m vaut 0 et que Z représente aryle éventuellement substitué ou hétéroaryle éventuellement substitué, alors R?4 et R5¿ ne représentent pas hydrogène ou alkyle inférieur; n est un nombre entier compris entre 6 et 20; et p est un nombre entier compris entre 0 et 1, à condition que p soit égal à 0 lorsque Z représente aryle éventuellement substitué ou hétéroaryle éventuellement substitué.
EP95906035A 1993-12-30 1994-12-20 Hexanamides de phenylmethyle et leur utilisation Withdrawn EP0738144A4 (fr)

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JP3441665B2 (ja) 1999-02-04 2003-09-02 株式会社資生堂 （２−置換オキシフェニル）アルカンアミド誘導体及び養毛剤、皮膚外用剤
GB9908662D0 (en) * 1999-04-15 1999-06-09 Smithkline Beecham Plc Novel process for preparing benzodiazepines
JP4622047B2 (ja) * 1999-06-09 2011-02-02 アステラス製薬株式会社 新規なヘテロ環カルボキサミド誘導体
DE60017898T2 (de) * 1999-06-09 2006-01-12 Yamanouchi Pharmaceutical Co., Ltd. Neuartige heterocyclische carboxamidderivate
WO2000076980A1 (fr) * 1999-06-10 2000-12-21 Yamanouchi Pharmaceutical Co., Ltd. Nouveaux derives heterocycliques azotes ou leurs sels
ES2321535T3 (es) 2004-12-23 2009-06-08 Glaxo Group Limited Compuestos de piridina para el tratamiento de enfermedades mediadas por prostaglandinas.
US8173633B2 (en) * 2006-08-04 2012-05-08 Toyama Chemical Co., Ltd. Protein kinase C activity enhancer containing alkyl ether derivative or salt thereof
CA2704199C (fr) * 2007-11-01 2016-01-19 Acucela Inc. Composes derives d'amines pour le traitement de maladies et de troubles ophtalmiques
WO2011078295A1 (fr) * 2009-12-25 2011-06-30 味の素株式会社 Composé de benzyle
WO2014097178A1 (fr) * 2012-12-18 2014-06-26 Jawaharlal Nehru Centre For Advanced Scientific Research Composés antimicrobiens, leur synthèse et leurs applications
KR102496364B1 (ko) * 2014-09-10 2023-02-06 에피자임, 인코포레이티드 Ｓｍｙｄ 억제제

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EP0183271B1 (fr) * 1984-11-30 1990-05-16 Shosuke Okamoto Dérivé de lysine et inhibiteur de protéinase

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US2665309A (en) * 1951-01-04 1954-01-05 American Home Prod Substituted glycinamides
US3631102A (en) * 1969-04-23 1971-12-28 Squibb & Sons Inc N-aminoalkyl-2 5-cyclohexadiene-1-carboxamides
US5238962A (en) * 1983-03-03 1993-08-24 Hoffmann-La Roche Inc. Benzamide derivatives

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