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WO1989007100A1 - Glycerol 2,2-disubstitue et composes analogues au glycerol, compositions et procedes d'utilisation - Google Patents

Glycerol 2,2-disubstitue et composes analogues au glycerol, compositions et procedes d'utilisation Download PDF

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Publication number
WO1989007100A1
WO1989007100A1 PCT/US1989/000336 US8900336W WO8907100A1 WO 1989007100 A1 WO1989007100 A1 WO 1989007100A1 US 8900336 W US8900336 W US 8900336W WO 8907100 A1 WO8907100 A1 WO 8907100A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
title compound
alkyl
methyl
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.)
Ceased
Application number
PCT/US1989/000336
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English (en)
Inventor
Daniel M. Solomon
James J. Kaminski
Steven K. White
Laura S. Lehman
Ashit K. Ganguly
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.)
Merck Sharp and Dohme LLC
Original Assignee
Schering Corp
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Publication date
Priority claimed from PCT/US1988/000315 external-priority patent/WO1989007099A1/fr
Application filed by Schering Corp filed Critical Schering Corp
Priority to JP1502646A priority Critical patent/JPH0662542B2/ja
Priority to PCT/US1989/000336 priority patent/WO1989007100A1/fr
Publication of WO1989007100A1 publication Critical patent/WO1989007100A1/fr
Priority to DK185790A priority patent/DK185790A/da
Anticipated expiration legal-status Critical
Priority to US07/955,784 priority patent/US5449680A/en
Ceased legal-status Critical Current

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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
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    • 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
    • C07D213/65—One oxygen atom attached in position 3 or 5
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    • 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
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    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
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    • C07—ORGANIC CHEMISTRY
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D277/18—Nitrogen atoms
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
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    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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 in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D295/08—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 bound oxygen or sulfur atoms
    • C07D295/084—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 bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—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 bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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    • C07F9/08—Esters of oxyacids of phosphorus
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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    • C07F9/6539—Five-membered rings

Definitions

  • the present invention relates to 2,2-disubstituted glycerol and glycerol-like compounds, compositions containing such compounds, and methods of using such compounds.
  • R 1 is alkyl containing 6 to 22 carbon atoms or -C(O)-D wherein -D is NR 5 R 6 , wherein
  • R 5 is hydrogen, alkyl containing x carbon atoms, aryl, heteroaryl, heteroalkyl, arylalkyl, or cycloalkyl;
  • R 6 is alkyl containing y carbon atoms, aryl, heteroaryl, heteroalkyl, arylalkyl, or cycloalkyl, such that the sum of x and y, when at least one of R 5 or R 6 is alkyl is an integer of from 1 to 22, or R 5 and R 6 together with the nitrogen to which they are attached may form a heterocycloalkyl group which may be substituted with alkyl or arylalkyl;
  • R 2 is lower alkyl, trifluoromethyl, aralkyl or aryl
  • R 3 is T-U-V, wherein
  • R a is H, lower alkyl or acyl
  • U is -(CH 2 ) e - wherein e is an integer of from 2
  • V is -A-B, wherein
  • A is a direct bond between U and B, -O-, -S-, -O-(CH 2 ) n - where n is 1, 2 or 3, -O-C(O)- or -N(R a )- where R a is as previously defined,
  • B is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, heteroaryl, substituted heteroaryl
  • W is O,S or NR , wherein R b is H, lower alkyl or CN and each R c is independently H or lower alkyl, such that the group -A-B contains at least one nitrogen atom, and
  • R 4 represents -X-C b H 2b+1 where b is an integer of from 1 to 6 and X is methylene, O, S(O) c where c is 0, 1 or 2 or -N(R a )- where R a is as previously defined, with the proviso that when R 1 is alkyl, T cannot be -OPO 3 .
  • Preferred compounds falling within the invention include compounds where R 1 is -C(O)-D where D is NR 5 R 6 , with preferred values of R 5 and R 6 being alkyl. Most preferably one of R 5 and R 6 is methyl, and the other group is alkyl containing six to nineteen carbon atoms, most preferably ten to eighteen carbon atoms.
  • Preferred compounds falling within the invention also include preferred values of R 2 where R 2 is lower alkyl, more preferably lower alkyl containing one to three carbon atoms, and most preferably lower alkyl containing one or two carbon atoms.
  • Preferred compounds of the invention also include compounds having preferred values of T, which include -O-, -O-C(O)-O-, -O-C(O)-NR a - and -NR a -C(O)-O- where R a is preferably H or acyl and most preferably H.
  • the more preferred values of T are -O-, -O-C(O)-NR a - and -NR a -C(O)-O-, with the most preferred value of T being -O-.
  • U examples include -(CH 2 ) e - and in particular where e is the integer 4, 5, 6 or 7.
  • Another preferred value of U is -(CH 2 ) f -phenyl-(CH 2 ) f - wherein f is as defined previously.
  • V include those wherein A is a direct bond between U and B and B is heteroaryl or substituted heteroaryl, and wherein A is a direct bond between U and B and B is heterocycloalkyl or substituted heterocycloalkyl, and wherein A is -O- and B is heteroaryl or substituted heteroaryl.
  • R examples include those compounds where X is O or S(O) 2 and b in the group C b H 2b+1 is 1.
  • quaternary ammonium compounds both cyclic and acyclic
  • the preferred cyclic compounds being quaternary ammonium compounds where the ring contains a quaternary nitrogen
  • the preferred acyclic compounds being quaternary ammonium compounds, quaternized with lower alkyl substituent groups.
  • the vast majority of the compounds of this invention contain at least one assymetric carbon atom.
  • This invention covers all individual stereoisomers of the compounds of formula I as well as mixtures of two or more different stereoisomers.
  • the invention further encompasses a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by structural formula I in combination with a pharmaceutically acceptable carrier.
  • the invention also encompasses a method of treating allergy in a mammal comprising administering to said mammal an antiallergic effective amount of a compound represented by structural formula I.
  • the invention further encompasses a method of treating inflammation in a mammal comprising administering to said mammal an antiinflammatory effective amount of a compound represented by structural formula I.
  • Another aspect of the invention comprises the use of a compound of formula I for preparing a pharmaceutical composition useful for treating allergy or inflammation.
  • Yet another aspect of the invention comprises a method for making a pharmaceutical composition by mixing a compound of formula I with a pharmaceutically acceptable carrier.
  • X- represents a negatively charged ion such as Cl- or CH 3 SO 2 -:
  • alkyl - represents a straight or branched carbon chain containing from one to twenty carbon atoms, preferably one to eighteen carbon atoms;
  • lower alkyl - represents a straight or branched carbon chain containing from one to six carbon atoms
  • methylene - represents the divalent group -CH 2 -;
  • cycloalkyl - represents a saturated carbocyclic ring of from three to eight carbon atoms
  • heterocycloalkyl - represents a saturated ring containing from three to seven atoms, preferably two to six carbon atoms and 1 to 3 hetero groups selected from -O-, -S- or Preferred heterocycloalkyl groups include morpholino, pyrrolidinyl, thiazolidinyl, and thiazolidinium.
  • heteroalkyl - represents a saturated branched or unbranched chain containing from one to ten carbon atoms and at least one hetero group selected from -O-, -S- or -N-;
  • acyl - represents a group -alkyl-C(O)- or - -cycloalkyl-C(O) - where alkyl, and cycloalkyl are as defined above;
  • aryl - represents a carbocyclic group containing from 6 to 14 carbon atoms and having at least, one aromatic ring (e.g., phenyl); aralkyl - saturated branched or unbranched chain containing 1 to 6 carbon atoms and one or more phenyl substituents (e.g., benzyl);
  • heteroaryl - represents a 5 or 6 membered aromatic ring containing from 1 to 4 heteroatoms; preferred heteroaryl groups include thiazolyl, thiazolium, imidazolyl, imidazolium, pyridinyl, pyridinium, and thiazolyl;
  • halo - means chloro, bromo or fluoro
  • Substituted heterocycloalkyl also includes non-aromatic quaternary ammonium compounds;
  • Certain compounds of the invention may exist in isomeric forms.
  • the invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures.
  • the compounds of the invention of formula I can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., hemihydrate.
  • solvated forms including hydrated forms, e.g., hemihydrate.
  • pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention.
  • Certain compounds of the invention are acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts are the sodium, potassium, calcium, aluminum, gold, copper and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
  • Certain basic compounds of the invention are pharmaceutically acceptable salts, e.g., acid addition salts and quaternary ammonium salts.
  • thiazolidinyl nitrogen atoms may form acid addition salts with strong acid.
  • suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art.
  • the salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner.
  • the free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate.
  • the quaternary ammonium salts are typically prepared by reaction of a tertiary amino group in a compound of formula I with a compound containing a suitable leaving group, such as an alkyl iodide, etc.
  • B may contain a quaternary nitrogen.
  • the compounds of the invention which possess an aromatic ring nitrogen atom, as defined above, may also form quaternary ammonium salts at the aromatic ring nitrogen atom.
  • a in the definition of V is -O-, or -S-, and B is heteroalkyl, substituted heteroalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl
  • the heteroatom in the B group is located at any position other than attached to the A group.
  • the free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of the invention.
  • the compounds of the present invention are produced by the following processes:
  • R 1 , R 2 , R 4 , T, U, A and B are defined previously and L 1 and L 2 are leaving groups;
  • B is a free compound that is the same as the B radical defined previously without a bond; (C) to produce a compound of formula I wherein T is -OCO 2 -, reacting a compound of the formula
  • R 1 , R 2 , R 4 and L 1 are as defined previously with a compound of the formula
  • Typical leaving groups L 1 are -OSO 2 CH 3 , -Br, -I, and -Cl.
  • Typical leaving groups L 2 are -H, and a metal ion. Of course, many other leaving groups will suffice.
  • Compounds II and III below are conventional starting materials, or may be prepared using conventional methods.
  • R 2 is alkyl, trifluoromethyl, aryl or aralkyl.
  • R 2 is aryl
  • said compound may be prepared by conventional methods, taking into account, in particular Searles, et. al., J. Org. Chem. Vol. 24, p. 1839 (1960) where R 2 is phenyl.
  • the teachings of Searles are incorporated herein by reference.
  • R 6 is alkyl containing 6 to 22 carbon atoms, as defined above.
  • R 1 represents
  • R 1 and are used below interchangably when appropriate.
  • R 5 in structural formula I represents hydrogen
  • R 5 is designated as H.
  • R 5 is a value other than H
  • L as used throughout the general process description designates a leaving group
  • P throughout the general process description designates any appropriate protecting group.
  • Compound IX may be deprotected, for example, using ethereal hydrochloric acid or alternatively catalytic hydrogenation.
  • R 1 in formula I is alkyl
  • R 1 -L where L is, e.g., I, Br, Cl, tosylate, mesylate, etc.
  • L is, e.g., I, Br, Cl, tosylate, mesylate, etc.
  • Compound II may be treated with a strong base, such as NaH, to form an alkoxide, after which the reaction with R 1 -L occurs.
  • R 3 is -O-
  • compound XII When compound XII is converted to compound XIII, it is treated with an appropriate nucleophilic reagent to displace the mesylate leaving group.
  • the reaction may be run neat or in the presence of inert solvents, one example of which is dimethylformamide ("DMF").
  • DMF dimethylformamide
  • a tertiary amine is typically reacted with compound XII.
  • compound XII may be reacted with a primary or secondary amine, and the resulting secondary or tertiary amine may be reacted with a suitable reagent to form a quaternary compound.
  • R 3 contains a phosphate group, i.e. R 3 is T-U-V where
  • the phosphate group of compound XVII may transfer its hydrogen to the -A-B moiety becoming negatively charged, thereby forming a zwitterionic compound XVII.
  • Zwitterionic forms of the compounds falling within the scope of formula I are included as part of this invention.
  • R 4 is typically methyl or ethyl, but any other appropriate group could be substituted therefore.
  • R 2 and R 4 may be the same or different.
  • the diester XXI may be reduced to the corresponding diol without affecting the R 2 and R 4 substituents at carbon atom 2.
  • the carbamate nitrogen in the side chain attached to carbon atom 1 of the glycerol backbone may be substituted with a group R 5 , where R 5 is other than hydrogen, and the 3-hydroxy substituent may undergo deprotection.
  • Phosphorylation of compound XXV may be performed as described with respect to compound X.
  • an alkyl side chain -(CH 2 ) e - may be added to the hydroxyl group at carbon atom 3 to form an ether as was previously described with respect to compound X.
  • the silyl protecting group may be removed by conventional means , and the resulting hydroxyalkyl side chain can be mesylated .
  • the mesylate compound XXVIII readily reacts with H-A-B or A-B, to form a compound falling within the scope of formula I.
  • compound XXX may be treated with base and 1-alkylthiosulfonyl-4-methyl benzene to form compound XXXI below.
  • Compound XXXI may then be reduced at positions 1 and 3, to form a corresponding 1,3-diol.
  • Compound XXXII may be treated with the appropriate alkyl isocyanate, under an inert atmosphere, with appropriate heating as necessary. Protection, N-alkylation, and deprotection steps may be performed as appropriate.
  • the 3-hydroxy compound XXXVI may be alkylated to form compound XXXVII using a protected alkyl chain reagent, which then undergoes deprotection.
  • Compound XXXVIII may be subjected to mesylate formation thereby making compound XXXIX, and subsequent mesylate displacement with, H-A-B or A-B as appropriate to form a compound of formula I.
  • the thioether compound XXXIX may be oxidized to the sulfoxide or sulfone using equimolar or an excess amount of metachloroperbenzoic acid (m- CPBA), respectively.
  • Displacement of the mesylate protecting group may be performed as described above.
  • the diol compound LII may be monobrominated in the presence of triphenyl phosphine with carbon tetrabromide and the remaining hydroxy function is protected by silylation.
  • Compound LIII may be utilized in a reaction with any appropriately protected intermediate compound containing a 3-hydroxy group to alkylate said intermediate at position 3.
  • a suitable alcohol may first be treated with a strong base to form the anion, then treated with trichloromethyl chloroformate, to yield a compound LVIII.
  • Compound LVIII may then be treated with V-U-O-Na + , to yield compound LIX.
  • the intermediate compound below may be treated with tr ichloromethyl chloroformate, and the intermediate product LX treated with V-U-O- Na + .
  • Compounds LIX and LXI may be alkylated or acylated on the carbamate nitrogen by treating with an appropriate base, such as NaH, followed by a suitable aIkylating or acylating agent, such as CH 3 l and CH 3 C(O)CI, respectively.
  • an appropriate base such as NaH
  • a suitable aIkylating or acylating agent such as CH 3 l and CH 3 C(O)CI, respectively.
  • an appropriate mercapto compound is treated with strong base to form a sulfur anion.
  • the sulfur anion may then be reacted with a mesylate compound, such as compound XII, causing mesylate displacement.
  • Certain compounds of the invention are prepared from starting materials containing an endo and an exo nitrogen. End products of the invention may therefore contain an exo or endo nitrogen linkage.
  • exo refers to a nitrogen substituent group
  • endo refers to a nitrogen contained within the ring.
  • the mesylate compound XII is treated with the substituted heteroalkyl containing the desired substitutent, which may be protected, if necessary.
  • the protecting group, if present, is thereafter cleaved to give the compound of the invention.
  • B represents heterocycloalkyl which contains an amino group
  • compounds where A is a direct bond are prepared as described above from the mesylate intermediate.
  • B represents a substituted heterocycloalkyl group
  • the substituent may or may not require protection, and the protected form of B is used to displace the mesylate intermediate.
  • the compound may then be deprotected to form a compound of the invention.
  • the mesylate intermediate XII is displaced with a cyano compound, which is subsequently treated with an alcohol in the presence of acid to form an imino ester, which is then treated with a primary or secondary amine.
  • the compounds of the invention possess platelet activating factor ("PAF") antagonistic activity.
  • PAF platelet activating factor
  • PAF is an important mediator of such processes as platelet aggregation, smooth muscle contraction (especially in lung tissue), vascular permeability and neutrophil activation. Recent evidence implicates PAF as an underlying factor involved in airway hyperreactivity.
  • the compounds of the invention are therefore useful where PAF is a factor in the disease or disorder. This includes allergic diseases such as asthma, adult respiratory distress syndrome, urticaria and inflammatory diseases such as rheumatoid arthritis and osteoarthritis.
  • the PAF antagonistic properties of these compounds may be demonstrated by use of standard pharmacological testing procedures as described below. These test procedures are standard tests used to determine PAF antagonistic activity and to evaluate the usefulness of said compounds for counteracting the biological effects of PAF.
  • the in vitro assay is a simple screening test, while the in vivo test mimics clinical use of the compounds described herein.
  • PRP Platelet-poorplasma
  • Platelet Aggregation Assay When an aggregating agent such as PAF is added to PRP, platelets aggregate. An aggregometer quantifies this aggregation by measuring light transmission through PRP and comparing to PPP. The aggregation assays were performed using a dual-channel aggregometer (Model 440, Chrono-Log Corp., Havertown, PA). PRP (0.45 ml) in aggregometer cuvettes was continually stirred (37°C). Solutions of test compounds or vehicle were added to the PRP, and after incubation for 2 min., 10-15 ⁇ l aliquots of PAF solution were added so as to achieve a final concentration of 1-5 X 10 -8 M.
  • IC 50 is the concentration of compound in micromoles at which 50% of the aggregation is inhibited, as measured by the light transmission through each sample of PRP as compared to
  • PAF is also a known bronchoconstrictive agent in mammals.
  • PAF antagonism can be evaluated in vivo by measuring inhibition by the compounds of the invention in PAF-induced bronchoconstriction in guinea pigs.
  • Non-sensitized guinea pigs are fasted overnight, and the following morning are anesthetized with 0.9 ml/kg i.p. of dialurethane (0.1 g/ml of diallybarbituric acid, 0.4 g/ml of ethylurea and 0.4 g/ml of urethane).
  • the trachea is cannulated and the animals are ventilated by a Harvard rodent respirator at 55 strokes/min. with a stroke volume of 4 ml.
  • a side arm to the tracheal cannula is connected to a Harvard pressure transducer to obtain a continuous measure of intratracheal pressure, which is recorded on a Harvard polygraph.
  • the jugular vein is cannulated for the administration of compounds.
  • the animals are challenged i.v. with PAF (0.4 ug/kg in isotonic saline containing 0.25% BSA) and the peak increase in inflation pressure that occurrs within 5 min. after challenge is recorded.
  • Test compounds are administered either orally (2 hrs. prior to PAF as a suspension in 0.4% methylcellulose vehicle) or intravenously (10 min. prior to PAF as a solution in dimethylsulfoxide).
  • the compounds of formula I are effective PAF antagonists useful for the treatment of allergy and inflammation.
  • the methods of treating allergy and inflammation are part of the invention described herein.
  • the compounds When used for the treatment of allergy, the compounds may be administered by any conventional route of administration in an amount ranging from about 0.001 mg/kg to about 100 mg/kg per day, in single or multiple daily doses.
  • the compounds when used for the treatment of inflammation, may be administered by any conventional route of administration in an amount ranging from about 0.001 mg/kg to about 100 mg/kg per day, in single or multiple daily doses.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active compound.
  • the active compound is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets may be comprised of from about 5 to about 70 percent active ingredient.
  • suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like.
  • preparation is intended to include the formulation of the active compound with an encapsulating materiala serving as a carrier, thereby providing a capsule in which the active component (with or without other carriers) is surrounded by the carrier, which is thus in association with it.
  • cachets are included. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.
  • Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Liquid preparations can also be formulated in solution in polyethylene glycol and/or polypropylene glycol, which may contain water.
  • Aqueous solutions suitable for oral use can be prepared by adding the active component in water and adding suitable colorants, flavors, stabilizing, sweetening, solubilizing and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents.
  • Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas.
  • Inhalation aerosols may be packaged in a pressure resistant container, which may have a metered dose feature suitable for administration into the oral cavity for inhalation, or into the nasal passageways, thereby delivering a precise amount of aerosol per use.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. These particular solid form preparations are most conveniently provided in unit dose form and as such are used to provide a single liquid dosage unit.
  • sufficient solid may be provided so that after conversion to liquid form, multiple individual liquid doses may be obtained by measuring predetermined volumes of the liquid form preparation as with a syringe, teaspoon or other volumetric container.
  • multiple liquid doses are so prepared, it is preferred to maintain the unused portion of said liquid doses at low temperature (i.e., under refrigeration) in order to retard possible decomposition.
  • the solid form preparations intended to be converted to liquid form may contain, in addition to the active material, flavorants, colorants, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like.
  • the solvent utilized for preparing the liquid form preparation may be water, isotonic water, ethanol, glycerine, propylene glycol and the like as well as mixtures thereof. Naturally, the solvent utilized will be chosen with regard to the route of administration, for example, liquid preparations containing large amounts of ethanol are not suitable for parenteral use.
  • the compounds of the invention may also be deliverable transdermally.
  • the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • the pharmaceutical preparation is in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, for example, packeted tablets, capsules and powders in vials or ampoules.
  • the unit dosage form can also be a capsule, cachet or tablet itself or it can be the appropriate number of any of these in packaged form.
  • the compositions can, if desired, also contain other therapeutic agents.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.001 mg to 1000 mg, more preferably from about 1 mg to 100 mg, according to the particular application.
  • the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
  • a typical recommended dosage regimen for oral administration is from 0.25 to 100 mg/day, preferably 10 to 20 mg/day, in two to four divided doses to achieve relief of the symptoms.
  • PREPARATIVE EXAMPLE 7 Substitute the compound shown in column one of the Table below for 2-methyl-2-propen-1-ol in the procedure described in Preparative Example 5 above to make the product shown in column two.
  • PREPARATIVE EXAMPLE 8 Substitute an appropriate reactant olefin disclosed in the Table below into the process of preparative example 6 to make the diol shown in column two.
  • reaction When reaction is complete, wash the reaction solution with saturated NaHCO 3 (2 X 200 ml), then stir the CH 2 Cl 2 solution in aqueous 10% NaHSO 3 for 20 minutes to form a cloudy white precipitate in the organic layer. Wash the organic layer with saturated NaHCO 3 (1 X 200 ml), then with NaOH (1N, 2 X 200 ml) to remove the precipitate. Dry the CH 2 Cl 2 solution over MgSO 4 , filter and concentrate the filtrate to obtain the title compound as a clear oil.
  • the mixture may be rewashed with NaHCO 3 (2 ⁇ 1.1 m) and H 2 O (1X), then dried over MgSO 4 , rotavaped and high vac dried for 18 hours to yield an amber oil, (1.42 g) which contains the sulfoxide:sulfide (3:1) .
  • the sample may be dissolved in hexane (7 ml) at -11°C. Filter off a soft, white solid, which melts on warming to room temperature to give a viscous oil. Redissolve the sample in hexane and stir with Darco 660 (0.3g), filter, rotavap and high vac dry to yield an offwhite sticky glass. High vac dry over P 2 O 5 to obtain the title compound as a waxy gum which darkens slightly over time.
  • the compounds shown in column 1 of Table 4 below may be debenzylated under a H 2 atmosphere by treating with Pd on carbon (10%) under standard reaction conditions to synthesize the compounds shown in column two.
  • active compound designates 3-[7-[3- (2,3-dihydro-2-imino)thiazolyl]heptyloxy]-2-methoxy-2-methylpropyl-N-methyloctadecyl carbamate. It is contemplated, hov/ever, that this compound may be replaced by an effective amount of another compound of formula I.
  • Active Compound 10 0 Phenyl Mercuric Acetate 0. 02 Aminoacetic Acid USP 3 . 7 Sorbitol Solution, USP 57 . 0 Benzalkonium Chloride S ioolluuttiioonn 0. 2 Sodium Hydroxide IN Solution to - - - - - adjust pH Water Purified USP to make 1.0 ml
  • Example F Ointment
  • Disperse active compound in a portion of the mineral oil Mix and heat to 65°C, a weighed quantity of white petrolatum, the remaining mineral oil and benzyl alcohol, and cool to 50°-55°C. with stirring. Add the dispersed active compound to the above mixture with stirring. Cool to room temperature.

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Abstract

On a mis au point de nouveaux composés de glycérol 2,2-disubstitués utilisés comme composés anti-allergiques et anti-inflammatoires. Lesdits composés sont des antagonistes du facteur d'activation de plaquettes (''FAP''). On a également mis au point des procédés de synthèse et l'utilisation des composés de l'invention, ainsi que leurs compositions pharmaceutiques. Lesdits composés ont la formule (I), dans laquelle R1, R2, R3 et R4 sont tels que définis dans la revendication.
PCT/US1989/000336 1988-02-05 1989-02-02 Glycerol 2,2-disubstitue et composes analogues au glycerol, compositions et procedes d'utilisation Ceased WO1989007100A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP1502646A JPH0662542B2 (ja) 1988-02-05 1989-02-02 ２、２‐二置換グリセロールおよびグリセロール類似化合物、組成物および使用方法
PCT/US1989/000336 WO1989007100A1 (fr) 1988-02-05 1989-02-02 Glycerol 2,2-disubstitue et composes analogues au glycerol, compositions et procedes d'utilisation
DK185790A DK185790A (da) 1988-02-05 1990-08-03 2,2-disubstituerede glycerol- og glycerolagtige forbindelser, praeparater indeholdende saadanne forbindelser og fremgangsmaader til anvendelse heraf
US07/955,784 US5449680A (en) 1988-02-05 1992-10-02 2,2 disubstituted glycerol and glycerol-like compounds, compositions and methods of use

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
PCT/US1988/000315 WO1989007099A1 (fr) 1988-02-05 1988-02-05 Glycerol 2,2-disubstitue et composes analogues au glycerol, compositions et modes d'utilisation
USPCT/US88/00315 1988-02-05
PCT/US1989/000336 WO1989007100A1 (fr) 1988-02-05 1989-02-02 Glycerol 2,2-disubstitue et composes analogues au glycerol, compositions et procedes d'utilisation

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5973000A (en) * 1996-06-03 1999-10-26 Shiseido Company, Ltd. Hair revitalization tonic composition containing a lipid derivative and use thereof
US6177067B1 (en) 1996-08-09 2001-01-23 Shiseido Company, Ltd. Hair revitalizing tonic composition containing a 2,2-dimethylpropanediol compound and use thereof

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Publication number Priority date Publication date Assignee Title
EP0094586A2 (fr) * 1982-05-13 1983-11-23 Ono Pharmaceutical Co., Ltd. Dérivés de glycérol, procédé pour leur préparation et compositions pharmaceutiques les contenant
EP0109255A2 (fr) * 1982-11-11 1984-05-23 Ono Pharmaceutical Co., Ltd. Dérivés du glycérol
EP0142333A2 (fr) * 1983-11-08 1985-05-22 Ono Pharmaceutical Co., Ltd. Dérivés du glycérol
EP0145303A1 (fr) * 1983-11-14 1985-06-19 Ono Pharmaceutical Co., Ltd. Dérivés du glycérol
EP0146258A2 (fr) * 1983-11-10 1985-06-26 Ono Pharmaceutical Co., Ltd. Dérivés de glycérol
EP0147768A2 (fr) * 1983-12-30 1985-07-10 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Dérivés du glycérol
EP0208932A2 (fr) * 1985-06-18 1987-01-21 F. Hoffmann-La Roche Ag Dérivés de glycérine
EP0254540A2 (fr) * 1986-07-22 1988-01-27 Takeda Chemical Industries, Ltd. Dérivés du glycérol, procédé de préparation et utilisation
EP0255366A2 (fr) * 1986-07-30 1988-02-03 Takeda Chemical Industries, Ltd. Composé lipidique contenant de l'azote et du soufre, production et utilisation

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Publication number Priority date Publication date Assignee Title
EP0094586A2 (fr) * 1982-05-13 1983-11-23 Ono Pharmaceutical Co., Ltd. Dérivés de glycérol, procédé pour leur préparation et compositions pharmaceutiques les contenant
EP0109255A2 (fr) * 1982-11-11 1984-05-23 Ono Pharmaceutical Co., Ltd. Dérivés du glycérol
EP0142333A2 (fr) * 1983-11-08 1985-05-22 Ono Pharmaceutical Co., Ltd. Dérivés du glycérol
EP0146258A2 (fr) * 1983-11-10 1985-06-26 Ono Pharmaceutical Co., Ltd. Dérivés de glycérol
EP0145303A1 (fr) * 1983-11-14 1985-06-19 Ono Pharmaceutical Co., Ltd. Dérivés du glycérol
EP0147768A2 (fr) * 1983-12-30 1985-07-10 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Dérivés du glycérol
EP0208932A2 (fr) * 1985-06-18 1987-01-21 F. Hoffmann-La Roche Ag Dérivés de glycérine
EP0254540A2 (fr) * 1986-07-22 1988-01-27 Takeda Chemical Industries, Ltd. Dérivés du glycérol, procédé de préparation et utilisation
EP0255366A2 (fr) * 1986-07-30 1988-02-03 Takeda Chemical Industries, Ltd. Composé lipidique contenant de l'azote et du soufre, production et utilisation

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5973000A (en) * 1996-06-03 1999-10-26 Shiseido Company, Ltd. Hair revitalization tonic composition containing a lipid derivative and use thereof
US6177067B1 (en) 1996-08-09 2001-01-23 Shiseido Company, Ltd. Hair revitalizing tonic composition containing a 2,2-dimethylpropanediol compound and use thereof

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