WO2001045744A2 - Novel compounds of unsaturated fatty acids - Google Patents

Novel compounds of unsaturated fatty acids Download PDF

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Publication number
WO2001045744A2
WO2001045744A2 PCT/GB2000/004919 GB0004919W WO0145744A2 WO 2001045744 A2 WO2001045744 A2 WO 2001045744A2 GB 0004919 W GB0004919 W GB 0004919W WO 0145744 A2 WO0145744 A2 WO 0145744A2
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Prior art keywords
compound
disorders
group
formula
hereinbefore defined
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PCT/GB2000/004919
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French (fr)
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WO2001045744A3 (en
Inventor
Chaniyilparampu Nanappan RAMCHAND
Alan Christopher Spivey
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Sun Pharmaceutical Industries Ltd
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Priority to AU22058/01A priority Critical patent/AU2205801A/en
Publication of WO2001045744A2 publication Critical patent/WO2001045744A2/en
Publication of WO2001045744A3 publication Critical patent/WO2001045744A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound

Definitions

  • the present invention relates to novel compounds of unsaturated fatty acids, methods for their preparation, compositions thereof and the use thereof as a therapeutic.
  • a common problem in many areas of drug development is to improve the efficacy and minimise any undesirable side effects of drugs found to have activity in alleviating or combating therapeutic disorders. Since a further problem in developing new drugs is the need to conduct prolonged trials to assess the long-term effects of the drug and gain regulatory approval, there are advantages in improving existing drugs which have been granted regulatory approval.
  • D is a therapeutic drug in covalently or electrovalently bound form
  • A is an unsaturated fatty acid in covalently or electrovalently bound form
  • each of n and m are selected from 1-6;
  • L is a linking scaffold
  • p 0, 1, 2 or 3.
  • Unsaturated fatty acids are selected from any known dietary and health promoting supplements, typically derived from fish oils. These are of wide spread use and a number of benefits are associated with the daily intake of fish oils as dietary and general health promoting supplements.
  • Fish oils comprise unsaturated fatty acids, including as one of the acids, a compound known as Omega 3, Omega 6 or EPA, which is also available in isolated form, as dietary and health promoting supplement.
  • Therapeutic drugs are selected from any known therapeutic drugs, in any known form, including their various and preferred isomeric forms. In particular in the case of drugs including chiral centres, these may be in the form of a specific enantiomer associated with additional favorable properties or performance by comparison with the racemate. Preferably therapeutic drugs are selected from any drugs suited for oral administration.
  • the scaffolding and/or linking of components A, D as hereinbefore defined may be selected in manner to control the dosage of therapeutic drugs and in particular to control the efficacy thereof.
  • a given therapeutic drug may therefore be suited for use in a compound of formula I as hereinbefore defined having a particular ratio of D to A.
  • n,m,p are therefore determined by the nature of D,A and L and their respective valences and molar ratios within the compound of formula I.
  • n and m as hereinbefore defined are selected from 1, 2 and 3, more preferably n is 1 and m is 1 or 2.
  • D, A and/or L suitably comprise from 1 - 6, preferably 1, 2 or 3 mono or multivalent linking sites X which are each independently selected from reactive species capable of mono or multi covalently or electrovalently associating units D and A as herein before defined.
  • Linking sites X are preferably selected from pairs of cationic and anionic moieties generated by introduction or abstraction of a proton H + , or by introduction of a positively charged amino or azo group or negatively charged nitro, carbonate, sulphonate, sulphenate, sulphurate, oxide, phosphate, phosphonate, silicate, chlorosilicate, chlorate group and the like, or are selected from pairs of covalent moieties such as nucleophilic and electrophilic groups suited for substitution or addition-elimination reactions selected from carboxylic acid derivatives such as acid chloride, acid anhydride, cyanide and the like, alkenyl, alkynyl, haloalkyl and haloaryl wherein halo may be fluoride, chloride, bromide or iodide, hydroxyl, amino and the like.
  • linking sites X present on D and A as herein before defined are generated by respective addition and removal of protons and on L, where present, by generation of hydroxyl or carboxylic acid groups.
  • a as hereinbefore defined may be any non-toxic C 15-25 unsaturated acid, preferably a C 16 , C ]7 , C 18 , C 20 or C 2 unsaturated fatty acid, more preferably is a C 20 unsaturated fatty carboxylic acid having unsaturation at C 3 , C 6 , C 9 , C ]2 and C 15 and a carboxylic group at C 20 , or analogue or derivative thereof, for example is Omega 3, Omega 6 or EPA, in covalent or electrovalently bound form .
  • each L as hereinbefore defined may support and/or link some or all of D and A present in the compound of formula I as hereinbefore defined.
  • all or some of D and A present in the compound of formula I as hereinbefore defined may be linked or self-supporting in combination.
  • L comprises a C 1-8 aliphatic straight or branched chain alkyl including from one to five in-chain or pendant linking sites X selected from sites as hereinbefore defined for X, and preferably comprising hydroxyl, amino or carboxylic acid derivatives.
  • L comprises straight chain or branched C 1-8 alkyl having linking sites X interspersed along the chain or pendant therefrom.
  • L is selected from CH 2 X(CHX) 1-6 CH 2 X, CH 2 X(CH 2 ) 1-6 CH 2 X, CH 2 X(CHX) 1-6 (CH 2 ) 6-1 CH 2 X, CH[(CHX) 0-1 (CH 2 ) 0-1 CH 2 X] 3 and C[(CHX) 0- i(CH 2 ) 0- iCH 2 X] 4 .
  • At least one group X present on L is the group -OH which is suited for linking to nucleophilic groups X present on A which are the carboxyl group of the acid in ionic form; and at least one group X present on L is a nucleophilic group -C0 2 " which is suited for covalent linking to a group X present on D, for example the sulphonyl amide group of the sulpiride in ionic form.
  • p is preferably 0 and the or each component D is covalently or electrovalently bonded by sites X to the or each A.
  • most preferably X present on A is a carboxyl group of the fatty acid in ionic form which is suited for linking to a group X present on D, for example the tertiary amine group of the sulpiride in ionic form.
  • D as hereinbefore defined is therefore selected from ions of known therapeutic drugs including those known as Clozapine, Chlorpromazine, Sulpiride, Haloperidol, Amitriptyline and Orphenadrine, other known anti-psychotic drugs, anti-histamines, anti-hypertensives and the like and drugs including but not limited to:
  • Drugs for treating infections such as antiviral drugs, antibacterial drugs, antifungal drugs, antiprotozoal drugs, antihelmintics;
  • Cardiovascular system such as positive inotropic drugs, diuretics, anti- arrhythmic drugs, beta-adrenoceptor blocking drugs, calcium channel blockers, sympathomimetics, anticoagulants, antiplatelet drugs, fibrinolytic drugs, lipid-lowering drugs;
  • Gastro-intestinal system agents such as antacids, antispasmodics, ulcer- healing, drugs, anti-diarrhoeal drugs, laxatives, central nervous system, hypnotics and anxiolytics, antipsychotics, antidepressants, central nervous system stimulants, appetite suppressants, drugs used to treat nausea and vomiting, analgesics, antiepileptics, drugs used in parkinsonism, drugs used in substance dependence;
  • Malignant disease and immunosuppresion agents such as cytotoxic drugs, immune response modulators, sex hormones and antagonists of malignant diseases;
  • Respiratory system agents such as bronchodilators, corticosteroids, cromoglycate and related therapy, antihistamines, respiratory stimulants, pulmonary surfactants, systemic nasal decongestants;
  • Musculoskeletal and joint diseases agents such as drugs used in rheumatic diseases, drugs used in neuromuscular disorders; and
  • optically active drugs including for example sulpiride, haloperidol and arphenadrone are provided in their preferred enantiomeric form as known in the art.
  • Compounds of Formula I as herein before defined in which n and/or m are independently 2 or 3 may comprise the same or different therapeutic drug and the same or different unsaturated fatty acid.
  • composition comprising a therapeutically effective amount of a compound of formula I as hereinbefore defined.
  • the composition may comprise any additional components selected from carriers, diluents, adjuvants, preservatives, dispersants, solvants, emulsifying agents and the like, as known in the art.
  • composition may include additional amounts of the therapeutic drug and/or of the unsaturated fatty acid in physical admixture with the compound of Formula I. This is of particular advantage for example if it is desired to achieve a form of staged or controlled release or active materials.
  • composition may include an amount of any other desired drugs, dietary and health promoting supplements and the like in physical admixture with the compound of formula I as hereinbefore defined.
  • compositions may comprise creams, gels, syrups, pastes, sprays, solutions, suspensions, powders, microparticles, granules, pills, capsules, tablets, pellets, suppositories, pessaries, colloidal matrices, monoliths and boluses and the like, for administration by topical, oral, rectal, parenteral, epicutaneous, mucosal, intravenous, intramuscular, intrarespiratory or like application routes.
  • the composition is suited for oral administration and is in the form of a neat liquid (oil), suspension, solution, emulsion, paste, gel, foam, aerosol, spray, powder, granule, capsule, tablet, and the like.
  • a process for the preparation of a composition as hereinbefore defined comprising admixing a therapeutic effective amount of a compound of formula I with additional components as hereinbefore defined and providing in form as hereinbefore defined.
  • Y and Z are each independently respectively counterions or leaving groups or moieties associated with linking sites X as hereinbefore defined, and are selected from species as hereinbefore defined for X, and q and r are selected from 1-6 and are determined by their valence, the valence of linking sites X and the molar ratios of A, D and L .
  • Reaction is preferably carried out in suitable solvent or otherwise in intimate admixture. Reaction may be carried out with regulated molarity or may generate compounds of formula I of different molarity with subsequent isolation of desired product. Compounds of formula I may be obtained by successive reaction of precursors II and III, in manner to introduce multiple components A and/or D.
  • Precursors of formula II and III may be obtained by interconversion from the commercially available D and A, by ionic or covalent reaction with L and/or sources of Y and Z as hereinbefore defined.
  • Therapeutic disorders include infections, cardiovascular disorders, gastrointestinal disorders, malignant disease and immune response disorders, respiratory system disorders, musculosleletal and joint disorders, immunological disorders and the like as hereinbefore described.
  • the combined administration may be by administration of compounds of formula I as hereinbefore defined, in a suitable regime which may be adapted to include reduced amounts of the therapeutic drug, in comparison with conventional regimes for sole administration of the drug, equivalent levels with increased efficacy, reduced or equivalent frequency with equal or increased efficacy or the like.
  • Figures 1 and 2 Structures of D, A and L as hereinbefore defined according to a preferred embodiment are shown in Figures 1 and 2.
  • Figure 1 are shown structures of known therapeutic drugs.
  • Figure 2 is shown a flow scheme for reaction of L, A and D according to the invention.

Abstract

Compound of formula I: DnLpAm, wherein D is a therapeutic drug in covalently or electrovalently bound form; A is an unsaturated fatty acid in covalently or electrovalently bound form; each of n and m are selected from 1-6; L is a linking scaffold; and p is 0, 1, 2 or 3; composition comprising a therapeutically effective amount of a compound of formula I with additional components selected from carriers, diluents, adjuvants, preservatives, dispersants, solvants, emulsifying agents; process for the preparation thereof; and the Compound or composition for use in alleviating or combating therapeutic disorders, which include infections, cardiovascular disorders, gastrointestinal disorders, malignant disease and immune response disorders, respiratory system disorders, musculoskeletal and joint disorders, immunological disorders.

Description

NOVEL COMPOUNDS OF UNSATURATED FATTY ACIDS
The present invention relates to novel compounds of unsaturated fatty acids, methods for their preparation, compositions thereof and the use thereof as a therapeutic.
A common problem in many areas of drug development is to improve the efficacy and minimise any undesirable side effects of drugs found to have activity in alleviating or combating therapeutic disorders. Since a further problem in developing new drugs is the need to conduct prolonged trials to assess the long-term effects of the drug and gain regulatory approval, there are advantages in improving existing drugs which have been granted regulatory approval.
We have now surprisingly found that a novel class of compounds of unsaturated fatty acids are admirably suited to address these problems and provide a range of therapeutic compounds which may provide a number of advantages and improvements and moreover, may gain the benefit of existing regulatory approval for existing therapeutic drugs.
In the broadest aspect of the present invention, there is provided a novel compound of formula I:
(I) Dn LpAm
wherein D is a therapeutic drug in covalently or electrovalently bound form; A is an unsaturated fatty acid in covalently or electrovalently bound form;
each of n and m are selected from 1-6;
L is a linking scaffold; and
p is 0, 1, 2 or 3.
Unsaturated fatty acids are selected from any known dietary and health promoting supplements, typically derived from fish oils. These are of wide spread use and a number of benefits are associated with the daily intake of fish oils as dietary and general health promoting supplements. Fish oils comprise unsaturated fatty acids, including as one of the acids, a compound known as Omega 3, Omega 6 or EPA, which is also available in isolated form, as dietary and health promoting supplement.
Therapeutic drugs are selected from any known therapeutic drugs, in any known form, including their various and preferred isomeric forms. In particular in the case of drugs including chiral centres, these may be in the form of a specific enantiomer associated with additional favorable properties or performance by comparison with the racemate. Preferably therapeutic drugs are selected from any drugs suited for oral administration.
We have surprisingly found that combinations of drugs as herein before defined and fatty acids as herein before defined can lead to significant improvements in subjects suffering from therapeutic disorders, in particular disorders such as schizophrenia, and the benefits may be apparent in a number of therapeutic areas. Without being limited to this theory it also thought that compounds of formula I as herein before defined provide access to a number of novel uses of known drugs which are thought to have effect in treating additional therapeutic disorders.
It is a particular advantage of the invention that the scaffolding and/or linking of components A, D as hereinbefore defined may be selected in manner to control the dosage of therapeutic drugs and in particular to control the efficacy thereof. A given therapeutic drug may therefore be suited for use in a compound of formula I as hereinbefore defined having a particular ratio of D to A.
Values of integers n,m,p are therefore determined by the nature of D,A and L and their respective valences and molar ratios within the compound of formula I.
Preferably n and m as hereinbefore defined are selected from 1, 2 and 3, more preferably n is 1 and m is 1 or 2.
D, A and/or L suitably comprise from 1 - 6, preferably 1, 2 or 3 mono or multivalent linking sites X which are each independently selected from reactive species capable of mono or multi covalently or electrovalently associating units D and A as herein before defined.
Linking sites X are preferably selected from pairs of cationic and anionic moieties generated by introduction or abstraction of a proton H+, or by introduction of a positively charged amino or azo group or negatively charged nitro, carbonate, sulphonate, sulphenate, sulphurate, oxide, phosphate, phosphonate, silicate, chlorosilicate, chlorate group and the like, or are selected from pairs of covalent moieties such as nucleophilic and electrophilic groups suited for substitution or addition-elimination reactions selected from carboxylic acid derivatives such as acid chloride, acid anhydride, cyanide and the like, alkenyl, alkynyl, haloalkyl and haloaryl wherein halo may be fluoride, chloride, bromide or iodide, hydroxyl, amino and the like.
Preferably linking sites X present on D and A as herein before defined are generated by respective addition and removal of protons and on L, where present, by generation of hydroxyl or carboxylic acid groups.
A as hereinbefore defined may be any non-toxic C15-25 unsaturated acid, preferably a C16, C]7, C18, C20 or C2 unsaturated fatty acid, more preferably is a C20 unsaturated fatty carboxylic acid having unsaturation at C3, C6, C9, C]2 and C15 and a carboxylic group at C20, or analogue or derivative thereof, for example is Omega 3, Omega 6 or EPA, in covalent or electrovalently bound form .
The or each L as hereinbefore defined may support and/or link some or all of D and A present in the compound of formula I as hereinbefore defined. Alternatively or additionally all or some of D and A present in the compound of formula I as hereinbefore defined may be linked or self-supporting in combination.
Preferably p is 1 and L comprises a C1-8 aliphatic straight or branched chain alkyl including from one to five in-chain or pendant linking sites X selected from sites as hereinbefore defined for X, and preferably comprising hydroxyl, amino or carboxylic acid derivatives. Preferably L comprises straight chain or branched C1-8 alkyl having linking sites X interspersed along the chain or pendant therefrom. More preferably L is selected from CH2X(CHX)1-6CH2X, CH2X(CH2)1-6CH2X, CH2X(CHX)1-6(CH2)6-1CH2X, CH[(CHX)0-1(CH2)0-1CH2X]3 and C[(CHX)0-i(CH2)0-iCH2X]4. Most preferably at least one group X present on L is the group -OH which is suited for linking to nucleophilic groups X present on A which are the carboxyl group of the acid in ionic form; and at least one group X present on L is a nucleophilic group -C02 " which is suited for covalent linking to a group X present on D, for example the sulphonyl amide group of the sulpiride in ionic form.
Alternatively p is preferably 0 and the or each component D is covalently or electrovalently bonded by sites X to the or each A. In this case, most preferably X present on A is a carboxyl group of the fatty acid in ionic form which is suited for linking to a group X present on D, for example the tertiary amine group of the sulpiride in ionic form.
D as hereinbefore defined is therefore selected from ions of known therapeutic drugs including those known as Clozapine, Chlorpromazine, Sulpiride, Haloperidol, Amitriptyline and Orphenadrine, other known anti-psychotic drugs, anti-histamines, anti-hypertensives and the like and drugs including but not limited to:
Drugs for treating infections such as antiviral drugs, antibacterial drugs, antifungal drugs, antiprotozoal drugs, antihelmintics;
Cardiovascular system such as positive inotropic drugs, diuretics, anti- arrhythmic drugs, beta-adrenoceptor blocking drugs, calcium channel blockers, sympathomimetics, anticoagulants, antiplatelet drugs, fibrinolytic drugs, lipid-lowering drugs;
Gastro-intestinal system agents such as antacids, antispasmodics, ulcer- healing, drugs, anti-diarrhoeal drugs, laxatives, central nervous system, hypnotics and anxiolytics, antipsychotics, antidepressants, central nervous system stimulants, appetite suppressants, drugs used to treat nausea and vomiting, analgesics, antiepileptics, drugs used in parkinsonism, drugs used in substance dependence;
Malignant disease and immunosuppresion agents such as cytotoxic drugs, immune response modulators, sex hormones and antagonists of malignant diseases;
Respiratory system agents such as bronchodilators, corticosteroids, cromoglycate and related therapy, antihistamines, respiratory stimulants, pulmonary surfactants, systemic nasal decongestants;
Musculoskeletal and joint diseases agents such as drugs used in rheumatic diseases, drugs used in neuromuscular disorders; and
Immunological products and vaccines.
Preferably optically active drugs including for example sulpiride, haloperidol and arphenadrone are provided in their preferred enantiomeric form as known in the art. Compounds of Formula I as herein before defined in which n and/or m are independently 2 or 3 may comprise the same or different therapeutic drug and the same or different unsaturated fatty acid.
In a further aspect of the invention there is provided a composition comprising a therapeutically effective amount of a compound of formula I as hereinbefore defined. The composition may comprise any additional components selected from carriers, diluents, adjuvants, preservatives, dispersants, solvants, emulsifying agents and the like, as known in the art.
The composition may include additional amounts of the therapeutic drug and/or of the unsaturated fatty acid in physical admixture with the compound of Formula I. This is of particular advantage for example if it is desired to achieve a form of staged or controlled release or active materials.
The composition may include an amount of any other desired drugs, dietary and health promoting supplements and the like in physical admixture with the compound of formula I as hereinbefore defined.
For use as pharmaceutical products fabricated using the inventive compounds, compositions may comprise creams, gels, syrups, pastes, sprays, solutions, suspensions, powders, microparticles, granules, pills, capsules, tablets, pellets, suppositories, pessaries, colloidal matrices, monoliths and boluses and the like, for administration by topical, oral, rectal, parenteral, epicutaneous, mucosal, intravenous, intramuscular, intrarespiratory or like application routes. Preferably the composition is suited for oral administration and is in the form of a neat liquid (oil), suspension, solution, emulsion, paste, gel, foam, aerosol, spray, powder, granule, capsule, tablet, and the like.
In a further aspect of the invention there is provided a process for the preparation of a composition as hereinbefore defined comprising admixing a therapeutic effective amount of a compound of formula I with additional components as hereinbefore defined and providing in form as hereinbefore defined.
In a further aspect of the invention there is provided a process for the preparation of a compound of formula I as hereinbefore defined comprising the reaction of precursor of formula II:
(II) DnLpYq
with precursor of formula III:
(III) AmL'p.Zr
wherein D, A, n, m, L and p are as hereinbefore defined, and L' and p' are as hereinbefore defined for L and p; and
Y and Z are each independently respectively counterions or leaving groups or moieties associated with linking sites X as hereinbefore defined, and are selected from species as hereinbefore defined for X, and q and r are selected from 1-6 and are determined by their valence, the valence of linking sites X and the molar ratios of A, D and L . Reaction is preferably carried out in suitable solvent or otherwise in intimate admixture. Reaction may be carried out with regulated molarity or may generate compounds of formula I of different molarity with subsequent isolation of desired product. Compounds of formula I may be obtained by successive reaction of precursors II and III, in manner to introduce multiple components A and/or D.
Precursors of formula II and III may be obtained by interconversion from the commercially available D and A, by ionic or covalent reaction with L and/or sources of Y and Z as hereinbefore defined.
In a further aspect of the invention there is provided a compound or composition as hereinbefore defined for use in alleviating or combating therapeutic disorders. Therapeutic disorders include infections, cardiovascular disorders, gastrointestinal disorders, malignant disease and immune response disorders, respiratory system disorders, musculosleletal and joint disorders, immunological disorders and the like as hereinbefore described.
Studies have shown that certain neurological disorders may be alleviated with a greater efficacy as a result of the combined administration of schizophrenic drugs, for example, together with unsaturated fatty acids as hereinbefore defined. The combined administration may be by administration of compounds of formula I as hereinbefore defined, in a suitable regime which may be adapted to include reduced amounts of the therapeutic drug, in comparison with conventional regimes for sole administration of the drug, equivalent levels with increased efficacy, reduced or equivalent frequency with equal or increased efficacy or the like. The invention is now illustrated in non limiting manner with reference to the following figures wherein:
Structures of D, A and L as hereinbefore defined according to a preferred embodiment are shown in Figures 1 and 2. In Figure 1 are shown structures of known therapeutic drugs. In Figure 2 is shown a flow scheme for reaction of L, A and D according to the invention.
Further advantages of the invention are apparent from the foregoing.

Claims

1. Compound of formula I:
(I) Dn LpAm
wherein D is a therapeutic drug in covalently or electrovalently bound form;
A is an unsaturated fatty acid in covalently or electrovalently bound form;
each of n and m are selected from 1-6;
L is a linking scaffold; and
p is 0, 1, 2 or 3.
2. Compound as claimed in Claim 1 wherein n and m are selected from 1, 2 and 3.
3. Compound as claimed in Claims 1 or 2 wherein n is 1 and m is 1 or 2.
4. Compound as claimed in any of Claims 1-3 wherein D, A and/or L comprise 1 - 6 mono or multivalent linking sites X which are each independently selected from reactive species capable of mono or multi covalently or electrovalently associating units D and A.
5. Compound as claimed in Claim 4 wherein linking sites X are selected from pairs of cationic and anionic moieties generated by introduction or abstraction of a proton H+, or by introduction of a positively charged amino or azo group or negatively charged nitro, carbonate, sulphonate, sulphenate, sulphurate, oxide, phosphate, phosphonate, silicate, chlorosilicate, chlorate group, or are selected from pairs of covalent moieties such as nucleophilic and electrophilic groups suited for substitution or addition-elimination reactions selected from carboxylic acid derivatives such as acid chloride, acid anhydride, cyanide and the like, alkenyl, alkynyl, haloalkyl and haloaryl wherein halo is fluoride, chloride, bromide or iodide, hydroxyl, amino.
6. Compound as claimed in Claim 4 or 5 wherein linking sites X present on D and A as herein before defined are generated by respective addition and removal of protons and on L, where present, by generation of hydroxyl or carboxylic acid groups.
7. Compound as claimed in any of Claims 1-6 wherein A is any non-toxic Ci5-25 unsaturated acid.
8. Compound as claimed in any of Claims 1-7 wherein A is a C20 unsaturated fatty carboxylic acid having unsaturation at C3, C6, C9, C! 2 and Ci5 and a carboxylic group at C20, or analogue or derivative thereof.
9. Compound as claimed in any of Claims 1-8 wherein the or each L as hereinbefore defined supports and/or links some or all of D and A present in the compound.
10. Compound as claimed in any of Claims 1-8 wherein all or some of D and A present in the compound are linked or self-supporting in combination.
11. Compound as claimed in any of Claims 1-10 wherein p is 1 and L comprises a CI-8 aliphatic straight or branched chain alkyl including from one to five in-chain or pendant linking sites X selected from sites as hereinbefore defined in Claims 3-5 for X, and preferably comprising hydroxyl, amino or carboxylic acid derivatives.
12. Compound as claimed in Claim 11 wherein L comprises straight chain or branched C]-8 alkyl having linking sites X interspersed along the chain or pendant therefrom.
13. Compound as claimed in Claim 11 or 12 wherein L is selected from CH2X(CHX)1-6CH2X, CH2X(CH2)1-6CH2X, CH2X(CHX)1-6(CH2)6-1CH2X, CH[(CHX)0-1(CH2)0-1CH2X]3 and C[(CHX)0-1(CH2)0-1CH2X]4.
14. Compound as claimed in any of Claims 11-13 wherein at least one group X present on L is the group -OH which is suited for linking to nucleophilic groups X present on A which are the carboxyl group of the acid in ionic form; and at least one group X present on L is a nucleophilic group -CO2 " which is suited for covalent linking to a group X present on D, for example the sulphonyl amide group of the sulpiride in ionic form.
15. Compound as claimed in any of Claims 1-10 wherein p is 0 and the or each component D is covalently or electrovalently bonded by sites X to the or each A.
16. Compound as claimed in Claim 15 wherein X present on A is a carboxyl group of the fatty acid in ionic form which is suited for linking to a group X present on D.
17. Compound as claimed in any of Claims 1-16 wherein D is selected from ions of known anti-psychotic drugs, anti-histamines, anti- hypertensives drugs for treating infections, cardiovascular system agents, gastro-intestinal system agents, malignant disease and immunosuppresion agents, respiratory system agents, musculoskeletal and joint diseases agents, immunological products and vaccines.
18. Compound as claimed in any of Claims 1-17 wherein D is selected from Clozapine, Chlorpromazine, Sulpiride, Haloperidol, Amitriptyline and Orphenadrine.
19. Compound as claimed in any of Claims 1-18 wherein n and/or m are independently 2 or 3 comprising the same or different therapeutic drug and the same or different unsaturated fatty acid.
20. Composition comprising a therapeutically effective amount of a compound of formula I as claimed in any of Claims 1-19, with additional components selected from carriers, diluents, adjuvants, preservatives, dispersants, solvants, emulsifying agents.
21. Composition as claimed in Claim 20 including additional amounts of the therapeutic drug and or of the unsaturated fatty acid in physical admixture with the compound of Formula I.
22. Composition as claimed in Claim 20 or 21 which is suited for oral administration and is in the form of a neat liquid (oil), suspension, solution, emulsion, paste, gel, foam, aerosol, spray, powder, granule, capsule, tablet, and the like.
23. Process for the preparation of a compound of formula I as hereinbefore defined comprising the reaction of precursor of formula II: (II) DnLpYq
with precursor of formula III:
(III) AmL'p-Zr
wherein D, A, n, m, L and p are as hereinbefore defined, and L' and p' are as hereinbefore defined for L and p; and
Y and Z are each independently respectively counterions or leaving groups or moieties associated with linking sites X as hereinbefore defined, and are selected from species as hereinbefore defined for X, and q and r are selected from 1-6 and are determined by their valence, the valence of linking sites X and the molar ratios of A, D and L .
24. Compound or composition as claimed in any of Claims 1-22 for use in alleviating or combating therapeutic disorders, which include infections, cardiovascular disorders, gastrointestinal disorders, malignant disease and immune response disorders, respiratory system disorders, musculosleletal and joint disorders, immunological disorders.
25. Compound or composition as hereinbefore described and/or illustrated in the description and/or Figures.
PCT/GB2000/004919 1999-12-21 2000-12-21 Novel compounds of unsaturated fatty acids WO2001045744A2 (en)

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Cited By (7)

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US9085527B2 (en) 2008-07-08 2015-07-21 Catabasis Pharmaceuticals, Inc. Fatty acid acylated salicylates and their uses
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CN102149673A (en) * 2008-07-08 2011-08-10 凯特贝希制药公司 Fatty acid acetylated salicylates and their uses
EP3064230A1 (en) 2009-07-10 2016-09-07 Boston Scientific Scimed, Inc. Use of nanocrystals for a drug delivery balloon
US9238077B2 (en) 2009-09-01 2016-01-19 Catabasis Pharmaceuticals, Inc. Fatty acid niacin conjugates and their uses
US9486534B2 (en) 2009-09-01 2016-11-08 Catabasis Pharmaceuticals, Inc. Niacin conjugated fatty acid mixtures and their uses
USRE46605E1 (en) 2009-09-01 2017-11-14 Catabasis Pharmaceuticals, Inc. Fatty acid niacin conjugates and their uses
USRE46608E1 (en) 2009-09-01 2017-11-14 Catabasis Pharmaceuticals, Inc. Fatty acid niacin conjugates and their uses
EP2685969A4 (en) * 2011-03-18 2014-08-06 Catabasis Pharmaceuticals Inc Use of intracellular enzymes for the release of covalently linked bioactives
EP2685969A2 (en) * 2011-03-18 2014-01-22 Catabasis Pharmaceuticals, Inc. Use of intracellular enzymes for the release of covalently linked bioactives

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