WO2003002593A2 - Structures peptidiques utiles pour la modulation competitive de la catalyse de dipeptidyle peptidase iv - Google Patents

Structures peptidiques utiles pour la modulation competitive de la catalyse de dipeptidyle peptidase iv Download PDF

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WO2003002593A2
WO2003002593A2 PCT/EP2002/007128 EP0207128W WO03002593A2 WO 2003002593 A2 WO2003002593 A2 WO 2003002593A2 EP 0207128 W EP0207128 W EP 0207128W WO 03002593 A2 WO03002593 A2 WO 03002593A2
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acid
pro
amino acid
compound
gly
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PCT/EP2002/007128
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English (en)
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WO2003002593A3 (fr
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Hans Ulrich Demuth
Torsten Hoffmann
Susanne Manhart
Matthias Hoffmann
Jochen Heins
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Probiodrug Ag
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Priority to CA002419888A priority Critical patent/CA2419888A1/fr
Priority to JP2003508973A priority patent/JP2004530729A/ja
Priority to EP02762308A priority patent/EP1399469A2/fr
Publication of WO2003002593A2 publication Critical patent/WO2003002593A2/fr
Priority to NO20030900A priority patent/NO20030900L/no
Publication of WO2003002593A3 publication Critical patent/WO2003002593A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/081—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic

Definitions

  • the present invention relates to the function of dipeptidyl peptidase IV (DP IV, synonym: DPP IV, CD26, EC 3.4.14.5) and DP IV-like enzymes within a subject and their biological effects on the plasma levels of the insulinotropic peptides gastric inhibitory polypeptide 1-42 (GIP 1-42 ) and glucagon-like peptide amides-1 (GLP-1 7-36 ) and (GL.P-I 7 . 37 ) or analogues thereof.
  • DP IV dipeptidyl peptidase IV
  • GIP 1-42 insulinotropic peptides gastric inhibitory polypeptide 1-42
  • GLP-1 7-36 glucagon-like peptide amides-1
  • GL.P-I 7 . 37 or analogues thereof.
  • the invention relates further to the treatment of impaired glucose tolerance, diabetes mellitus, glucosuria and metabolic acidosis by selective modulation of the activity of DP IV-like enzymes due to the use of tri-, tetra- and pentapeptide substrates of dipeptidyl peptidase IV in pharmacological doses to inhibit the physiological turnover of endogenous peptide hormones.
  • Dipeptidyl peptidase IV is a serine protease which cleaves off N-terminal dipeptides from a peptide chain containing, preferably a proline residue in the penultimate position.
  • DP IV-like enzymes are structurally related enzymes to DP IV (Blanco et. al., 1998) which may share a certain sequence homology to the DP IV sequence, but which share even if they are not structurally related (by convergent evolution) the substrate specificity of DP IV of removing dipeptides from the N-termini of polypeptides by cleaving after a penultimate proline residue.
  • Such enzymes including DP IV, DP II at one hand and attractin on the other hand (Fukasawa et al., 2001) - are also capable to remove dipeptides with a penultimate alanine (or serine or glycine residues) from the N-termini of polypeptides but usually with reduced catalytic efficacy as compared to the post-proline cleavage (Yaron & Naider, 1993). They show the common feature that they accommodate in the Pro-position of the target-protein also Ala, Ser, Thr and other amino acids with small hydrophobic side-chains as, Gly or Val. The hydrolytic efficacy is ranked Pro>Ala» Ser, Thr » Gly, Val.
  • DPIV-like enzymes are disclosed in WO 01/19866, WO 02/04610, WO 02/34900 and WO02/31134.
  • WO 01/19866 discloses human dipeptidyl aminopeptidase 8 (DPP8) with structural und functional similarities to DPIV and fibroblast activation protein (FAP) :
  • DPP8 human dipeptidyl aminopeptidase 8
  • FAP fibroblast activation protein
  • the dipeptidyl peptidase IV-like enzyme of WO 02/04610 is well known in the art.
  • this enzyme is registered as KIAA1492 (registration in February 2001 , submitted on April 04, 2000, AB040925) and in the MEROPS data base.
  • WO 02/34900 discloses a dipeptidyl peptidase 9 (DPP9) with significant homology to the amino acid sequences of DPIV and DPP8.
  • DPP9 dipeptidyl peptidase 9
  • WO 02/31134 discloses three DPIV-like enzymes, DPRP1 , DPRP2 and DPRP3. Sequence analysis revealed that DPRP1 is identical to DPP8, as disclosed in WO 01/19866, that DPRP2 is identical to DPP9 and that DPRP3 is identical to KIAA1492 as disclosed in WO 02/04610.
  • DP IV is responsible for cleaving glucagon-like peptide-1 and gastric inhibitory peptides, thereby shortening the half life of GLP-1 and GIP and their physiological response in the circulation. From inhibition of serum DP IV, a significant increase in the bioactivity of the incretins has been shown. Since the incretins are major stimulators of pancreatic insulin secretion and have direct beneficial effects on glucose disposal, DP IV inhibition represents an attractive approach for treating impaired glucose tolerance and non-insulin-dependent diabetes mellitus (NIDDM) and related disorders, like glucosuria and metabolic ac'idosis (see DE 196 16486 and WO 97/40832).
  • NIDDM non-insulin-dependent diabetes mellitus
  • the substrate specificity of the enzyme dipeptidyl peptidase IV may be summarized in the following way:
  • Dipeptidyl peptidase IV hydrolyzes oligopeptides and proteins from the N- terminus, splitting off dipeptide units, when the penultimate residue is proline, hydroxyproline, dehydroproline, pipecolic acid or alanine.
  • the best substrates according to their k ca /K m values are those with a proline residue in the P1- position.
  • DP IV requires a 'trans' peptide-bond between P1 and P2 residues.
  • N-terminal amino group of substrates must be protonated in order to be susceptible to DP IV.
  • a proline residue in the P1 '-position of substrates prevents substrate hydrolysis by dipeptidyl peptidase IV. This enzyme does not release arginylproline from bradykinin, for instance.
  • the present invention is directed to compounds represented by formula (I),
  • DP IV-like enzymes are substrates of proline-specific peptidases, in particular of DP IV and other enzymes having similar DP IV-like enzymatic activity profiles ("DP IV-like enzymes"), and may be useful either as substrates or as antagonists of DP IV and DP IV-like enzymes to inhibit the physiological turnover of endogenous peptide hormones by competitive catalysis.
  • the compounds of formula (l) may be used for treating impaired glucose tolerance, diabetes mellitus, glucosuria, metabolic acidosis diagnosed in a subject, cancer and multiple sclerosis.
  • Figure 1 shows plasma DP IV activity after intravasal administration of 10, 30 and 100 mg/kg b.w. Ile-Pro-Ile in Wistar rats;
  • Figure 2 shows plasma DP IV activity after administration of 10, 30 and 100 mg/kg b.w. Ile-Pro-Ile and of 10 mg/kg b.w. and isoleucyl thiazolidine fumarate as positive control in Wistar rats (AUC 0-20 min);
  • Figure 3 shows plasma DP IV activity after intravasal administration of 10, 30 and 100 mg/kg b.w. Val-Pro-Leu in Wistar rats;
  • Figure 4 shows plasma DP IV activity after administration of 10, 30 and 100 mg/kg b.w. Val-Pro-Leu and of 10 mg/kg b.w. isoleucyl thiazolidine fumarate as positive control in Wistar rats (AUC 0-20 min);
  • Figure 5 shows plasma DP IV activity after oral and intravasal administration of 100 mg/kg b.w. f-butyl-Gly-Pro-lle in Wistar rats;
  • Figure 6 shows plasma DP IV activity after oral and intravasal administration of 100 mg/kg b.w. f-butyl-Gly-Pro-lle, and of 10 mg/kg b.w. isoleucyl thiazolidine fumarate as positive control in Wistar rats(AUC 0-120 min);
  • Figure 7 shows the course of plasma glucose concentration after oral administration of 100 mg/kg b.w. f-butyl-Gly-Pro-lle, and of 10 mg/kg b.w. isoleucyl thiazolidine fumarate as positive control in diabetic Zucker rats;
  • Figure 8 shows the improvement of glucose tolerance and G-AUC during OGTT after oral administration of 100 mg/kg b.w. f-butyl-Gly-Pro-lle, and of 10 mg/kg b.w. isoleucyl thiazolidine fumarate as positive control diabetic Zucker rats (G-AUC 0-60 min).
  • the present invention is directed to peptides of the following formula 0) :
  • A, B, C, D and E are any amino acids including proteinogenic amino acids, non- proteinogenic amino acids, L-amino acids and D-amino acids and wherein E and/or D may be absent or B and/or A may be absent with additional conditions as hereinafter detailed:
  • A is any amino acid residue except a D-amino acid
  • B is an amino acid selected from Pro, Ala, Ser, Gly, Hyp, acetidine-(2)-carboxylic acid and pipecolic acid,
  • C is any amino acid except Pro, Hyp, acetidine-(2)-carboxylic acid, pipecolic acid and except N-alkylated amino acids, e.g. N-methyl valine and sarcosine,
  • D is any amino acid or missing
  • E is any amino acid or missing
  • or C is any amino acid except Pro, Hyp, acetidine-(2)-carboxylic acid, pipecolic acid, except N-alkylated amino acids, e.g. N-methyl valine and sarcosine and except a D- amino acid,
  • D is an amino acid selected from Pro, Ala, Ser, Gly, Hyp, acetidine-(2)-carboxylic acid and pipecolic acid, and
  • E is any amino acid except Pro, Hyp, acetidine-(2)-carboxylic acid, pipecolic acid and except N-alkylated amino acids, e.g. N-methyl valine and sarcosine..
  • the present invention especially refers to compounds of formula (I)
  • A is any amino acid except a D-amino acid
  • B is an amino acid selected from Pro, Ala, Ser, Gly, Hyp, acetidine-(2)-carboxylic acid and pipecolic acid,
  • C is any amino acid except Pro, Hyp, acetidine-(2)-carboxylic acid, pipecolic acid and except N-alkylated amino acids, e.g. N-methyl valine and sarcosine,
  • D is any amino acid or missing
  • E is any amino acid or missing.
  • A is any amino acid except a D-amino acid
  • B is an amino acid selected from Pro, Ala, Ser, Gly, Hyp, acetidine-(2)-carboxylic acid and pipecolic acid,
  • C is any amino acid except Pro, Hyp, acetidine-(2)-carboxylic acid, pipecolic acid, except N-alkylated amino acids, e.g. N-methyl valine and sarcosine and except a D- amino acid, D is an amino acid selected from Pro, Ala, Ser, Gly, Hyp, acetidine-(2)-carboxylic acid and pipecolic acid, and
  • E is any amino acid except from Pro, Hyp, acetidine-(2)-carboxylic acid, pipecolic acid and except N-alkylated amino acids, e.g. N-methyl valine and sarcosine.
  • A is a L-amino acid.
  • C is a L-amino acid
  • A is t-butyl-Gly, He or Val
  • especially preferred A is t-butyl-Gly
  • C is t-butyl-Gly, lie or Val; more preferred
  • C is t-butyl-Gly or Val
  • especially preferred C is t-butyl-Gly
  • f-butyl-Gly-Pro-lle especially preferred are f-butyl-Gly-Pro-lle; f-butyl-Gly-Pro-Val; Val-Pro-f-butyl-Gly, lle-Pro-f-butyl-Gly or t- butyl-Gly-Pro- -butyl-Gly and pharmaceutically acceptable salts thereof.
  • the compound of the present invention can be in the free acid peptide form or the C- terminal amide peptide form.
  • the compounds of the present invention may be present as the free C-terminal acid or as the C-terminal amide form.
  • the free acid peptides or the amides may be varied by side chain modifications.
  • Such side chain modifications are for instance, but not restricted to, homoserine addition, pyroglutamic acid addition, disulphide bond formation, deamidation of asparagine or glutamine residues, methylation, t-butylation, t-butyloxycarbonylation, 4-methylbenzylation, thioanysilation, thiocresylation, benzyloxymethylation, 4-nitrophenylation, benzyloxycarbonylation, 2- nitrobencoylation, 2-nitrosulphenylation, 4-toluenesulphonylation, pentafluorophenylation, diphenylmethylation, 2-chlorobenzyloxycarbonylation, 2,4,5- trichlorophenylation, 2-bromobenzyloxycarbonylation, 9- fluor
  • the amino acids A, B, C, D, and E are attached to the adjacent amino acid with amide bonds in a usual manner and according to standard nomenclature so that the amino-terminus (N-terminus) of the amino acids is drawn on the left and the carboxyl-terminus of the amino acid is drawn on the right.
  • L and D-amino acids N-methyl-amino-acids; allo- and #?reo-forms of lie and Thr, which can, e.g. be ⁇ - ⁇ - or ⁇ -amino acids, whereof ⁇ -amino acids are preferred.
  • amino acids are: aspartic acid (Asp), glutamic acid (Glu), arginine (Arg), lysine (Lys), histidine (His), glycine (Gly), serine (Ser) and cysteine (Cys), threonine (Thr), asparagine (Asn), giutamine (Gin), tyrosine (Tyr), alanine (Ala), proline (Pro), valine (Val), isoleucine (lie), leucine (Leu), methionine (Met), phenylalanine (Phe), tryptophan (Trp), hydroxyproline (Hyp), beta-alanine (beta-Ala), 2-amino octanoic acid (Aoa), azetidine- (2)-carboxyIic acid (Ace), pipecolic acid (Pip), 3-amino propionic, 4-amino butyric and so forth, alpha-aminoisobutan
  • Examples of ⁇ j-amino acids are e.g.: 5-Ara (aminoraleric acid), 6-Ahx (aminohexanoic acid), 8-Aoc (aminooctanoic aicd), 9-Anc (aminovanoic aicd), 10-Adc (aminodecanoic acid), 11-Aun (aminoundecanoic acid), 12-Ado (aminododecanoic acid).
  • amino acids are: indanylglycine (Igl), indoline-2-carboxylic acid (Idc), octahydroindole-2-carboxylic acid (Oic), diaminopropionic acid (Dpr), diaminobutyric acid (Dbu), naphtylalanine (1-Nal), (2-Nal), 4-aminophenylalanin (Phe(4-NH 2 )), 4- benzoylphenylalanine (Bpa), diphenylalanine (Dip), 4-bromophenylalanine (Phe(4- Br)), 2-chlorophenylalanine (Phe(2-CI)), 3-chlorophenylalanine (Phe(3-CI)), 4- chlorophenylalanine (Phe(4-CI)), 3,4-chlorophenylalanine (Phe (3.4-CI2)), 3- fluorophenylalanine (Phe(3-F)), 4- fluoroph
  • the present invention furthermore refers to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of the present invention and a pharmaceutically acceptable carrier and/or diluent.
  • Such pharmaceutical compositions can be prepared by mixing at least one compound of the present invention and a pharmaceutically acceptable carrier and/or diluent.
  • the compounds and compositions according to the present invention can be used for the preparation of a medicament for the prophylaxis or treatment of a condition mediated by modulation of the dipeptidyl peptidase IV activity.
  • Such conditions are, e.g. selected from impaired glucose tolerance, diabetes mellitus, glucosuria, metabolic acidosis, cancer and multiple sclerosis.
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human, being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • composition is intended to encompass a product comprising at least one of the compounds of the present invention in the therapeutically effective amounts, as well as any product which results, directly or indirectly, from combinations of the claimed compounds.
  • the compounds of the present invention may also be present in the form of a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt generally takes a form in which an amino acids basic side chain is protonated with an inorganic or organic acid.
  • Representative organic or inorganic acids include, e.g.
  • the present invention further includes within its scope prodrugs of the compounds of this invention.
  • prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound.
  • the use of the present invention shall encompass the treatment of the various disorders described with prodrug versions of one or more of the claimed compounds, but which converts to the above specified compound in vivo after administration to the subject.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985 and the patent applications DE 198 28 113; WO 99/67278, DE 198 28 114 and WO 99/67279, fully incorporated herein by reference.
  • the compounds according to this invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms of the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e. hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
  • peptide substrates of the proline- specific serine protease dipeptidyl peptidase IV in vitro are the tripeptides Diprotin A (Ile-Pro-Ile), Diprotin B (Val-Pro-Leu) and Diprotin C (Val-Pro-lle). These compounds per se are excluded from the present invention.
  • Applicants have unexpectedly discovered that the compounds disclosed here act as substrates of dipeptidyl peptidase IV in vivo and, in pharmacological doses, inhibit the physiological turnover of endogenous peptide hormones by competitive catalysis.
  • Particularly preferred compounds or prodrugs of the present invention that could be useful as modulators of dipeptidyl peptidase IV and DP IV - like enzymes include those compounds or prodrugs which show Kj-values for DP IV binding, effectivity in DP IV inhibition in vivo after intravasal (i.v.) and/or oral (p.o.) administration to Wistar rats and improved glucose tolerance in vivo after i.v. and p.o. administration to fa/fa Zucker rats.
  • the modulators of this invention may be prepared using solid phase chemistry or, alternatively, via normal solution chemistry, using conventional methods known in the art.
  • the utility of the compounds of formula (I) to act as DP IV substrates to inhibit the physiological turnover of endogenous peptide hormones by competitive catalysis in vivo can be determined according to the procedures described in Examples 3 and 4.
  • the present invention therefore provides a method of preventing or treating a condition mediated by modulation of the DP IV activity in a subject in need thereof which comprises administering any of the compounds or pharmaceutical compositions thereof in a quantity and dosing regimen therapeutically effective to treat the condition.
  • the present invention includes the use of a compound of formula (I) for the preparation of a medicament for the prevention or treatment of a condition mediated by modulation of the DP IV activity in a subject.
  • the compound may be administered to a patient by any conventional route of administration, including, but not limited to, intravenous, oral, subcutaneous, intramuscular, intradermal and parenteral or combinations thereof. Oral administration is preferred.
  • the present invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier and/or diluent.
  • compositions of this invention one or more compounds of formula (I) or salts thereof as the active ingredients, are intimately admixed with a pharmaceutical carrier and/or diluent according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
  • a pharmaceutical carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
  • any of the usual pharmaceutical media may be employed.
  • suitable carriers and additives may advantageously include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desired, tablets may be sugar coated or enteric coated by standard techniques.
  • the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included.
  • Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above.
  • the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 0.01 mg to about 1000 mg (preferably about 5 to about 500 mg) and may be given at a dosage of from about 0.1 to about 300 mg/ kg bodyweight per day (preferably 1 to 50 mg/kg per day).
  • the dosages may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed.
  • the use of either daily administration or post-periodic dosing may be employed.
  • the dosage will be regulated by the physician based on the characteristics of the patient, his/her condition and the therapeutic effect desired.
  • compositions are in unit dosage forms from such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
  • the principal active ingredient is ideally mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water
  • a pharmaceutical carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium
  • the tablets or pills of the novel composition can be advantageously coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be advantageously incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.
  • the processes for the preparation of the compounds according to the invention give rise to a mixture of stereoisomers
  • these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their components enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • the compounds may also resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
  • any of the processes for preparation of the compounds of the present invention it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 , fully incorporated herein by reference.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • the method of treating conditions modulated by dipetidyl peptidase IV and DP IV - like enzymes described in the present invention may also be carried out using a pharmaceutical composition comprising one or more of the compounds as defined herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may contain between about 0.01 mg and 1000 mg, preferably about 5 to about 500 or 250 mg of the compounds, and may be constituted into any form suitable for the mode of administration selected.
  • Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
  • compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixirs, emulsions, and suspensions.
  • forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen and dosage strength will need to be accordingly modified to obtain the desired therapeutic effects.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or betalactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • liquid forms in suitable flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • suitable suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • tragacanth for example, tragacanth, acacia, methyl-cellulose and the like.
  • methyl-cellulose methyl-cellulose and the like.
  • suitable suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • sterile suspensions and solutions are desired.
  • Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
  • the compound of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines using processes well described in the art.
  • Compounds of the present invention may also be delivered by the use of antibodies, most preferably monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyl eneoxidepolyllysine substituted with palmitoyl residue.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polyactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross- linked or amphipathic block copolymers of hydrogels.
  • a drug for example, polyactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross- linked or amphipathic block copolymers of hydrogels.
  • Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of the addressed disorders is required.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1.000 mg per adult human per day.
  • the compositions are preferably provided in the form of tablets containing, 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, 500 and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.1 mg/kg to about 300 mg/kg of body weight per day.
  • the range is from about 1 to about 50 mg/kg of body weight per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day.
  • Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, bioavailability due to the mode of administration, and the advancement of disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, should generally be considered in adjusting dosages.
  • the compounds or compositions of the present invention may be taken before a meal, while taking a meal or after a meal.
  • the compounds or compositions of the present invention can be taken 1 hour, preferably 30 or even 15 or 5 minutes before eating.
  • the compounds or compositions of the present invention When taken while eating, the compounds or compositions of the present invention can be mixed into the meal or taken in a separate dosage form as described above. When taken after a meal, the compounds and compositions of the present invention can be taken 5, 15, or 30 minutes or even 1 hour after finishing a meal.
  • Pre-loaded Fmoc-Yaa-Wang resin (2.8 g/ substitution level 0.57 mmol/g) was deprotected using 20% piperidine/ N,N-dimethylformamide (DMF). After washing with DMF a solution of 2 eq (1.1 g) of Fmoc-Pro-OH were solved in DMF (12ml solvent per gram resin). 2eq (1.04 g) of 2-(1 H-Benzotriazole 1-yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TBTU) and 4 eq (1.11ml) of N,N-diisopropylethylamine (DIEA) were added and placed in the reaction vessel.
  • DIEA N,N-diisopropylethylamine
  • the yields of crude peptides were 80-90% on the average.
  • the crude peptides were purified by HPLC on a Nucleosil C18 column (7 ⁇ m, 250*21.20 mm, 100 A) using a linear gradient of 0.1 % TFA/H 2 0 with increasing concentration of 0.1 % TFA acetonitrile (from 5% to 65% in 40 min) at 6 ml/min.
  • the pure peptides were obtained by lyophilization, identified by Electrospray mass spectrometry and HPLC analysis.
  • UV detection 214nm gradient system: acetonitrile (ACN)/H 2 0 (0.1% TFA) from 5% ACN to 50% in15 min, flow 1 ml/min
  • Ser(Bzl) and Ser(P) are defined as benzyl-serine and phosphoryl-serine, respectively.
  • Tyr(P) is defined as phosphoryl-tyrosine.
  • DP IV activity was measured in the same way as described above at final substrate concentrations of 0.05, 0.1 , 0.2, and 0.4 mM and further 7 inhibitor concentrations covering the IC 50 concentration. Calculations were performed using the GraFit Software.
  • f-butyl-Gly is defined as:
  • Ser(BzI) and Ser(P) are defined as benzyl-serine and phosphoryl-serine, respectively.
  • Tyr(P) is defined as phosphoryl-tyrosine.
  • f-butyl-Gly is defined as:
  • Ser(Bzl) and Ser(P) are defined as benzyl-serine and phosphoryl-serine, respectively.
  • Tyr(P) is defined as phosphoryl-tyrosine.
  • N 10 male Wistar rats (Shoe:Wist(Sho)) with a body weight >350 g were purchased from Tierzucht Schonwalde (Schonwalde, Germany).
  • catheters were implanted into the carotid artery of Wistar rats under general anaesthesia (i.p. injection of 0.25 ml/kg b.w. Rompun ® [2 %], BayerVital, Germany and 0.5 ml/kg b.w. Ketamin 10, Atarost GmbH & Co., Twistringen, Germany). The animals were allowed to recover for one week. The catheters were flushed with heparin-saline (100 lU/ml) three times per week.
  • test substances were dissolved freshly in 1.0 ml saline (0.154 mol/l) and were given at 0 min either oral via a feeding tube (15g, 75 mm; Fine Science Tools, Heidelberg, Germany) or intravasal.
  • a feeding tube 15g, 75 mm; Fine Science Tools, Heidelberg, Germany
  • intravasal the catheter was immediately flushed with 30 ⁇ l saline and an additional 1 ml of saline was given orally via the feeding tube.
  • Plasma DP IV activity The assay mixture consisted of 80 ⁇ l reagent and 20 ⁇ l plasma. Kinetic measurements of the formation of the yellow product 4-nitroaniline were performed at 390 nm for 1 min at 30 °C after 2 min pre-incubation at the same temperature. The activity was expressed as arbitrary units [AU] and DP IV activity [mU/ml]. STATISTICAL METHODS
  • the compounds lle-Pro-lle and Val-Pro-Leu inhibit plasma DP IV-activity in Wistar rats after intravasal administration in relatively high doses (100 mg/kg b.w.). With lle- Pro-lle it seems to be a dose dependent inhibition of DP IV after intravasal administration.
  • f-butyl-Gly-Pro-lle 100 mg/kg b.w. f-butyl-Gly-Pro-lle was administered oral and intravasal. With reference to figure 5, f-butyl-Gly-Pro-lle did decrease plasma DP IV slowly over a time period of 40 min when given orally. 100 mg/kg b.w. given intravasal, induced a very rapid decline below 10 mU/ml at 5 min (p ⁇ 0.05). Thereafter a restoration (p ⁇ 0.05 5min vs.40 min) was found.
  • DP IV-AUCo-i20 min was more declined after intra-vasal (- 617+234 mU-min-ml "1 ) than after oral administration (-336 ⁇ 162 mU-min-ml '1 ; p ⁇ 0.05 vs. intra-vasal).
  • Table 8 shows the results of selected Xaa-Pro-Yaa tripeptides, tested for their inhibitory potential of DPIV and DPIV-like enzyme activity after oral and intravasal administration to Wistar rats.
  • N 30 male Zucker rats (fa/fa), mean age 11 weeks (5-12 weeks), mean body weight 350 g (150-400 g), were purchased from Charles River (Sulzfeld, Germany). They were kept for >12 weeks until all the fatty Zucker rats had the characteristics of manifest Diabetes mellitus.
  • fatty Zucker rats were given placebo, positive control and test substance, respectively, via feeding tube orally (15 G, 75 mm; Fine Science Tools, Heidelberg, Germany) at -10 min.
  • An oral glucose tolerance test (OGTT) with 2 g/kg b.w. glucose as a 40 % solution (B. Braun Melsungen, Melsungen, Germany) was implemented at ⁇ 0 min.
  • the glucose was administered via a second feeding tube.
  • Arterial blood samples from the carotid catheter were collected at -30 min, -15 min, +0 min and at 5, 10, 15, 20, 30, 40, 60, 90 and 120 min into 20 ⁇ l glass capillaries, which were placed in standard tubes filled with 1 ml solution for hemolysis (blood glucose measurement).
  • Eppendorf tubes Eppendorf-Netheler-Hinz, Hamburg, Germany
  • 10 ⁇ l sodium citrate buffer pH 3.0
  • Eppendorf tubes were centrifuged immediately (12000 rpm for 2 min, Hettich Zentrifuge EBA 12, Tuttlingen; Germany): The plasma fractions were stored on ice until analysis.
  • Glucose levels were measured using the glucose oxidase procedure (Super G Glukoseme ⁇ gerat; Dr. M ⁇ ller Geratebau, Freital, Germany).
  • each test compound was compared in the same oocyte with the current elicited by 5 mM of the dipeptide glycyl-L-glutamine (Gly-Gln). Currents of test compounds are therefore given relative to that by Gly-Gln as %l Giy-Gin, expressed as residual uptake in table 10.

Abstract

L'invention concerne un composé représenté par la formule (I), et ses sels acceptables sur le plan pharmaceutique. On peut utiliser ces composés afin de préparer un médicament prophylactique ou thérapeutique pour un état dans lequel la modulation de l'activité de dipeptidyle peptidase IV joue un rôle intermédiaire, cet état étant, de préférence, sélectionné dans la diminution de la tolérance au glucose, le diabète sucré, la glycosurie ou l'acidose métabolique.
PCT/EP2002/007128 2001-06-27 2002-06-27 Structures peptidiques utiles pour la modulation competitive de la catalyse de dipeptidyle peptidase iv WO2003002593A2 (fr)

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CA002419888A CA2419888A1 (fr) 2001-06-27 2002-06-27 Structures peptidiques utiles pour la modulation competitive de la catalyse de dipeptidyle peptidase iv
JP2003508973A JP2004530729A (ja) 2001-06-27 2002-06-27 ジペプチジルペプチダーゼｉｖ触媒作用の拮抗調節に有用なペプチド構造
EP02762308A EP1399469A2 (fr) 2001-06-27 2002-06-27 Structures peptidiques utiles pour la modulation competitive de la catalyse de dipeptidyle peptidase iv
NO20030900A NO20030900L (no) 2001-06-27 2003-02-26 Peptidstrukturer nyttige for kompetitiv modulering av dipeptidyl peptidaseIV-katalyse

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NO20030900D0 (no) 2003-02-26
RU2299066C2 (ru) 2007-05-20
EP1399469A2 (fr) 2004-03-24
CN1471538A (zh) 2004-01-28
CN1688599A (zh) 2005-10-26
NO20030900L (no) 2003-04-24
ZA200300833B (en) 2004-02-10
CA2419888A1 (fr) 2003-01-09
JP2004530729A (ja) 2004-10-07
RU2003105463A (ru) 2004-11-27
ZA200300595B (en) 2004-02-13
ZA200301312B (en) 2004-03-30
WO2003002593A3 (fr) 2003-09-04

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