Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Tripeptides – e.g. – tripeptide thyroliberin – etc.
Reexamination Certificate
2000-03-31
2002-08-06
Low, Christopher S. F. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Tripeptides, e.g., tripeptide thyroliberin , etc.
C514S017400, C514S018700, C514S019300, C514S020800, C530S330000, C530S331000, C562S553000
Reexamination Certificate
active
06429288
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to new peptide mimetics for the treatment of bone disorders, methods for their production, and drugs containing these compounds.
In healthy individuals. the formation and degradation processes in the bones are virtually at equilibrium, i.e., the activity of the osteoblasts and osteociasts is balanced. However, if this equilibrium is disturbed in favor of the osteoclasts and/or to the disadvantage of the osteoblasts, a reduction in bone mass and a negative change in bone structure and function will be the result.
Up to now, bone resorption inhibitors such as estrogens, calcitonin and bisphosphonates are primarily used in the treatment of bone metabolic disorders. However, the use of these substances is limited and in addition, does not show the desired effect in all of the cases. Compounds having a stimulating effect on bone formation and contributing to increase an already diminished bone mass are therefore of particular importance in the treatment of bone disorders.
It is known that PTHrP(107-111) and the peptide derivatives thereof have a positive influence on the inhibition of bone resorption (WO 9210511; WO 9424153). However, Valin et al. in J. Cell Physiol. 170(2), 209-15 (1997), describe an anti-proliferative effect of PTHrP(107-111) on UMR106 cells. Whitfield et al. in J. Cell Physiol. 166(1), 1-11 (1996), demonstrate a stimulating effect on the PKC and a modulation of keratinocyte proliferation by PTHrP(107-111), whereas Kali et al. in Endocrinology 136(3), 842-8 (1995), describe a stimulation of the osteoclasts by PTHrP(107-111).
SUMMARY OF THE INVENTION
Surprisingly, it has now been found that the peptide mimetics of the present invention have a stimulating effect on bone formation and thus, are suitable for the general treatment of bone disorders. In particular, they can be used quite well in those cases where bone formation is disturbed, i.e., they are particularly suited for the treatment of osteopenic diseases of the skeletal system, such as osteoporosis, brittle bone disease among others, as well as for the local promotion of bone regeneration and osteoinduction as, e.g., in orthopedic and orthodontic indications, in fracture curing, osteosyntheses, pseudarthroses and for bone implants to become incorporated.
Due to these properties, they are also used in the prophylaxis of osteoporosis.
Moreover, due to their influence on the bone metabolism, drugs containing the peptide mimetics of the present invention as active substances constitute a basis for the local and systemic treatment of rheumatoid arthritis, osteoarthritis and degenerative arthrosis.
The present invention is directed to compounds of general formula (I)
wherein
R
1
, R
2
, R
3
and X may be the same or different, and wherein
R
1
, R
2
represent hydrogen, an amino, peptidyl, alkyl or aryl residue;
R
3
represents hydroxy, lower alkoxy, or an —NR
31
R
32
residue, where R
31
, R
32
and represent idependently hydrogen an amino acid, peptidyl, alkyl or aryl residue;
X represents an amino acid or a peptide.
R
4
represents hydrogen, hydroxy, amino or C
1
-C
4
-alkyl;
m represents a number between 0 and 5;
R
5
represents an optionally substituted saturated or unsaturated mono- or bicyclic moiety which may contain one or more heteroatoms, a C
1
-C
11
alkyl group which may have substitutions or intermittent heteroatoms;
their tautomers, optical isomers, pharmaceutically acceptable salts and prodrugs.
X is preferably a &ohgr;-Amino acid or the dipeptide serinylalaryl;
R
4
represents preferably methyl or hydroxy;
R
1
and R
2
are independently of each other preferably hydrogen;
R
3
is preferably hydroxy or amino;
m is preferably 1 to 3, more preferably 1;
The residue (CHR
4
)mR
5
represents especially preferred a residue attached to C&agr; of a proteinogenic or non-proteinogenic amino acid.
DETAILED DESCRIPTION OF THE INVENTION
Alkaline salts, earth alkaline salts like Ca or Mg salts, ammonium salts, acetates or hydrochlorides are mainly used as pharmacologically acceptable salts which are produced in the usual manner e.g. by tritrating the compounds with inorganic or organic bases or inorganic acids such as e.g. sodium hydroxide, potassium hydroxide, aqueous ammonia, C
1
-C
4
-alkyl-amines such as e.g. triethylamine or hydrochloric acid. The salts are usually purified by reprecipitation from water/acetone.
Prodrugs of the compounds of the invention are such which are converted in vivo to the pharmacological active compound. The most common prodrugs are carboxylic acid esters, like ethylesters.
Peptidyl represents are peptide residue. Peptide is understood to be a residue consisting of 2 to 10 proteinogenic or non-proteinogenic identical or different amino acids. Peptides having 2-5 amino acids are preferred; particularly preferred are those having 2 amino acids.
Amino acid residue normally means the residue of a proteinogenic or non-proteinogenic amino acid. Non-proteinogenic amino acids are understood to be &agr;-, &bgr;-, &ggr;-, and &ohgr;-aminocarboxylic acids which may optionally have substitutions or intermittent heteroatoms.
Preferred &ohgr;-amino acids are —HN—(CH
2
)
n
—CO—with n=1-10; the —(CH
2
)
n
-group may be branched or unbranched.
Examples of such amino acids are the L- and D-amino acids, like 2-amino-3-hydroxy-4-methylpentanoic acid, 2-amino-3-hydroxy-4-methylpentanoic acid, 2-amino-3-methoxybutanoic acid, 2,3-diaminopropionic acid, 2-amino-2-methyl-3-hydroxypropanoic acid, 2-amino-2-methylbutanedioic acid, 2-amino-3-hydroxy-3-methylbutanoic acid, 2-amino-3-hydroxy-3-methylbutanoic acid, 2,3-diaminopropionic acid, 2-amino-2-methyl-3-hydroxypropanoic acid, 2-amino-2-methylbutanedioic acid, 2-amino-2-methylbutanoic acid, 2-amino-2-methyl-4-pentenoic acid, 2-amino-3-methoxypropanoic acid, 1-amino-1-cyclohexanecarboxylic acid, 1-amino-1-cyclopentanecarboxylic acid, 1-aminocyclobutanecarboxylic acid, 1-aminocyclopropanecarboxylic acid, 2-(2-furyl)glycine, 2-amino-3-fluorobutyric acid, 2-aminoisobutyric acid, 3-chloroalanine, 3-fluoronorleucine, 3-fluorovailne, 3-fluoroalanine, 3-methoxyvaline, alpha-cyanoalanine, alpha-methylleucine, beta-chloroalanine, beta-cyanoalanine, beta-hydroxyleucine, beta-hydroxyaspartic acid, 3-hydroxyaspartic acid, 2-aminobutyric acid, allylglycine, gamma-methylleucine, homoserine, norleucine, norvaline, tert-leucine, 2,3-diaminopropionic acid, 2,3-diaminosuccinic acid, 2-amino-4-pentenoic acid, 2-aminobutyric acid. 2-aminoheptanoic acid, 2-cyclopropyl-2-methylglycine, 4-thiaisoleucine, allothreonine, alpha-methylaspartic acid, alpha-methylserine, beta-hydroxynorvaline, beta-methylaspartic acid, homocysteine, homoserine, norleucine, norvaline, O-methylserine, penicillamine, propargaylglycine, beta-hydroxyaspartic acid vinylglycine, beta-hydroxyaspartic acid, H-4,5-dehydro-LEU-OH, H-alpha-MeVAL-OH, H-propargayl-GLY-OH, H-allo-ILE-OH, H-PRA-OH, H-trans-4,5-dehydroLYS-OH, 3-hydroxyaspartic acid, 6-hydroxynorleucine, allo-isoleucine, allyl glycine, alpha-amino-N-butyric acid, gamma-methylleucine, homoserine, norvaline, penicillamine, tert-leucine, vinylglycine, meso-alpha beta-diaminosuccinic acid, O-carbamoyl-serine, S-methylcysteine, 2-amino-2-methylbutanedioic acid, 2-fluoro-beta-alanine, beta-alanine, beta-aminobutyric acid, 2,3-diaminosuccinic acid, beta-aminoisobutyric acid, isoserine,
Preferred amino acids are alanine, serine, tryptophan, tyrosine, phenylalanine, threonine, histidine, citrulline, homocysteine, homoserine, hydroxyproline, hydroxylysine, ornithine, sarcosine, tranexamic acid, Cha (cyclohexylalanine), aminobutyric acid, aminovaleric acid, and aminopropionic acid.
Lower alkoxy denote methoxy, ethoxy, propoxy, ispropoxy or butoxy, preferably methoxy.
Alkyl normally means linear or branched alkyl residues having from one to six carbon atoms.
Aryl normally means a carbocyclic moiety having from 6 to 14 C atoms or a 5- or 6-membered heterocyclic moiety having 1, 2 or 3 heteroatoms selected from O, N, S, which moiety may optionally have one or multiple substitutions, with unsubstitute
Esswein Angelika
Hoffmann Eike
Kling Lothar
Konetschny-Rapp Silvia
Johnston George W.
Low Christopher S. F.
Lukton David
Roche Diagnostics GmbH
Tramaloni Dennis P.
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