Organic compounds -- part of the class 532-570 series – Organic compounds – Fatty compounds having an acid moiety which contains the...
Reexamination Certificate
1999-09-29
2002-09-03
Carr, Deborah D. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Fatty compounds having an acid moiety which contains the...
C554S066000, C554S069000, C514S625000, C514S627000
Reexamination Certificate
active
06444832
ABSTRACT:
The present invention concerns new amino alcohol derivatives, processes for their production as well as pharmaceutical agents which contain these substances.
In healthy persons the anabolic and catabolic processes in the bone are almost in equilibrium i.e. the activity of the osteoblasts and osteoclasts is balanced. However, if this equilibrium is disturbed in favour of the osteoclasts and/or in favour of the osteoblasts the bone mass is reduced and there is a negative change in bone structure and function.
Inhibitors of bone resorption such as oestrogens, calcitonin and bisphosphonates have previously been used to treat disturbances of bone metabolism. However, the use of these substances is limited and also does not exhibit the desired effect in all cases. Compounds which have a stimulating effect on the formation of bone and in addition contribute to increasing an already reduced bone mass are therefore extremely important for the treatment of disturbances of bone metabolism. Substances with an osteoanabolic action for the therapy of osteoporosis were described in the European Patent Applications EP-A-625522 and EP-A-524023.
Surprisingly it was now found that amino alcohol derivatives of the present invention have a stimulating effect on the formation of bone and are therefore suitable for the broad treatment of disturbances of bone metabolism. They can be used particularly well for cases in which the formation of bone is disturbed i.e. they are suitable for the treatment of osteopenic diseases of the skeletal system such as e.g. osteoporosis including osteogenesis imperfecta but also to support bone regeneration and osteoinduction such as e.g. in orthopaedic and orthodontic indications, in the healing of fractures, osteosyntheses, pseudoarthroses and the settling of bone implants.
Based on these properties they can also be used in the prevention of osteoporosis.
As a result of their influence on bone metabolism they additionally form a basis for the treatment of rheumatoid arthritis, osteoarthritis and degenerative arthrosis.
The present invention concerns new compounds of the general formula (I)
in which
R
1
=hydrogen or methyl
R
2
=lower straight-chained or branched alkyl with 1 to 10 carbon atoms
R
3
=hydrogen or lower alkyl
n=0-12
R
4
=alkyl, alkenyl or alkinyl with 6 to 24 carbon atoms,
wherein in the case that
R
4
denotes alkyl, —(CH
2
)
n
—R
4
may not be an unbranched alkyl chain with 8, 10, 12, 14 or 16 carbon atoms
and in the case that
R
2
denotes methyl or isobutyl, —(CH
2
)
n
—R
4
may not be (all-cis-4,7,10,13)-octadecatetraene
as well as pharmacologically acceptable salts and optical isomers thereof.
In EP-A-208961 amino alcohol derivatives of formula (I) are described in which R
1
denotes hydrogen or methyl, R
3
denotes hydrogen, R
2
denotes methyl or isopropyl and in which —(CH
2
)
n
—R
4
denotes an unbranched alkyl chain with 14 carbon atoms. In J. Med. Chem. 35, 2939-51 (1995) amino alcohol derivatives of formula (I) are described in which R
1
, R
3
denote hydrogen, R
2
denotes methyl or isobutyl and in which —(CH
2
)
n
—R
4
denotes an unbranched alkyl chain with 14 carbon atoms. A compound of formula (I) is described in Biochem. J. 288, 167-73 (1992) in which R
1
, R
3
denote hydrogen, R
2
denotes isobutyl and in which —(CH
2
)
n
—R
4
denotes an unbranched alkyl chain with 10 carbon atoms. In J. Lipid Res. 13 (1), 86-91 (1972) and in DE-A-3418525 compounds of formula (I) are described in which R
1
, R
3
denote hydrogen, R
2
denotes ethyl and in which —(CH
2
)
n
—R
4
denotes an unbranched alkyl chain with 8, 10, 12, 14 and 16 carbon atoms. All compounds are described as intermediate products without information on a possible use as pharmaceutical agents. Compounds of formula (I) in which R
1
, R
3
are hydrogen, R
2
is methyl or isobutyl and in which —(CH
2
)
n
—R
4
is (all-cis-4,7,10,13)-octadecatetraene have been described in Life Sci. 56 (23/24), 2041-8 (1995) as cannabinoid receptor ligands.
Therefore pharmaceutical agents are also a subject matter of the invention which contain compounds of formula I
in which
R
1
=hydrogen or methyl
R
2
=lower straight-chained or branched alkyl with 1 to 10 carbon atoms
R
3
=hydrogen or lower alkyl
n=0-12
R
4
=alkyl, alkenyl or alkinyl with 6 to 24 carbon atoms
as well as pharmacologically acceptable salts and optical isomers thereof.
Lower alkyl is intended in all cases to represent a straight-chained or branched C
1
-C
6
alkyl group such as e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or hexyl in particular methyl, ethyl, propyl and butyl.
Alkyl is intended in all cases to represent a straight-chained or branched C
6
-C
18
alkyl group such as e.g. hexyl, isohexyl, 2,2-dimethylhexyl, 5-methylhexyl, heptyl, isoheptyl, 6-methylheptyl, octyl, isooctyl, nonyl, isononyl, decyl, isodecyl, undecyl, isoundecyl, dodecyl, isododecyl, tridecyl, isotridecyl, tetradecyl, isotetradecyl, pentadecyl, isopentadecyl, hexadecyl, heptadecyl, isoheptadecyl or octadecyl in particular heptyl, decyl and dodecyl.
Alkenyl denotes in all cases a monounsaturated or polyunsaturated, optionally substituted, residue with 6-20 carbon atoms such as e.g. &Dgr;
1
-hexenyl, &Dgr;
1
-octenyl, &Dgr;
9
-nonenyl, &Dgr;
1
-decenyl, &Dgr;
10
-decenyl, &Dgr;
1,4
-decadienyl, &Dgr;
1,4,7
-decatrienyl, &Dgr;
1,4,7,10
-hexadecatetraenyl, &Dgr;
1
-dodecenyl, &Dgr;
5
-dodecenyl, &Dgr;
1,4
-undecadienyl, &Dgr;
14
-tetradecenyl, in particular &Dgr;
1
-decenyl, &Dgr;
1,4
-decadienyl, &Dgr;
1,4,7
-decatrienyl in which the double bonds can be cis or trans and in the case of polyunsaturated compounds all combinations are possible.
Alkinyl denotes in all cases a monounsaturated or polyunsaturated optionally substituted, residue with 6-20 carbon atoms such as e.g. &Dgr;
1
-decinyl, &Dgr;
1
-noninyl, &Dgr;
1,3
-tetradecadiinyl, &Dgr;
1,3
-hexadecadiinyl, &Dgr;
1,3
-octadecadiinyl, in particular &Dgr;
1
-decinyl.
Compounds of the general formula (I) contain at least one asymmetric carbon atom and therefore optically active compounds of the general formula (I) are also a subject matter of the present application.
Compounds of the general formula (I) are obtained by known processes for the formation of carboxylic acid amides from the amino alcohols of the general formula (II),
in which R
1
, R
2
and R
3
have the above-mentioned meanings and carboxylic acid derivatives of the general formula (III),
in which R
4
and n have the meanings stated above and X can be a hydroxy or an activation group whereby if X denotes hydroxy, the carboxyl group can be activated by the carbodiimide process and if X denotes an activating group, mixed anhydrides come into consideration and especially with lower alkyl esters of carbonic acid such as ethyl or isobutyl esters or active esters in particular p-nitrophenyl, 2,4,5-trichlorophenyl, N-hydroxysuccinimide or 1-hydroxybenzotriazole esters,
or by condensation with nitrites of the general formula (IV)
R
4
—(CH
2
)
n+1
—CN (IV)
in which R
4
and n have the meanings stated above (cf. Liebigs Ann. Chem. 986-96 (1979)).
Compounds of the general formula (II) are produced by known processes preferably by the reduction of amino acids or they are commercially available.
Compounds of the general formula (III) are produced by known processes from compounds of the general formula (V)
R
4
—(CH
2
)
n+l
—COOH (V)
in which R
4
and n have the meanings stated above.
Compounds of the general formula (IV) are produced by known processes for the synthesis of nitriles or they are commercially available.
Compounds of the general formula (V) are produced by known processes for chain elongation or synthesis of carboxylic acids or they are commercially available.
Pure enantiomers of the compounds of formula (I) can be obtained by using optically active amino alcohols which can be produced by known processes e.g. by classical racemate resolution via salt formation with optically active acids or by reduction of optically active
Esswein Angelika
Friebe Walter-Gunar
Kling Lothar
Leser Ulrike
LandOfFree
Amino alcohol derivatives, method of producing said... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Amino alcohol derivatives, method of producing said..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Amino alcohol derivatives, method of producing said... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2865865