2-amino-5-pyrimidine acetic acid compounds

Details 2-amino-5-pyrimidine acetic acid compounds 2-amino-5-pyrimidine acetic acid compounds

2000-01-24

2001-12-11

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S275000, C544S320000, C544S331000

Reexamination Certificate

active

06329383

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to new benzimidazole compounds with the following general structure (I):
in which
Y—X is >C═X when X is NR8, O, or S and R2 is H, alkyl, substituted alkylaryl or substituted aryl; or
Y—X is >C—X when X is H, alkyl, substituted alkyl, aryl, substituted aryl, OR9 or NHR9 and R2 is a bond to Y;
Z is O, S or NR12;
R1 is H, alkyl, substituted alkyl, aryl or substituted aryl;
R3 is H, alkyl, substituted alkyl, aryl or substituted aryl, OR9 or NHR9;
R4, R5, R6 and R7 are H, halogen, OR10, NR10, R11, NO2, CF3, CN, COR8, COOR8, CONHR8 and/or N3 in any combination and/or two adjacent R4, R5, R6 or R7 form a carbocyclic or heterocyclic ring; and
R8, R9, R10, R11, R12 and R13 are H, alkyl, substituted alkylaryl, aryl and/or substituted aryl in any combination.
One compound included in formula I is known to have anti-inflammatory activity, and this is the compound in which R1 is C
2
H
5
, Y—X is >C—OH, Z is N, and R2, R3, R4, R5, R6, R7 and R13 are H.
The compounds included in formula I are useful as a human (Growth Hormone (hGH) mimetic, which trigger GH agonist effects in animals and especially as an orally available human Growth Hormone (hGH).
BACKGROUND
hGH is a protein consisting of a single chain of 191 amino acids. The molecule is cross-linked by two disulphide bridges and the monomeric form has a molecular weight of 22 kDa. Recombinant hGH (22 kDa) has been commercially available for several years. It is preferred over the pituitary derived products because the product prepared from human tissue might contain infectious agents such as that for the Creutzfeldt-Jacob's disease. Two types of therapeutically useful recombinant hGH preparations are present on the market: the natural sequence, e.g. Genotropin®, Kabi Pharmacia AB, and an analogue with an additional methionine residue at the N-terminal end, e.g. Somatonorm®. hGH is used to stimulate linear growth in patients with hypopituitary dwarfism or Turner's syndrome but other indications have also been suggested. The protein hGH must be administered by injection and there is a need for an oral available compound with the same biological activity as the natural occuring GH. The benzimidazoles falling under the general formula I are new with one exception i.e. the compound in formula I in which R1 is C
2
H
5
, Y—X is >C—OH, Z is N and R2, R3, R4, R5, R6, R7 and R13 are H. That compound is known to have anti-inflammatory activity from Singh et al. Indian J of Chemistry. Vol 22B, January 1983. 37-42. (Compound IId, IIp and IIu in Table 1).
SUMMARY OF THE INVENTION
We have unexpectedly found a group of compounds having the biological activity of growth hormone and which could be useful as alternatives to recombinant and native growth hormone.
A number of compounds have been identified. e.g. 2-[(5,6-Dimetlhyl-2-benzoimidazolyl)amino]-4-hydroxy-6-methyl-5-pyrimidine acetic acid (2) and 2-[(5,6-Dimethyl-2-benzoimidadazolyl)amino]-4-hydroxy-6-methyl-5-pyrimidine acetic acid, ethyl ester (1). (1) is found to be a selective agonist for the growth hormone receptor against the closely related prolactin receptors which is of importance when looking for a specific growth hormone mimetic.
The invention thus relates to compounds with the general structure (I):
in which
Y—X is >C═X when X is NR8, O, or S and R2 is H, alkyl, substituted alkylaryl or substituted aryl; or
Y—X is >C—X when X is H, alkyl, substituted alkyl, aryl, substituted aryl, OR9 or NHR9 and R2 is a bond to Y;
Z is O, S or NR12;
R1 is H, alkyl, substituted alkyl, aryl or substituted aryl;
R3 is H, alkyl, substituted alkyl, aryl or substituted aryl, OR9 or NHR9;
R4, R5, R6, and R7 are H, halogen, OR10, NR10, R11, NO2. CF3, CN, COR8, COOR8, CONHR8 and/or N3 in any combination and/or two adjacent R4, R5, R6 or R7 form a carbocyclic or heterocyclic ring; and
R8, R9, R10, R11, R12 and R13 are H, alkyl, substituted alkylaryl, aryl and/or substituted aryl in any combination with the proviso that R1 is not C
2
H
5
when Y—X is >C—OH, Z is N R12 and R2, R3, R4, R5, R6, R7 and R13 are H.
By alkyl is meant a straight or branched chain with 1 to 8 carbton atoms, preferably 1 to 4 carbon atoms, e.g. methyl, ethyl, propyl, bultyl and isoforms thereof.
By aryl is preferably meant a ring having 5-12 carbon atoms, e.g. cyclopropyl, phenyl, cyclohexyl and possibly one or two hetero atoms.
By “substituted” is preferably meant a substitution by halogen, —OH, alkyl OR10, NR10, R11, NO2, CF3, CN, COR8 and/or COOR8.
By “hetero atom” is preferably meant O, S and/or N.
The compounds could be a pharmaceutical acceptable salts and esters thereof.
More particular the following compounds are of interest:
2-[(5,6-Dimethyl-2-benzoimidazolyl)amino]-4-hydroxy-6-methyl-5-pyrimidine acetic acid, ethyl ester (1) and
2-[(5,6-Dimethyl-2-benzoimidazolyl)amino]-4-hydroxy-6-methyl-5-pyrimidine acetic acid (2).
The invention also relates to use of the claims compounds, pharmaceutical compositions comprising the compounds and method for the preparation of the compounds as claimed.
We have shown biological activity for the claimed compounds by different assays, such as a dimerisation assay in which the compounds which mimics the quench induced upon hGH binding in this assay also may mimic the full biological effects of native hormone and increased glucose transport.
The claimed compounds can be useful for treatment of diseases related to e.g. growth hormone deficiency, Turner syndrome, infertility, wound healing, dystrophy, osteoporosis, and/or lactation failure, for preoperative administration and other diseases and conditions which are treated or could be treated by administration of hGH.


REFERENCES:
Streitwieser, A. and Heathcock, C.H., “Introduction to Organic Chemistry, 2nd Ed.”, Macmillan, New York, 1981, p. 649.*
Singh, S.P.; Prakash, Indra; Tomer, R. K.; Prakash, O. M.; Sawhney, S. N., Indian J. Chem., Sect. B, 22B(1), 37-42, 1983.*
Singh et al,Indian Journal of Chemistry, 22B:37-42 (Jan. 1983).

Affiliated with

Also associated with

Rating

2-amino-5-pyrimidine acetic acid compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with 2-amino-5-pyrimidine acetic acid compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 2-amino-5-pyrimidine acetic acid compounds will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2581215