Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Tripeptides – e.g. – tripeptide thyroliberin – etc.
Reexamination Certificate
2001-03-19
2003-07-29
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.
C530S330000, C514S018700
Reexamination Certificate
active
06600015
ABSTRACT:
BACKGROUND OF THE INVENTION
Obesity is widely recognized as a serious health problem for the developed countries, and has reached epidemic status in the United States. More than 50% of the U.S. population is considered overweight, with >25% diagnosed as clinically obese and at considerable risk for heart disease, non-insulin dependent diabetes mellitus (NIDDM), hypertension, and certain cancers. This epidemic presents a significant burden on the health care system as projected obesity treatment costs of more than $70 billion annually are expected in the U.S. alone. Strategies for treating obesity include reducing food intake or enhancing the expenditure of energy.
It has been demonstrated that, when injected into the third ventricle of the brain or intraperitoneally, a cyclic heptapeptide analog of &agr;-melanocyte stimulating hormone (&agr;MSH) having melanocortin-4 receptor (MC4-R) agonist activity caused long lasting inhibition of food intake in mice. This effect was reversible when co-administered with a MC4-R antagonist. (Fan, et al., Nature (1997) 385: 165-168) Therefore, agonists of MC4-R activity would be useful in treating or preventing obesity.
There are five known melanocortin receptors based on sequence homology that ranges from 35-60% homology between family members ((Cone, et al., Rec. Prog. Hormone Res. (1996) 51: 287-318), but these receptors differ in their functions. For example, the MC1-R is a G-protein coupled receptor that regulates pigmentation in response to the &agr;MSH, which is a potent agonist of MC1-R. (Cone, et al., ibid.). Agonism of the MC1-R receptor results in stimulation of the melanocytes which causes eumelanin and increases the risk for cancer of the skin. Agonism of MC1-R can also have neurological effects. Stimulation of MC2-R activity can result in carcinoma of adrenal tissue. The effects of agonism of the MC3-R and MC5-R are not yet known. All of the melanocortin receptors respond to the peptide hormone class of melanocyte stimulating hormones (MSH). These peptides are derived from pro-opiomelanocortin (POMC), a prohormone of 131 amino acids that is processed into three classes of hormones; the melanocortins (&agr;, &bgr; and &ggr;), adrenocorticotropin hormone (ACTH), and various endorphins (e.g. lipotropin) (Cone, et al., ibid.). Because of their different functions, simultaneous agonism of the activities of multiple melanocortin receptors has the potential of causing unwanted side effects. Therefore it is desirable that an agonist of MC4-R be more selective for the MC4-R than for one or more of the other melanocortin receptors.
Haskell-Luevano, et al. (Peptides (1996) 17(6): 995-1002) disclose peptides that contain the tripeptide (D)Phe-Arg-Trp and exhibit melanotropic (skin darkening) activity in the frog (
Rana pipiens
) skin bioassay. Haskell-Luevano, et al. (ibid.) do not disclose any compound of formula I, II or III described below.
SUMMARY OF THE INVENTION
This invention provides a compound of the formula:
In compounds of formula I m is 0 or 1. n is 0 or 1. R
1
is an unsubstituted linear or branched alkyl having from 1 to 8 carbon atoms; linear or branched alkyl having from 1 to 8 carbon atoms mono-substituted by phenyl or carboxyl; unsubstituted phenyl; or phenyl mono-substituted by fluoro, chloro or linear or branched alkyl having from 1 to 4 carbon atoms. X is
R
2
, R
3
and R
4
are independently hydrogen or a linear or branched alkoxy having from 1 to 4 carbon atoms, wherein when R
3
is alkoxy, R
2
and R
4
are both hydrogen. R
9
is hydrogen, linear or branched alkyl having from 1 to 3 carbons, linear or branched alkoxy having from 1 to 3 carbons, or unsubstituted phenoxy. R
11
is cyclohexyl, cycloheptyl, or a branched alkyl having from 3 to 8 carbon atoms. R
6
is hydrogen or methyl. R
7
is
and R
8
is hydrogen or methyl; or
Y is
and R
8
is hydrogen.
This invention provides a compound of the formula:
In the compounds of formula II m is 0 or 1. n is 0 or 1. R
1
is an unsubstituted linear or branched alkyl having from 4 to 8 carbon atoms; linear or branched alkyl having from 1 to 8 carbon atoms mono-substituted by phenyl or carboxyl; or unsubstituted phenyl; or phenyl mono-substituted by fluoro, chloro or linear or branched alkyl having from 1 to 4 carbon atoms. R
7
is
and R
8
is hydrogen or methyl; or
Y is
and R
8
is hydrogen.
R
10
is hydrogen, halo, linear or branched alkyl having from 1 to 3 carbon atoms, linear or branched alkoxy having from 1 to 3 carbon atoms, or —NR
12
N
13
wherein R
12
and R
13
are each independently a linear or branched alkyl having from 1 to 3 carbons or together are —(CH
2
)
q
— wherein q is 3, 4 or 5.
This invention provides a compound of the formula:
In the compounds of formula III, R
1
is unsubstituted linear or branched alkyl having from 4 to 8 carbon atoms. R
6
is hydrogen or methyl. R
8
is hydrogen or methyl. p is 2, 3 or 4 and R
14
is
or p is 4 and R
14
is
or p is 3 and R
14
is
The compounds of formulae I, II and III as well as Penta-Adpc-(D)Phe-Arg-Trp-Gly-NH
2
and Penta-Ape-(D)Phe-Arg-Trp-Gly-NH
2
are agonists of the MC4-R. It is known that agonists of MC4-R activity cause reduction of food intake in a mouse model of human obesity. Therefore the compounds of formula I are useful in the treatment or prevention of obesity.
All of the compounds of formulae I, II and III exemplified below as well as Penta-Adpc-(D)Phe-Arg-Trp-Gly-NH
2
and Penta-Ape-(D)Phe-Arg-Trp-Gly-NH
2
were tested for MC4-R agonist activity and MC1-R agonist activity in the in vitro assay described below in Biological Activity Example A. All of the tested compounds had an EC50 for MC4-R agonist activity of less than 500 nM, and all exhibited at least 10-fold greater MC4-R agonist activity than MC1-R agonist activity. In contrast, the compound Bu-His-(D)Phe-Arg-Trp-Gly-NH
2
(Example 30) exhibited greater MC1-R agonist activity than MC4-R agonist activity.
DETAILED DESCRIPTION OF THE INVENTION
Nomenclature and Abbreviations
The nomenclature used to define the peptides is that typically used in the art wherein the amino group at the N-terminus appears to the left and the carboxyl group at the C-terminus appears to the right. By natural amino acids is meant one of the naturally occurring amino acids found in proteins, i.e., Gly, Ala, Val, Leu, Ile, Ser, Thr, Lys, Arg, Asp, Asn, Glu, Gln, Cys, Met, Phe, Tyr, Pro, Trp, and His. Where the amino acid has isomeric forms, it is the L form of the amino acid that is represented unless otherwise explicitly indicated.
The following abbreviations or symbols are used to represent amino acids, protecting groups, solvents, reagents and the like.
Symbol
Meaning
&bgr;-Ala
beta-Alanine
(2)-Nal
(2)-Naphthylalanine
Atc
2-
A
mino
t
etraline-2-
c
arboxylic acid
5-BrAtc
5-Bromo-2-aminotetraline-2-carboxylic acid
5-ClAtc
5-Chloro-2-aminotetraline-2-carboxylic acid
5-MeOAtc
5-Methoxy-2-aminotetraline-2-carboxylic acid
5-EtOAtc
5-Ethoxy-2-aminotetraline-2-carboxylic acid
5-iPrOAtc
5-Isopropoxy-2-aminotetraline-2-carboxylic acid
5-MeAtc
5-Methyl-2-aminotetraline-2-carboxylic acid
5-EtAtc
5-Ethyl-2-aminotetraline-2-carboxylic acid
5-iPrAtc
5-Isopropyl-2-aminotetraline-2-carboxylic acid
5-DmaAtc
5-Dimethylamino-2-aminotetraline-2-carboxylic acid
Sar
Sarcosine (N-methylglycine)
Cit
Citrulline
Apc
1-
A
mino-4-
p
henylcyclohexane-1-
c
arboxylic acid
4-HOApc
1-Amino-4-(4-hydroxyphenyl)cyclohexane-1-carboxylic
acid
4-MeOApc
1-Amino-4-(4-methoxyphenyl)cyclohexane-1-carboxylic
acid
3-MeOApc
1-Amino-4-(4-methoxyphenyl)cyclohexane-1-carboxylic
acid
4-EtOApc
1-Amino-4-(4-ethoxyphenyl)cyclohexane-1-carboxylic
acid
4-iPrOApc
1-Amino-4-(4-isopropoxyphenyl)cyclohexane-1-carboxylic
acid
4-MeApc
1-Amino-4-(4-methylphenyl)cyclohexane-1-carboxylic acid
4-ClApc
1-Amino-4-(4-chlorophenyl)cyclohexane-1-carboxylic acid
Appc
4-
A
mino-1-
p
henyl
p
iperidine-4-
c
arboxylic acid
2-MeAppc
4-Amino-1-(2-methylphenyl)piperidine-4-carboxylic acid
2-iProAppc
4-Amino-1-(2-isopropoxyphenyl)piperidine-4-carboxylic
acid
3-MeAppc
4-Amino-1-(3-methylphenyl)piperidine-4-carboxylic acid
3-MeOAppc
4-Amin
Chen Li
Cheung Adrian Wai-Hing
Chu Xin-Jie
Danho Waleed
Swistok Joseph
Ebel Eileen M.
Hoffmann-La Roche Inc.
Johnston George W.
Low Christopher S.F.
Lukton David
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