Histogranin peptides and their analgesic use

Details Histogranin peptides and their analgesic use Histogranin peptides and their analgesic use

2000-07-06

2003-05-20

Russel, Jeffrey E. (Department: 1654)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S015800, C514S016700, C514S017400, C514S018700, C530S321000, C530S328000, C530S329000, C530S330000

Reexamination Certificate

active

06566327

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel peptides and pseudopeptides useful as analgesics.
BACKGROUND OF THE INVENTION
Chronic pain may have multiple causes including inflammation, peripheral nerve injury, cancer, AIDS, and diabetes. Treatment of chronic pain has included the administration of analgesics.
Analgesic compounds are agents which alleviate pain without causing a loss of consciousness; they may also reduce inflammation. Known analgesics have not been particularly effective in the treatment of chronic pain. For instance, aspirin derivatives and non-steroidal anti-inflammatory agents have limited efficacy and have a number of side-effects including interference with blood coagulation and the exacerbation of peptic ulcers; morphine and opioid analgesics have shown some beneficial effects, but cause side-effects such as marked tolerance, and addiction and withdrawal syndromes; and the known N-methyl-D-aspartate (NMDA) receptor antagonists are effective in certain animal models, but produce behavioural side-effects including motor impairment, learning impairment, and ataxia.
U.S. Pat. No. 5,656,267 (Aug. 12, 1997) describes a method of alleviating chronic pain involving the transplantation of cells into a region of the central nervous system of patients suffering from chronic pain. However, this method is not practical.
SUMMARY OF THE INVENTION
In one aspect the invention provides novel linear peptides and pseudopeptides, having analgesic properties, of Formula I:
wherein
R
1
represents hydrogen, alkyl, alkenyl, alkynyl, —(CH
2
)
n
—NH
2
, —(CH
2
)
n
—NH—C(═NH)NH
2
, or
 wherein “n” is an integer from 0 to 10;
R
2
represents —(CH
2
)
n
CONH
2
, wherein “n” represents an integer from 0 to 10;
R
3
represents hydrogen, alkyl, alkenyl, alkynyl, the radical of formula:
 or the radical of formula:
 wherein
“n” represents an integer from 0 to 10; and
R
11
, R
12
and R
13
may be the same or different and represent hydrogen, alkyl, alkenyl, alkynyl, —I, —F, —Br, —Cl, or —OH; and
R
4
represents —(CH
2
)
n
NH
2
, —(CH
2
)
n
NHC(═NH)NH
2
, or
 wherein “n” represents an integer from 0 to 10;
R
5
and R
9
may be the same or different and represent hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, dialkylamino, or —(CH
2
)
n
aryl, wherein “n” is an integer from 1 to 10;
R
6
, R
7
, and R
8
may be the same or different and represent hydrogen, alkyl, alkenyl, or alkynyl;
R
10
represents hydroxy, alkoxy, alkenyloxy, alkynyloxy, amino, alkylamino, dialkylamino, alkylaryl, arylalkoxy, aryloxy, alkoxyaryl, A
1
, A
1
-A
2
, A
1
-A
2
-A
3
, A
1
-A
2
-A
3
-A
4
, or A
1
-A
2
-A
3
-A
4
-A
5
,
 wherein
A
1
represents threonine or serine;
A
2
represents leucine, glycine, alanine, valine, or isoleucine;
A
3
represents tyrosine, phenylalanine, or tryptophan;
A
4
represents glycine, alanine, leucine, isoleucine, or valine; and
A
5
represents phenylalanine, tyrosine, or tryptophan; pseudopeptide analogues thereof wherein one or more of the carbonyl groups of the peptide linkage is replaced by —C(═S)— or by —CH
2
—, and/or wherein one or more of the amide bonds, —C(O)—NH—, is replaced by the retro-verso form, —NH—C(O)—, thereof; and
pharmaceutically acceptable salts and esters thereof.
In another aspect, the invention provides novel cyclic peptides and cyclic pseudopeptides, having analgesic properties, of Formula II:
wherein
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, and R
8
, are as defined above; and
X represents an amino acid or peptide fragment represented by A
1
, A
1
-A
2
, A
1
-A
2
-A
3
, A
1
-A
2
-A
3
-A
4
, or A
1
-A
2
-A
3
-A
4
-A
5
,
 wherein
A
1
, A
2
, A
3
, A
4
, and A
5
are as defined above; or a divalent group of formula:
 wherein
“n” represents an integer from 0 to 10; and
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, and R
8
are as defined above; pseudopeptide analogues thereof wherein one or more of the carbonyl groups of the peptide linkage is replaced by —C(═S)— or by —CH
2
—, and/or wherein one or more of the amide bonds, —C(O)—NH—, is replaced by the retro-verso form, —NH—C(O)—, thereof; and
pharmaceutically acceptable salts and esters thereof.
In another aspect, the invention provides a pharmaceutical composition for the treatment of pain, especially chronic pain, comprising a peptide or pseudopeptide of the invention in admixture with a suitable pharmaceutically acceptable diluent or carrier.
In a further aspect, the invention provides use of a peptide or pseudopeptide of the invention for the treatment of pain, especially chronic pain.
In another aspect, the invention provides use of a peptide or pseudopeptide of the invention for the manufacture of a medicament for the treatment of pain, especially chronic pain.
The invention also provides a commercial package which contains the peptide or pseudopeptide of the invention together with instructions for the use thereof, for the treatment of pain.
DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION
Normally, the peptides of this invention will be based upon L-amino acids, and amino acids should be understood to be L-amino acids, unless otherwise indicated or unless the context requires otherwise. However, in certain instances, it may be advantageous to utilize the D-form of the acids. Accordingly, both forms are within the scope of this invention.
The preferred forms for the amino acids comprised within Formulae I and II are the levo (L) forms for amino acids with R
1
and R
3
side-chains and dextro (D) forms for amino acids with R
2
and R
4
side-chains.
As alkyl groups, we mention ones with up to 10 carbons, preferably up to 4 carbons, which can be straight or branched and can have from 0 to 4 carbon-carbon double and/or triple bonds. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and 2-ethyl-hexyl. As alkoxy groups we mention groups with up to 10 carbon atoms, preferably up to 4 carbon atoms. Examples of alkoxy groups include methoxy, ethoxy, propoxy, and tert-butoxy. As aryl groups, we mention 5- and 6-membered single-ring aromatic radicals which include from zero to four heteroatoms selected from nitrogen, oxygen, and sulfur, and the corresponding benzo-fused groups. Examples include phenyl, thienyl, furanyl, pyridinyl, imidazolyl, pyrimidyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrrolyl, naphthyl, indolyl, and quinolyl.
Preferred peptides and pseudopeptides according to Formula I have the following Formula III:
R
9
-Q
1
-Q
2
-Q
3
-Q
4
-R
10
wherein
Q
1
represents glycine, alanine, valine, leucine, isoleucine, lysine, histidine, or arginine;
Q
2
represents asparagine or glutamine;
Q
3
represents glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, or tyrosine;
Q
4
represents lysine, arginine, or histidine;
R
9
represents hydrogen; and
R
10
represents hydroxy;
pseudopeptide analogues thereof wherein one or more of the carbonyl groups of the peptide linkage is replaced by —C(═S)— or by —CH
2
—, and/or wherein one or more of the amide bonds, —C(O)—NH—, is replaced by the retro-verso form, —NH—C(O)—, thereof; and
pharmaceutically acceptable salts and esters thereof.
More preferred peptides and pseudopeptides are represented by Formula III
wherein
Q
1
represents glycine or arginine;
Q
2
represents L-glutamine or D-glutamine;
Q
3
represents glycine, alanine, or tyrosine;
Q
4
represents L-arginine or D-arginine;
R
9
represents hydrogen; and
R
10
represents hydroxy;
pseudopeptide analogues thereof wherein one or more of the carbonyl groups of the peptide linkage is replaced by —C(═S)— or by —CH
2
—, and/or wherein one or more of the amide bonds, —C(O)—NH—, is replaced by the retro-verso form, —NH—C(O)—,
pharmaceutically acceptable salts and esters thereof.
Preferred cyclic peptides and pseudopeptides have the following Formula IV:
wherein
Q
1
represents glycine, alanine, valine, leucine, isoleucine, lysine, histidine, or arginine;
Q
2
represents asparagine or glutamine;
Q
3
represents glycine, al

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