Fluorinated neurokinin A antagonists

Details Fluorinated neurokinin A antagonists Fluorinated neurokinin A antagonists

1996-04-26

2001-04-17

Achutamurthy, Ponnathapura (Department: 3738)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S016700, C514S015800, C514S002600, C514S803000, C530S329000, C530S328000, C530S323000, C530S332000, C930S031000, C930S030000, C930S010000, C930S220000

Reexamination Certificate

active

06218364

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel peptide derivatives which are antagonists of neurokinin A.
SUMMARY OF THE INVENTION The present invention comprises a peptide derivative of formula I:
X-A
1
-A
2
-A
3
-A
4
-A
5
-A
6
-A
7
  I
wherein X is Y or YT.
Y is hydrogen, an alkyl of from 1-6 carbons, an acyl group of from 2-10 carbon atoms, or B
1
and B
2
, wherein B
1
and B
2
are each independently selected from the group consisting of an alkyl of from 1-6 carbons or an acyl group of from 2-10 carbon atoms, with the proviso that only one of B
1
or B
2
is the acyl group. T is selected from the group consisting of 1-3 amino acid residues;
A
1
is -Asp-, -Glu- or a bond;
A
2
is -Ser-, -Thr-, -Ala-, -Asp-, -Glu-, -Val-, Tyr or PyroGlu;
A
3
is -Trp-, -Phe-, -&bgr;-(Napthyl)Ala-, or -Tyr-;
A
4
is -Val-, -Leu-, -Ile- or Phe;
A
5
is -Gly-, -Ala-, -Trp- or &bgr;-Ala;
A
6
is -Val-, -Leu-, -Ile-, -Trp- or -Phe-; and
A
7
is a residue of an amino acid derivative selected from the group consisting of Methioninol, Methioninamide, Norleucinol, Norleucinamide, Leucinol, Leucinamide, Argininol, Argininamide, Phenylalaninol or Phenylalaninamide.
The peptide derivative of Formula I is further characterized by modifying one of the peptide bonds between the amino acid residues of A
1
-A
2
, A
2
-A
3
, A
3
-A
4
, A
4
-A
5
, A
5
-A
6
, or A
6
-A
7
to a modified peptide bond of
wherein Q is CH
2
CF
3
, CH
2
CHF
2
, CH
2
CH
2
F, or CH
2
CF
2
CF
3
; or a pharmaceutically acceptable salt of Formula I.
The compounds of Formula I are useful in treating subjects in need of therapy where antagonism of neurokinin A is beneficial.
DETAILED DESCRIPTION OF THE INVENTION
Neurokinin A is a naturally occurring peptide having the formula of His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met(NH
2
)-SEQ ID NO:1. Neurokinin A is widely distributed within body tissues and has a variety of typically undesirable biological effects.
The present invention comprises a new class of neurokinin A antagonists useful for treating maladies associated with the release of neurokinin A in a subject. For example, the compounds of the present invention are useful as immunosuppressants, and for treating subjects with various conditions such as arthritis, asthma, urinary incontinence, pain, inflammation, gastrointestinal hypermotility, neuritis, neuralgia, and headache, including migrane. “Subject” as used herein means mammals such as humans, sheep, horses, cattle, pigs, dogs, cats, rats and mice.
The compounds of the present invention are peptide derivatives of formula I:
X-A
1
-A
2
-A
3
-A
4
-A
5
-A
6
-A
7
  I
wherein:
X is
Y, wherein Y is hydrogen, an alkyl of from 1-6 carbons, an acyl group of from 2-10 carbon atoms, or B
1
and B
2
, wherein B
1
and B
2
are each independently selected from the group consisting of an alkyl of from 1-6 carbons or an acyl group of from 2-10 carbon atoms, with the proviso that B
1
or B
2
are not simultaneously the acyl group, or
YT, wherein T is from 1 to 3 amino acid residues;
A
1
is -Asp-, -Glu- or a bond;
A
2
is -Ser-, -Thr-, -Ala-, -Asp-, -Glu-, -Val-, Tyr or PyroGlu;
A
3
is -Trp-, -Phe-, -&bgr;-(Napthyl)Ala-, or -Tyr-;
A
4
is -Val-, -Leu-, -Ile-, or Phe;
A
5
is -Gly-, -Ala-, -Trp- or &bgr;-Ala;
A
6
is -Val-, -Leu-, -Ile-, -Trp- or -Phe-; and
A
7
is a residue of an amino acid derivative selected from the group consisting of Methioninol, Methioninamide, Norleucinol, Norleucinamide, Leucinol, Leucinamide, Argininol, Argininamide, Phenylalaninol or Phenylalaninamide.
The peptide derivative of Formula I is further characterized by modifying at least one peptide bond (—CONH—) between the residues of A
1
-A
2
, when A
1
is not a bond, A
2
-A
3
, A
3
-A
4
, A
4
-A
5
, A
5
-A
6
, or A
6
-A
7
to a modified peptide bond having the formula:
wherein Q is CH
2
CF
3
, CH
2
CHF
2
, CH
2
CH
2
F, or CH
2
CF
2
CF
3
, or a pharmaceutically acceptable salt of Formula I.
The abbreviations and nomenclature used herein are described as follows:
Abbreviations
Compounds
 1) Ala
Alanine
 2) Asp
Aspartic Acid
 3) Glu
Glutamic acid
 4) Ile
Isoleucine
 5) Leu
Leucine
 6) Phe
Phenylalanine
 7) Ser
Serine
 8) Thr
Threonine
 9) Trp
Tryptophan
10) Tyr
Tyrosine
11) Val
Valine
12) &bgr;-(Napthyl)Ala
&bgr;-(Napthyl) Alanine
13) &bgr;-Ala
&bgr;-Alanine
14) PyroGlu
PyroGlutamic Acid
The following are amide derivatives of amino acids where
the hydroxyl group (—OH) of the terminal carboxyl group
(—COOH) has been replaced by an amino group (—NH
2
):
15) Met(NH
2
)
Methioninamide
16) Nle(NH
2
)
Norleucinamide
17) Leu(NH
2
)
Leucinamide
18) Arg(NH
2
)
Argininamide
19) Phe(NH
2
)
Phenylalaninamide
The following are alcohol derivatives of amino acids where
the terminal carboxyl group (—COOH) is replaced by
(—CH
2
OH).
20) Met(CH
2
OH)
Methioninol
21) Nle(CH
2
OH)
Norleucinol
22) Leu(CH
2
OH)
Leucinol
23) Arg(CH
2
OH)
Argininol
24) Phe(CH
2
OH)
Phenylalaninol
The term “amino acid” as used herein includes the naturally occurring amino acids as well as other “non-protein” &agr;-amino acids commonly utilized by those in the peptide chemistry arts when preparing synthetic analogs of naturally occurring peptides. The naturally occurring amino acids are glycine, alanine, valine, leucine, isoleucine, serine, methionine, threonine, phenylalanine, tyrosine, tryptophan, cysteine, proline, histidine, aspartic acid, asparagine, glutamic acid, glutamine, arginine, ornithine, and lysine.
Examples of “non-protein” &agr;-amino acids are norleucine, norvaline, alloisoleucine, homoarginine, thiaproline, dehydroproline, hydroxyproline, homoserine, cyclohexylglycine, &agr;-amino-n-butyric acid, cyclohexylalanine, homophenylalanine, phenylalanines substituted at the ortho, meta, or para position of the phenyl moiety with one or two of the following, a (C
1
-C
4
) alkyl, (C
1
-C
4
) alkoxy, halogen, or nitro groups or substituted with a methylenedioxy group, &bgr;-2- and 3-thienylalanine, &bgr;-2- and 3-furanylalanine, &bgr;-2-, 3-, and 4-pyridylalanine, &bgr;-(benzothienyl-2- and 3-yl)alanine,
62
-(1- and 2-naphthyl)alanine, O-alkylated derivates of serine, threonine, or tyrosine, S-alkylated cysteine, the O-sulfate ester of tyrosine, 3,5-diiodo-tyrosine and the D-isomers of the naturally occurring amino acids.
The natural amino acids with the exception of glycine, contain a chiral carbon atom. Unless otherwise specifically indicated, the optically active amino acids used in accordance with the present invention may be either the D or the L configuration, the L configuration being preferred. As is customary, the structure of peptides written out herein is such that the amino terminal end is on the left side of the chain and the carboxy terminal end is on the right side of the chain.
When two or more amino acids combine to form a peptide, the elements of water are removed, and what remains of each amino acid is called a residue. “Residue” is therefore an amino acid that lacks a hydrogen atom of the terminal amino group, and/or lacks the hydroxyl group of the terminal carboxyl group. Using accepted terminology, a dash (-)in front of (indicating loss of a hydrogen) and/or after (indicating loss of the hydroxyl) a three letter code for an amino acid or amino acid derivative indicates a residue.
Referring to Formula I, the moiety “X” may be any atom or group of atoms that do not adversely effect the function of the compound as described herein. X can be Y, wherein Y is hydrogen, an alkyl of from 1-6 carbons or an acyl group of from 2-10 carbon atoms. An “alkyl of from 1-6 carbons” means straight, branched or cyclic alkyls such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, sec-pentyl, cyclopentyl, hexyl, cyclohexyl, and isohexyl. An “acyl group of from 2 to 10 carbon atoms” means straight, branched, cyclic, saturated and unsaturated acyl groups having 1 or 2 carbonyl moieties per group, for example, acetyl, benzoyl, succinyl, maleyl, and glutaryl. Preferably, Y is hydrogen.
Alternatively, Y can be B
1
and B
2
. Each of B
1
and B
2

Affiliated with

Also associated with

Rating

Fluorinated neurokinin A antagonists does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Fluorinated neurokinin A antagonists, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Fluorinated neurokinin A antagonists will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2470432