Peptide derivatives having thiazolyl-alanine residue

Details Peptide derivatives having thiazolyl-alanine residue Peptide derivatives having thiazolyl-alanine residue

1999-05-12

2001-11-20

Low, Christopher S. F. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C548S535000, C562S553000

Reexamination Certificate

active

06319902

ABSTRACT:

This application is the national phase under 35 U.S.C. §371 of PCT International Application No. PCT/JP97/02917 which has an International filing date of Aug. 22, 1997 which designated the United States of America.
1. Technical Field
This invention relates to a new peptide derivative having the residue of 3-(4-thiazolyl or 5-thiazolyl)-alanine and having an effect of activating the central nervous system. The compound of this invention is useful as a medicament.
2. Background Art
The compound of this invention is derived from L-pyroglutamyl-L-histidyl-L-prolineamide (p-Glu-His-Pro-NH
2
), known as TRH (thyrotropin releasing hormone) isolated from hypothalamus.
TRH is a hormone consisting of 3 amino acid residues isolated from hypothalamus, and seems to show the activities through a TRH receptor. It is known not only to promote the secretion of TSH (thyroid stimulating hormone) and prolactin, but also to have the following activity; brain nervous system activation such as motor stimulating activity etc., sympathetic activity such as blood pressure elevation, respiratory stimulation, etc., spinal activity such as spinal motor nerve stimulation etc., central nervous activity such as antidepression etc., and peripheral activity such as gastrin secretion suppression, glucagon secretion stimulation, etc. Because TRH has such various activity, it has been investigated on the clinical use, and is being used as an intravenous injection for treating spinocerebellar degeneration for purposes of improvement of motility disturbance and cognitive disturbance accompanied by brain functional disturbance (Sofue, Kanazawa, Ogawa, “Neuropeptide”'91, Medicalreview).
However, there are various problems barring the clinical application of TRH. Typical ones are described below:
1) TRH shows very short half-time in blood and is required to be administered frequently, because it is digested by enzymes such as pyroglutamyl peptidase, TRH amidase, etc. in a living body.
2) Excessive secretion of TSH is caused by repeated administration of TRH due to the activity of stimulating secretion of TSH.
3) A slight mount of TRH is transferred into brain by peripheral administration because of its low hydrophobicity.
In order to solve the above problems concerning TRH, the development of TRH derivatives which have more potent activity than TRH in view of activation of the central nervous system (for example, awaking stimulation, anti-reserpine activity (hyperthermia), locomotor increment, spinal reflex increase, dopamine action potentiation, anti-anesthetic action, etc.) and have long duration of action has been attempted. Such compounds reported at the present time are illustrated below.
For example, 1-methyl-L-4,5-dihydroorotyl-L-hystidlyl-L-prolineamide (JP-B 2-36574), 2,3,4,5-tetrahydro-2-oxo-L-5-furancarbonyl-L-histidyl-L,-prolineamide (JP-A 52-116465), (1S, 2R)-2-methyl-4-oxocyclolentylcarbonyl-L-histidyl-L-prolineamide (JP-B-3-236397), orotyl-L-histydyl-L-prolineamide (JP-B 59-36612), TRH-SR (Eur. J. Pharmacol., 271, 357 (1994)), etc. are known
However, the above TRH derivatives do not have enough continuous action. Additionally, intravenous injection of these compounds makes it difficult to improve the compliance to the periodical administration of them and QOL (Quality of Life) of patients having the motor disturbance.
DISCLOSURE OF INVENTION
In the above situation, the inventors of the present invention found the compounds having superior activity known TRH and its derivatives in view of the activation of the central nervous system, for example, sustained acetylcholine releasing action, anti-reserpine action and locomotor increment activity. The present invention relates to
a) A peptide derivative of the formula (I):
wherein A is 4-thiazolyl or 5-thiazolyl wherein the nitrogen in the thiazolyl ring may be quarternary nitrogen which is formed with optionally substituted alkyl or alkenyl, X is a bond, oxygen, or sulfur, m is an integer of 0 to 4, Y is optionally substituted alkyl, optionally substituted carboxy, cyano, or the substituent represented by the formula:
wherein R
1
and R
2
are independently hydrogen or optionally substituted alkyl, or R
1
and R
2
taken together with may form a non-aromatic heterocyclic ring the adjacent nitrogen which may contain oxygen, nitrogen, or sulfur and may be substituted, Z is the substituent represented by the formula:
wherein R
3
is hydrogen, optionally substituted alkyl, optionally substituted carboxy, or optionally substituted acyl, R
4
and R
5
are each independently hydrogen or optionally substituted alkyl, and W is —(CH
2
)n— wherein n is 0, 1, 2, or 3, oxygen, sulfur, or optionally substituted imino, or the substituent, represented by the formula:
its pharmaceutically acceptable salt, or hydrate thereof.
b) A peptide derivative of the formula (II):
wherein X, Y, Z, and m are as defined above, and the nitrogen in the thiazolyl ring may be quarternary nitrogen which is formed with optionally substituted alkyl or alkenyl, its pharmaceutically acceptable salt, or hydrate thereof.
c) A peptide derivative of the formula (III):
wherein X, Y, Z, and m are as defined above, and the nitrogen in the thiazolyl ring may be quarternary nitrogen which is formed with optionally substituted alkyl or alkenyl, its pharmaceutically acceptable salt, or hydrate thereof.
d) A peptide derivative of the formula (IV):
wherein W, X, Y, m, R
3
, R
4
, and R
5
are as defined above, its pharmaceutically acceptable salt, or hydrate thereof.
e) A peptide derivative of the formula (V):
wherein Y is as defined above, its pharmaceutically acceptable salt, or hydrate thereof.
f) A peptide derivative of the formula (VI):
wherein Y is as defined above, its pharmaceutically acceptable salt, or hydrate thereof.
g) A peptide derivative of any one of a) to d) wherein m is 1 or 2, provided that X is not a bond when m is 1, its pharmaceutically acceptable salt, or hydrate thereof.
h) A peptide derivative of any one of a) to d) wherein m is 1 and Y is optionally substituted alkyl, optionally substituted carboxy, or optionally substituted carbamoyl, its pharmaceutically acceptable salt, or hydrate thereof.
i) A peptide derivative of any one of a) to d) wherein m is 2 or 3 and Y is optionally substituted alkyl, optionally substituted carboxy, or optionally substituted carbamoyl, its pharmaceutically acceptable salt, or hydrate thereof.
j) A pharmaceutical composition which contains any one of the compounds a) to i) as an active ingredient.
k) A composition for activating the central nervous system which contains any one of the compounds a) to i) as an active ingredient.
l) A TRH derivative having such effect that the ratio represented by the blood glucose level of the active substance-administered group/the blood glucose level of the physiological saline-administered group is 0.7 to 1.3 in the rat to which an effective amount of it for exhibiting the main activity is intravenously administered.
All of the compounds represented by the above formula have superior activity of activating the central nervous system. Specifically, the compounds having the substituents shown below in the formula (IV) are preferable.
1) A peptide derivative wherein W is oxygen, X is oxygen or sulfur, Y is carbamoyl or optionally substituted alkyl, m is 1, R
3
is hydrogen, R
4
is optionally substituted alkyl, and R
5
is hydrogen, its pharmaceutically acceptable salt, or hydrate thereof.
2) A peptide derivative wherein W is oxygen, X is a bond, Y is carbamoyl or optionally substituted alkyl, m is 2, R
3
is hydrogen, R
4
is optionally substituted alkyl, and R
5
is hydrogen, its pharmaceutically acceptable salt, or hydrate thereof.
As further preferable compounds, the compounds having the substituents shown below in the formula (IV) are exemplified.
1′) A peptide derivative wherein W is oxygen, X is oxygen or sulfur, Y is carbamoyl or alkyl, m is 1, R
3
is hydrogen, R
4
is alkyl, and R
5
is hydrogen, its pharmaceutically acceptable salt, or hydrate thereof.
2′) A peptide derivative wherein W

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