Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-21
2001-02-13
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S324000
Reexamination Certificate
active
06187781
ABSTRACT:
TECHNICAL FIELD
This invention relates to a treating agent for diseases which corticotropin releasing factor (CRF) is considered to take part in, such as depression, anxiety, Alzheimer's disease, Parkinson's syndrome, Huntington's chorea, eating disorders, hypertension, digestive diseases, drug dependence, cerebral infarction, cerebral ischemia, cerebral edema, head wounds, inflammation, and immunity-associated diseases.
BACKGROUND ART
CRF is a hormone composed of 41 amino acids (see
Science,
vol. 213, pp. 1394-1397 (1981),
J. Neurosci.,
vol. 7, pp. 88-100 (1987)). It has been suggested that CRF plays a key role in biological reactions to stress (see
Cell. Mol. Neurobiol.,
vol. 14, pp. 579-588 (1994),
Endocrinol.,
vol. 132, pp. 723-728 (1994), and
Neuroendocrinol.,
vol. 61, pp. 445-452 (1995)). CRF functions through two routes; a route through the hypothalamo-hypophysial-adrenal system for acting on the peripheral immune system and the sympathetic nervous system, and a route through the central nervous system in which it functions as a neurotransmitter (see
Corticotropin Releasing Factor: Basic and Clinical Studies of a Neuropeptide,
pp. 29-52 (1990)) CRF intracerebroventicularly administered to hypophysectomized rats and normal rats induces anxiety-like symptoms in both rats (see
Pharmacol. Rev.,
vol. 43, pp. 425-473 (1991) and
Brain Res. Rev.,
vol. 15, pp. 71-100 (1990)). That is, CRF is believed to participate in the hypothalamo-hypophysial-adrenal system and to function as a neurotransmitter in the CNS.
As Owens and Nemeroff collected in
Pharmacol. Rev.,
vol. 43, pp. 425-474 (1991), diseases in which CRF takes part include depression, anxiety, Alzheimer's disease, Parkinson's syndrome, Huntington's chorea, eating disorders, hypertension, digestive diseases, drug dependence, inflammation, and immunity-associated diseases. It has recently been reported that CRF is also involved in epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, and head wounds (see
Brain Res.,
vol. 545, pp. 339-342 (1991),
Ann. Neurol.,
vol. 31, pp. 48-498 (1992),
Dev. Brain Res.,
vol. 91, pp. 245-251 (1996), and
Brain Res.,
vol. 744, pp. 166-170 (1997)). Therefore, an antagonist against a CRF receptor is useful as a treating agent for these diseases.
An object of the invention is to provide a CRF receptor antagonist effective as a treating agent or a prophylactic agent for diseases in which CRF is said to participate, such as depression, anxiety, Alzheimer's disease, Parkinson's syndrome, Huntington's chorea, eating disorders, hypertension, digestive diseases, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head wounds, inflammation, and immunity-associated diseases.
DISCLOSURE OF THE INVENTION
As a result of extensive study on 4-tetrahydropyridylpyrimidine derivatives, the inventors have found that 4-tetrahydropyridylpyrimidine derivatives exhibits high affinity to a CRF receptor, thus completing the present invention.
The invention will be described hereinafter.
The invention relates to a 4-tetrahydropyridylpyrimidine derivative represented by formula (I):
wherein Ar represents a phenyl group substituted with 1 to 3 substituents selected from a halogen atom, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, and a trifluoromethyl group, a phenyl group, a thienyl group or a furanyl group; R
1
represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an amino group or an amino group substituted with 1 or 2 alkyl groups having 1 to 5 carbon atoms; R
2
represents an alkyl group having 1 to 5 carbon atoms, a cycloalkylalkyl group having 4 to 7 carbon atoms, an alkenyl group having 2 to 5 carbon atoms or an alkynyl group having 2 to 5 carbon atoms; and X
1
, X
2
, and X
3
, which may be the same or different, each represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, an amino group or an amino group substituted with 1 or 2 alkyl groups having 1 to 5 carbon atoms, or a pharmaceutically acceptable salt thereof.
In the invention, Ar substitutes the tetrahydropyridine ring at the 4- or 5-position. The phenyl group substituted with 1 to 3 substituents selected from a halogen atom, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, and a trifluoromethyl group includes a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, a 2-chlorophenyl group, a 3-chlorophenyl group, a 4-chlorophenyl group, a 2-bromophenyl group, a 3-bromophenyl group, a 4-bromophenyl group, a 2-methylphenyl group, a 3-methylphenyl group, a 4-methylphenyl group, a 2-methoxyphenyl group, a 3-methoxyphenyl group, a 4-methoxyphenyl group, a 3,4-difluorophenyl group, a 3,5-difluorophenyl group, a 2,4-difluorophenyl group, a 3,4-dichlorophenyl group, a 3,5-dichlorophenyl group, and a 3-trifluoromethylphenyl group. The alkyl group having 1 to 5 carbon atoms is a straight-chain or branched alkyl group, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a pentyl group, and an isopentyl group. The cycloalkylalkyl group having 4 to 7 carbon atoms includes a cyclopropylmethyl group, a cyclopropylethyl group, and a cyclopropylpropyl group. The amino group substituted with 1 or 2 alkyl groups having 1 to 5 carbon atoms includes a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, a propylamino group, a dipropylamino group, and an isopropylamino group. The alkynyl group having 2 to 5 carbon atoms includes a straight-chain or branched alkynyl group, such as a propargyl group and a 2-butynyl group. The halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The alkoxy group having 1 to 5 carbon atoms includes a straight-chain or branched alkoxy group, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a pentyloxy group, and an isopentyloxy group. The alkylthio group having 1 to 5 carbon atoms includes a straight-chain or branched alkylthio group, such as a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group, a pentylthio group, and an isopentylthio group.
The pharmaceutically acceptable salt according to the invention includes salts with mineral acids, such as sulfuric acid, hydrochloric acid, and phosphoric acid; and those with organic acids, such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzenesulfonic acid, and methanesulfonic acid.
In formula (I), R
1
is preferably a methyl group; R
2
is preferably an ethyl group, a cyclopropylmethyl group, an allyl group or a propargyl group; X
1
is preferably a hydrogen atom; X
2
is preferably a halogen atom or a methylthio group bonded at the 2-position of the benzene ring; and X
3
is preferably an isopropyl group or a dimethylamino group bonded at the 4-position of the benzene ring. Where Ar is at the 4-position of the tetrahydropyridine ring, it is preferably a phenyl group substituted with one halogen atom. Where Ar is at the 5-position, it is preferably a phenyl group having an alkyl group having 1 to 5 carbon atoms at the 2-position thereof.
The compound of formula (I) can be prepared in accordance with the following processes. In the reaction formulae shown below, Ar, R
1
, R
2
, X
1
, X
2
, and X
3
are as defined above; R
3
represents a hydrogen atom or R
2
; R
4
and R
5
, which may be the same or different, each represent an alkyl group having 1 to 5 carbon atoms, or they are connected to each other to form a 1,2-ethylenedioxy group or a 1,3-propylenedioxy group together with the respective adjacent oxygen atoms, R
4
O and R
5
O being bonded to the same carbon atom at the 3- or 4-position; X
4
represents a chlorine atom, a bromine atom or an iodine atom;
Aibe Izumi
Chaki Shigeyuki
Kumagai Toshihito
Nakazato Atsuro
Okubo Taketoshi
Berch Mark L.
Lorusso & Loud
McKenzie Thomas
Taisho Pharmaceutical Co. Ltd.
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