Carbamoyl tetrahydropyridine derivatives

Details Carbamoyl tetrahydropyridine derivatives Carbamoyl tetrahydropyridine derivatives

2001-08-30

2003-07-29

Berch, Mark L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Chalcogen in the nitrogen containing substituent

C544S117000, C544S118000, C544S254000, C544S262000, C544S265000, C544S277000, C544S280000

Reexamination Certificate

active

06600038

ABSTRACT:

FIELD OF TECHNOLOGY
The present invention relates to therapeutic agents for diseases involving Corticotropin Releasing Factor (CRF), such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorders, hypertension, digestive tract diseases, drug dependence, cerebral infarction, cerebral ischemia, cerebral edema, head trauma, inflammation, and immune system-related diseases.
BACKGROUND ART
CRF is a hormone comprising 41 amino acids (Science, 213, 1394-1397, 1981; and J. Neurosci., 7, 88-100, 1987) and it is suggested that CRF plays central roles in bioreactions in stress (Cell. Mol. Neurobiol., 14, 579-588, 1994; Endocrinol., 132, 723-728, 1994; and Neuroendocrinol. 61, 445-452, 1995). CRF acts in two pathways: one acting on the peripheral immune system and sympathetic nervous system via the hypothalamus-pituitary-adrenal system, and another in which it acts as a neurotransmitter in the central nervous system (in Corticotropin Releasing Factor: Basic and Clinical Studies of a Neuropeptide, pp 29-52, 1990). In the case where CRF is intraventricularly administered to hypophysectomized rats and to normal rats, symptoms of anxiety occur in both rats (Pharmacol. Rev., 43, 425-473, 1991; and Brain Res. Rev., 15, 71-100, 1990). Therefore, it is believed that CRF is involved in the hypothalamus-pituitary-adrenal system and that CRF functions as a neurotransmitter in the central nervous system.
The diseases in which CRF is involved are summarized in a review by Owens and Nemeroff in 1991 (Pharmacol. Rev., 43, 425-474, 1991). Namely, CRF is involved in depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, digestive tract diseases, drug dependence, inflammation, immune system-related diseases, and the like. Recently, it is reported that CRF is also involved in epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, and head trauma (Brain Res. 545, 339-342, 1991; Ann. Neurol. 31, 48-498, 1992; Dev. Brain Res. 91, 245-251, 1996; and Brain Res. 744, 166-170, 1997), and for this reason, CRF-receptor antagonists are useful as therapeutic agents for these diseases.
An objective of the present invention is to provide CRF antagonists effective on therapeutic agents or prophylactic agents for the diseases, which CRF participates in, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, digestive apparatus disease, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head trauma, inflammation, and immune system-related diseases.
DISCLOSURE OF THE INVENTION
As a result of diligent research with regard to carbamoyl tetrahydropyridine derivatives, the present inventors discovered novel carbamoyl tetrahydropyridine derivatives which exhibit high affinity for CRF receptors, and in addition, pyrrolopyrimidine derivatives, pyrrole derivatives, and carbamoyl-1,2,3,6-tetrahydropyridines which are intermediates necessary for synthesizing said novel carbamoyl tetrahydropyridine derivatives, consequently completed the present invention.
In the following, the present invention is explained.
The present invention corresponds to a carbamoyl tetrahydropyridine derivative represented by Formula [1] as follows:
[in the formula, R
1
and R
2
are identical or different, and each represents a hydrogen atom, a C
1
-C
5
alkyl group, or a phenyl group, or alternatively, R
1
and R
2
, taken together with the nitrogen atom to which they are adjacent, represent a 5- to 8-membered and saturated heterocyclic group represented by the formula:
(in the formula, A represents CH
2
, NH, N—(C
1
-C
5
alkyl), O or S); R
3
represents a hydrogen atom or a C
1
-C
5
alkyl group; Y
1
-Y
2
represents (R
4
)C═C(R
5
), (R
6
)C═N, N═N, (R
7
)N—CO, or N═C(R
8
); X
1
, X
2
, and X
3
are identical or different, and each represents a hydrogen atom, a halogen atom, a C
1
-C
5
alkyl group, a C
1
-C
5
alkoxy group, a C
1
-C
5
alkylthio group, a tuifluoromethyl group, a trifluoromethoxy group, an amino group, or a C
1
-C
5
alkylamino group; wherein R
4
and R
5
are identical or different, and each represents a hydrogen atom or a C
1
-C
5
alkyl group; R
6
represents a hydrogen atom or a C
1
-C
5
alkyl group; R
7
represents a hydrogen atom, a C
1
-C
5
alkyl group, a (C
1
-C
5
alkoxy)carbonylmethyl group, a carboxymethyl group, or a group represented by the formula: CH
2
CONR
11
(R
12
) (in the formula, R
11
and R
12
are identical or different, and each represents a hydrogen atom or a C
1
-C
5
alkyl group, or alternatively, R
11
and R
12
, taken together with the nitrogen atom to which they are adjacent, represent a 5- to 8-membered and saturated heterocyclic group represented by the formula:
(in the formula, B represents CH
2
, NH, N—(C
1
-C
5
alkyl), O or S); and R
8
represents a hydrogen atom or a carbamoyl group], or a pharmaceutically acceptable salt thereof. Among these, the compounds wherein R
1
and R
2
represent a hydrogen atom are preferable, and the compounds wherein R
3
represents a methyl group; Y
1
-Y
2
represents (R
4
)C═C(R
5
); and R
4
and R
5
are identical or different, and each represents a hydrogen atom or a methyl group are more preferable.
In addition, another present invention corresponds to a pyrrolopyrimidine derivative represented by Formula [2] as follows:
(in the formula R
3
represents a hydrogen atom or a C
1
-C
5
alkyl group; R
4
and R
5
are identical or different, and each represents a hydrogen atom or a C
1
-C
5
alkyl group; X
4
represents a hydroxyl group, a chlorine atom, a bromine atom, or an iodine atom; and X
5
represents a halogen atom, a C
1
-C
5
alkyl group, a C
1
-C
5
alkoxy group, a C
1
-C
5
alkylthio group, a trifluoromethyl group, or a trifluoromethoxy group).
Furthermore, another present invention corresponds to a pyrrole derivative represented by Formula [3] as follows:
(in the formula, R
4
and R
5
are identical or different, and each represents a hydrogen atom or a C
1
-C
5
alkyl group; and X
5
represents a halogen atom, a C
1
-C
5
alkyl group, a C
1
-C
5
alkoxy group, a C
1
-C
5
alkylthio group, a trifluoromethyl group, or a trifluoromethoxy group).
In addition, another present invention corresponds to a 4- or 5-carbamoyl-1,2,3,6-tetrahydropyridine represented by Formula [4] as follows:
or a pharmaceutically acceptable salt thereof.
In Formula [1] of the present invention, the substituent position of the (R
2
)R
1
NCO group is present at the 4-position or the 5-position.
In addition, the terms used in the present invention are defined as follows.
The C
1
-C
5
alkyl group means a straight-chain or branched-chain alkyl group having 1 to 5 carbon atoms. As an example thereof, mention may be made of a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a cyclopropylmethyl group, a pentyl group, an isopentyl group, or the like.
The saturated heterocyclic group means a 5- to 8-membered and saturated heterocyclic group which may include a nitrogen atom, an oxygen atom, or a sulfur atom as an atom for forming the ring, while it is not particularly restricted since any saturated heterocyclic groups capable of providing the compounds represented by Formula (10) shown in the reaction scheme described below may be synthesized. Examples thereof include a pyrrolidino group, a piperidino group, a morpholino group, a thiomorpholino group, a piperazino group, a 4-methylpiperazino group, and the like.
The halogen atom denotes a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
The C
1
-C
5
alkoxy group means a straight-chain or branched-chain alkoxy group having 1 to 5 carbon atoms. As an example thereof, mention may be made of a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a pentyloxy group,

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