Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
1998-10-14
2001-04-17
Raymond, Richard L. (Department: 1611)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C514S227800, C514S235800, C514S252010, C514S256000, C544S060000, C544S122000, C544S295000, C544S333000, C544S335000, C540S601000
Reexamination Certificate
active
06218538
ABSTRACT:
FIELD OF INVENTION
This invention relates to certain novel 2-aryl dihydropyrimidine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy. A further objective is to provide compounds which are potent ligands for N-type neuronal calcium channels.
BACKGROUND OF THE INVENTION
It is well known that there are several different types of voltage-gated calcium channels which can be distinguished on the basis of biophysical and pharmacological properties. These calcium channels are defined by differences in the amino acid sequence of the &agr;
1
subunits (“Molecular Determinants of Ca
2+
Channel Function and Drug Action”
TiPS
1995, 16, 43-49), and by different sensitivities to various ligands (“Synthetic Organic Ligands Active at Voltage-Gated Calcium Channels”,
Ann. N.Y. Acad. Sci.,
1991, 635, 123-138). These publications teach that the L-type calcium channel differs from the N-type calcium channel in regard to the amino acid sequence of the &agr;
1
subunits and the sensitivity to dihydropyridines (L-channels are sensitive, N-channels are not) and the sensitivity to &ohgr;-Conotoxins GVIA and MVIIA (N-channels are sensitive, L-channels are not).
L-Type calcium channel antagonists are clinically proven compounds for the treatment of cardiovascular disease, particularly hypertension.
The use of compounds which bind to N-type neuronal calcium channels has been discussed with respect to the treatment of a range of disorders involving abnormal calcium flux in cells, including ischaemia, Alzheimer's disease, neuroprotection and analgesia (“Neuronal Voltage-Sensitive Calcium Channels”
Drug News
&
Perspectives,
1994, 7, 261-268). N-Type neuronal calcium channels have also been found to be involved in the release of various neurotransmitters and therefore, compounds that bind to N-type calcium channels may also be useful in various disease states characterised by abnormal neurotransmitter release, for example, anxiety, schizophrenia, Parkinson's disease and migraine.
U.S. Pat. No. 4,822,798 discloses dihydropyrimidines of general structure:
as agents having circulation-influencing action. These compounds are distinguished from the scope of the present application by virtue of the definition of group R
5
, and by their different pharmacological activity.
DISCLOSURE OF THE INVENTION
According to the invention we provide a compound of formula (I)
wherein:
R
1
represents a monocyclic aromatic ring optionally incorporating one to three heteroatoms which may be the same or different and are selected from N, O or S, which ring may be optionally substituted by halogen, alkyl C1 to 6, alkoxy C1 to 6 or trifluoromethyl;
R
2
represents alkyl C1 to 6 or unsaturated alkyl C2 to 6, either optionally including O or S, and which is substituted by a phenyl or a monocyclic heteroaryl ring, which aromatic ring is optionally substituted by one or more substituents independently selected from halogen, alkyl C1 to 6 or alkoxy C1 to 6;
R
3
represents a monocyclic or bicyclic aromatic ring optionally incorporating one heteroatom selected from N, O or S, optionally substituted by one or more substituents independently selected from halogen, alkyl C1 to 6, alkoxy C1 to 6, cyano, benzyloxy, trifluoromethyl, amino, hydroxy, nitro or carbomethoxy;
R
4
and R
5
independently represent hydrogen, alkyl C1 to 6, or benzyl;
or the group NR
4
R
5
together represents piperidinyl, morpholinyl, 3,4-dehydropiperidinyl, perhydroazepinyl, thiomorpholinyl, pyrrolidinyl, piperazinyl or piperazinyl further substituted at N-4 by alkyl C1 to 6;
X represents O, S or NR
6
;
R
6
represents hydrogen or alkyl C1 to 6;
and n represents an integer 2 to 4;
and optical isomers and racemates thereof and pharmaceutically acceptable salts thereof.
Examples of said “monocyclic or bicyclic aromatic ring optionally incorporating one heteroatom selected from N, O or S” include, but are not limited to, phenyl; 1- and 2-naphthyl; 2-, 3- and 4-pyridyl; 2- and 3-thienyl; 2- and 3-furyl; quinolyl; isoquinolyl; indolyl; benzothienyl and benzofuryl.
Examples of said “monocyclic aromatic ring optionally incorporating one to three heteroatoms selected from N, O or S” include, but are not limited to, phenyl; 2-, 3- and 4-pyridyl; pyrimidinyl; 2- and 3-thienyl; 2- and 3-furyl; oxazolyl; thiazolyl; isoxazolyl; imidazolyl; and thiadiazolyl.
Unless otherwise indicated, the term “alkyl C1 to 6” referred to herein denotes a straight or branched chain alkyl group having from 1 to 6 carbon atoms or a cyclic alkyl group having from 3 to 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclopentyl and cyclohexyl.
Unless otherwise indicated, the term “unsaturated alkyl C2 to 6” referred to herein denotes a straight or branched chain alkyl group having from 2 to 6 carbon atoms and including one double bond or one triple bond or a cyclic alkyl group having from 3 to 6 carbon atoms and including one double bond. Examples of such groups include ethenyl, ethynyl, 1- and 2-propenyl, 1- and 2-propynyl, 2-methyl-2-propenyl, 2-butenyl, 2-butynyl,cyclopentenyl and cyclohexenyl.
Unless otherwise indicated, the term “alkoxy C1 to 6” referred to herein denotes a straight or branched chain alkoxy group having from 1 to 6 carbon atoms. Examples of such groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy and t-butoxy.
Unless otherwise indicated, the term “halogen” referred to herein denotes fluorine, chlorine, bromine and iodine.
1,4-Dihydropyrimidines such as compounds of formula (I) may exist to a greater or lesser extent in the tautomeric 3,4-dihydro form (Ia):
Wherever compounds are shown or named as 1,4-dihydropyrimidines, it is to be understood that both the 1,4-dihydro and 3,4-dihydro tautomers and mixtures thereof are included within the scope of the invention.
Preferred compounds of the invention are compounds of formula (I) wherein:
R
1
represents 2-furyl, 2-thienyl, phenyl or pyridyl, optionally further substituted;
R
2
represents 3-phenylpropyl or 3-(1-phenoxy)propyl, optionally substituted on the phenyl ring by halogen;
R
3
represents a 4-substituted phenyl, optionally further substituted in the 2- or 3-position, or 2-quinolyl;
R
4
and R
5
independently represent alkyl C1 to 6;
or the group NR
4
R
5
together represents piperidinyl, pyrrolidinyl or piperazinyl further substituted at N-4 by alkyl C1 to 6;
X represents O;
and n=2.
Particularly preferred compounds of the invention include:
3-phenylpropyl 4-(3,4-dichlorophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate,
3-phenylpropyl 4-(4-methyl-3-nitrophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate,
3-phenylpropyl 4-(3-chlorophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate,
3-phenylpropyl 4-(4-methylphenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate,
3-phenylpropyl 4-(4-chlorophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate,
3-phenylpropyl 4-(4-methoxycarbonylphenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate,
3-phenylpropyl 4-(3,4-dichlorophenyl)-2-(2-furyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate,
3-phenylpropyl 4-(3,4-dichlorophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(4-pyridyl)-1,4-dihydropyrimidine-5-carboxylate,
3-phenylpropyl 4-(3,4-dichlorophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(2-pyridyl)-1,4-dihydropyrimidine-5-carboxylate,
3-phenylpropyl 4-(3,4-dichlorophenyl)-6-[(2-(N,N-diethylamino)ethoxy)methyl]-2-(2-furyl)-1,4-dihydropyrimidine-5-carboxylate,
3-phenylpropyl 4-(3,4-dichlorophenyl)-6-[(2-(N,N-dimethylamino)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate,
3-phenylpropyl 6-[(2-(N,N-diethyl
Downs Eileen S.
Michne William F.
Pierson, Jr. M. Edward
Astra Aktiebolag
Balasubramanian Venkataraman
Nixon & Vanderhye
Raymond Richard L.
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