Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-04-24
2002-09-03
Shah, Mukund (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S318000, C514S344000, C514S356000, C544S365000, C546S193000, C546S194000, C546S286000, C546S288000
Reexamination Certificate
active
06444675
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to heterocyclic compounds comprising dihydropyridines having alkyl and cycloalkyl moieties connected to the 4-position of the pyridine ring. More particularly, the invention is directed to NPY antagonist of alkyl and cycloalkyl derivatives of 1,4-dihydropyridine.
BACKGROUND OF THE INVENTION
Neuropeptide Y (NPY) is a 36 amino acid peptide first isolated in 1982 from porcine brain. The peptide is a member of a larger peptide family which also includes peptide YY (PYY), pancreatic peptide (PP), and the non-mammalian fish pancreatic peptide Y (PY). Neuropeptide Y is very highly conserved in a variety of animal, reptile and fish species. It is found in many central and peripheral sympathetic neutrons and is the most abundant peptide observed in the mammalian brain. In the brain, NPY is found most abundantly in limbic regions. The peptide has been found to elicit a number of physiological responses including appetite stimulation, anxiolysis, hypertension, and the regulation of coronary tone.
Structure-activity studies with a variety of peptide analogs (fragments, alanine replacements, point mutations, and internal deletion/cyclized derivatives) suggest a number of receptor subtypes exist for NPY. These currently include the Y
1
, Y
2
, Y
3
, and the Y
1-like
or Y
4
subtypes.
Although a number of specific peptidic antagonists have been identified for most of the subtypes, few selective non-peptidic antagonists have been reported to date. The heterocyclic guanidine derivative He 90481 (4) was found to be a weak but competitive antagonist of NPY-induced Ca
++
entry in HEL cells (pA
2
=4.43). The compound was also found to have &agr;
2
-adrenergic and histaminergic activity at this dose range. D-Myo-inositol-1,2,6-triphosphate was reported to be a potent but non-competitive antagonist to NPY-induced contractions in guinea pig basilar artery. Similarly, the benextramine-like bisguanidines were reported to displace
3
H-NPY in rat brain (IC
50
, 19 and 18.4 &mgr;M) and to display functional antagonism in rat femoral artery. The bisguanidine was shown to be functionally selective for the Y
2
receptor since it antagonized the effect of the NPY
2
agonist NPY
13-36
but had no effect on the vasoconstrictive activity of the NPY
1
agonist [Leu
31
, Pro
34
]NPY as disclosed in
J. Med. Chem
., 1994, 37, 2242-48, C. Chauraisia, et al.
Compound BIBP 3226, as reported in K. Rudolf, et al.,
Eur. J. Pharmacol
., 1994, 271, R11-R13, displaces I-125 Bolton-Hunter labeled NPY in human neuroblastoma cells (SK-N-MC). BIBP antagonized the NPY-induced increase in intracellular Ca
++
in SK-N-MC cells as well as antagonizing the NPY-induced pressor response in pithed rat experiments.
In addition to displacing I-125 labeled NPY and PYY in human neuroblastoma cells, compound SR 120819A, as reported in C. Serradeil-LeGal, et al.,
FEBS Lett
., 1995, 362, 192-A6, also antagonized NPY-related increases in diastolic blood pressure in an anesthetized guinea pig model.
Over the past two decades, extensive work has been conducted relating to the 4-aryl-1,4-dihydropyridine class of compounds. Syntheses of compounds in this category have been driven by their pharmacological actions involving calcium channels rendering them useful for treating cardiovascular disorders such as ischemia and hypertension.
Numerous prior patents and publications disclose various dihydropyridine derivatives. One example is U.S. Pat. No. 4,829,076 to Szilagyi, et al. disclosing compounds of formula (1) as calcium antagonists for treating hypertension.
U.S. Pat. No. 5,635,503 to Poindexter, et al. discloses 4-(3-substituted-phenyl)-1,4-dihydropyridine derivatives having NPY antagonist properties. These derivatives conform to structural formula (2).
In (2), B is either a covalent bond or the group —NH—. The symbol Z denotes hetaryl moieties, examples being homopiperazinyl or piperazine.
U.S. Pat. No. 5,554,621 discloses related derivatives where Z is a fused ring or a spiro-fused nitrogen heterocycle. U.S. Pat. No. 5,668,151 also discloses related derivatives where Z is a piperidinyl or tetrahydropyrindinyl.
U.S. Pat. No. 6,001,836 to Poindexter, et al. discloses cyanoguanidine derivatives (3) of the 4-(3-substituted-phenyl)-1,4-dihydropyridines having NPY antagonist properties.
The above-noted compounds have shown to posses antagonist activity. However, there is a continuing need for dihydropyridine derivatives having improved NPY antagonist activity.
SUMMARY OF THE INVENTION
The present invention is directed to novel dihydropyridine derivatives having NPY antagonist activity. More particularly, the invention is directed to alkyl and cycloalkyl derivatives of dihydropyridines.
Another aspect of the invention is to provide dihydropyridine derivatives that are effective in promoting weight loss and treating certain disorders in a mammal by administering to the mammal an anorexiant effective dose of an active compound of the invention.
A further aspect of the invention is to provide a method of treating clinical disorders amenable to alleviation by eliciting an NPYY
1
response by administering to a patient an effective amount of a compound of the invention.
Another aspect of the invention is to provide a pharmaceutical composition for use in promoting weight loss and treating eating disorders, where the composition comprises an anorexiant effective amount of an active compound of the invention and a pharmaceutically acceptable carrier.
The compounds of the invention have the Formula I and its pharmaceutically acceptable acid addition salts or hydrates thereof
wherein
R
1
and R
4
are independently selected from lower alkyl and CO
2
R
5
, cyano and
where R
5
is a lower alkyl;
R
2
and R
3
are independently selected from hydrogen, cyano and lower alkyl;
A is an alkyl or cycloalkyl;
n is an integer selected from 2 to 5;
X is —NH— or a covalent bond;
in which R
6
and R
7
are independently selected from lower alkyl and lower alkanol; the solid and broken line denote a single or double covalent bond; R
8
is selected from hydrogen, lower alkyl, —CO
2
R
1
, —(CH
2
)
m
R
10
, hydroxy, cyano, —(CH
2
)
n
NR
11
R
12
, wherein
m is zero or an integer from 1 to 3;
R
10
is C
3-7
cycloalkyl, naphthyl, and
n is as above; and
with R
13
being lower alkyl, lower alkenyl, C
3-7
cycloalkyl, lower alkoxy, hydrogen, halogen, hydroxy, dialkylamino, phenoxy, amino, —NHCOR
1
, —CO
2
R
1
, NO
2
, trifluoromethyl, phenyl, and R
11
and R
12
are lower alkyl or are taken together as a C
3-5
alkylene chain or an ethyl-oxy-ethyl chain.
These and other aspects of the invention will become apparent to one skilled in the art as described in the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to novel compounds having NPYY
1
antagonist activity and pharmaceutical compositions containing the novel compounds. The invention is further directed to a method of treating clinical disorders, such as eating disorders, using the novel compounds of the invention.
The compounds of the invention have the Formula I
The compounds within the preview of the invention include the pharmaceutically acceptable acid addition salts and/or hydrates of the compounds of Formula I.
In the Formula I, R
1
and R
4
are independently selected from lower alkyl and CO
2
R
5
,
cyano and
where R
5
is a lower alkyl;
R
2
and R
3
are independently selected from hydrogen, cyano and lower alkyl;
A is an alkyl or cycloalkyl;
X is —NH— or a covalent bond;
n is an integer selected from 2 to 5;
in which R
6
and R
7
are independently selected from lower alkyl and lower alkanol; the solid and broken line denote a single or double covalent bond; R
8
is selected from hydrogen, lower alkyl, —CO
2
R
1
, —(CH
2
)
m
R
10
, hydroxy, cyano, —(CH
2
)
n
NR
11
R
12
, wherein
m is zero or an integer from 1 to 3;
R
10
is C
3-7
cycloalkyl, naphthyl,
n is as above; and
with R
13
being lower alkyl, lower alkenyl, C
3-7
cycloalkyl, lower alko
Bristol--Myers Squibb Company
Liu Hong
Ryan Richard P.
Shah Mukund
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