Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-02
2002-02-19
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S018000
Reexamination Certificate
active
06348472
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention concerns heterocyclic carbon compounds comprising spiroisoquinolinone derivatives which have been discovered to be NPY antagonists.
Antagonism of neuropeptide Y receptors has been postulated to reduce food consumption in mammals. Several non-peptidic chemotypes have been disclosed in the literature as being antagonists at the Y
1
and at the Y
5
subtypes of NPY receptors. (See Gehlert and Hipskind,
Exp. Opin. Invest. Drugs
, 1997, 6, pp. 1827-1838.)
Neither applicants' novel spiroisoquinolinone compounds nor the use of these and related spiroisoquinolinones for use in treating medical disorders by means of antagonizing NPY receptors following administration of these compounds is known or suggested by prior art.
Earlier work by our group involved 4-(3-substituted-phenyl)-1,4-dihydropyridine derivatives having NPY antagonist properties. These derivatives conform to structural formula (1).
In (1) B is either a covalent bond or the group —NH—. The symbol Z denotes hetaryl moieties, examples being piperidine or piperazine.
In U.S. Pat. No. 5,554,621, Z is a fused ring or spiro-fused nitrogen heterocyclic group giving rise to compounds having, for example, a structure such as formula (2).
Other work by our group has resulted in discovery of certain imidazolone derivatives of formula (3) having NPY antagonism (cf: U.S. Ser. No. 60/079,359).
As can be seen, these compounds differ significantly in structure from the compounds of the present invention.
SUMMARY AND DETAILED DESCRIPTION OF THE INVENTION
The present invention comprises compounds of Formula I, their
pharmaceutically acceptable acid addition salts and/or their hydrates thereof. In the foregoing structural Formula I, the symbol Z has the following meanings.
Z can be a C
9-10
alkyl, a C
2-6
alkenyl group or the moiety A—R, in which A denotes a C
1-6
linking alkanediyl or C
2-6
alkenediyl group connecting R to the piperidino-ring nitrogen atom.
R, in turn, is selected from —OH, —CH(OMe)
2
, —NR
1
R
2
, 1-adamantyl,
R
1
and R
2
are independently chosen from hydrogen, C
1-4
alkyl, or benzyl groups, R
3
is selected from hydrogen, C
1-4
alkyl, C
1-4
alkoxy, halogen, —NR
1
, R
2
, phenyl, phenoxy, and —O
2
C-phenyl.
In preferred compounds, A is a methylene or ethylene chain and R
In more preferred compounds, R is
and in most preferred compounds, R
3
is phenyl or phenoxy.
The present invention also pertains to pharmaceutically acceptable salts of the Formula I compounds. Such salts include those derived from organic and inorganic acids such as, without limitation, hydrochloric, hydrobromic, phosphoric, sulfuric, methanesulfonic, acetic, fumaric, tarytaric, moleic, succinic, lactic, citric acid, and the like.
Formula I compounds can be produced by using the general process shown in Scheme 1. The symbol Z is as previously defined.
The majority of Formula I compounds were synthesized by the route shown in Scheme 1.
For Formula I products wherein Z is
and A is at least three carbons in length, the synthetic process involves protection of the carbonyl moiety and in most instances straightforward ketal formation accomplishes this objective, as shown in Scheme 2.
Since structural diversity arises from the variation of Z, Formula II alkylating agents are the focus for synthetic elaboration. Many of the Formula II compounds are either commercially available or amenable to synthetic methods. Scheme 3 illustrates synthesis of Z—X compounds wherein Z is R—A- and R is, e.g.
with R
3
being phenoxy.
Another synthetic variation of the Formula I structure can be obtained by operation on a Formula I compound itself. This is illustrated in Scheme 4 where a Suzuki coupling is employed.
Similar processes employing synthetic modifications familiar to one skilled in the art of synthetic organic chemistry can be utilized to provide additional Formula I compounds. Additional examples and procedures are provided infra in the Specific Embodiments section of the specification.
The compounds of Formula I demonstrate binding affinity at NPY receptors. The binding interaction has been characterized as antagonism at NPY Y
5
receptors. This pharmacologic activity was characterized by using BRI-TN-5BI-4 insect cells infected with NPY Y
5
-recombinant Baculovirus. These cells which express Y
5
receptor were used in a radioligand binding assay employing Iodine-125 labeled PYY ligand. The spiroisoquinolones of this invention all showed IC
50
values of less than 10 &mgr;M, with preferred compounds having IC
50
values of less than 500 nM and most preferred compounds having IC
50
values of less than 100 nM.
Certain preferred compounds of Formula I were tested in a functional assay where they were found to antagonize NPY-mediated inhibition of forskolin-induced c-AMP accumulation in HEK-293 cells.
Pharmacologically, these compounds act as selective NPY antagonists at NPY Y
5
receptor sites. As such, the compounds of Formula I are of value in the treatment of a wide variety of clinical conditions which are characterized by the presence of an excess of neuropeptide Y. Thus, the invention provides methods for the treatment or prevention of a physiological disorder associated with an excess of neuropeptide Y, which method comprises administering to a mammal in need of said treatment an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof. The term “physiological disorder associated with an excess of neuropeptide Y” encompasses those disorders associated with an inappropriate stimulation of neuropeptide Y receptors, regardless of the actual amount of neuropeptide Y present in the locale.
These physiological disorders include:
disorders or diseases pertaining to the heart, blood vessels or the renal system, such as vasospasm, heart failure, shock, cardiac hypertrophy, increased blood pressure, angina, myocardial infarction, sudden cardiac death, congestive heart failure, arrythmia, peripheral vascular disease, and abnormal renal conditions such as impaired flow of fluid, abnormal mass transport, or renal failure;
conditions related to increased sympathetic nerve activity for example, during or after coronary artery surgery, and operations and surgery in the gastrointestinal tract;
cerebral diseases and diseases related to the central nervous system, such as cerebral infarction, neurodegeneration, epilepsy, stroke, and conditions related to stroke, cerebral vasospasm and hemorrhage, depression, anxiety, schizophrenia, dementia, seizure, and epilepsy;
conditions related to pain or nociception;
diseases related to abnormal gastrointestinal motility and secretion, such as different forms of ileus, urinary incontinence, and Crohn's disease;
abnormal drink and food intake disorders, such as obesity, anorexia, bulemia, and metabolic disorders;
diseases related to sexual dysfunction and reproductive disorders;
conditions or disorders associated with inflammation;
respiratory diseases, such as asthma and conditions related to asthma and bronchoconstriction;
diseases related to abnormal hormone release, such as leutinizing hormone, growth hormone, insulin and prolactin;
sleep disturbance and diabetes;
emesis.
There is evidence that NPY contributes to certain symptoms in these disorders: hypertension, eating disorders, and depression/anxiety; as well as circadian rhythms. Compounds of this invention are expected to be useful in treating these disorders as well as sleep disturbance and diabetes.
Selected compounds are tested further for their ability to block or stimulate NPY-induced feeding in test animals by intraperitoneal administration to the animal prior to inducing feeding behavior with NPY. Taken together, these tests indicate that the compounds of this invention would be useful anorexiants and would function as anti-obesity agents with further use in various clinical eating disorders. Thus, another aspect of the invention concerns a process for reducing food intake in an obese mammal or a mammal with an eating disorder. The process comprise
Antal Ildiko
Bruce Marc A.
Giupponi Leah M.
Poindexter Graham S.
Stoffel Robert H.
Rotman Alan L.
Ryan Richard R.
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