Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-17
2001-05-29
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S196000
Reexamination Certificate
active
06239147
ABSTRACT:
This invention relates to novel 1 -trifluoromethyl-4-hydroxy-7-piperidinylaminomethylchroman derivatives and their pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds, and the use of such compounds as substance P antagonists.
BACKGROUND
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt stimulatory action on smooth muscle tissue. More specifically, substance P is a pharmaceutically active neuropeptide that is produced in mammals (having originally been isolated from the gut) and possesses a characteristic amino acid sequence as illustrated by D. F. Veber et al. in U.S. Pat No. 4,680,283. The wide involvement of substance P and other tachykinins in the pathophysiology of numerous diseases has been amply demonstrated in the art. For instance, substance P has recently been shown to be involved in the transmission of pain or migraine, as well as in central nervous system disorders such as anxiety and schizophrenia, in respiratory and inflammatory diseases such as asthma and rheumatoid arthritis, respectively, and in gastrointestinal disorders and diseases of the GI tract, like ulcerative colitis, irritable bowel syndrome, Crohn's disease, etc. It is also reported that tachykinin antagonists are useful for the treatment of cardiovascular diseases, allergic conditions, immunoregulation, vasodilation, bronchospasm, reflex or neuronal control of the viscera, senile dementia of the Alzheimer type, emesis, sunburn and
Helicobacter pylori
infection.
European Patent Application 840,732, which was published on May 13, 1998 and international Patent Application PCT/IB97/01466, filed on Nov. 19, 1997, disclose a variety of substituted piperidine compounds, including piperidine compounds having a substituent comprising a fused ring moiety including an oxygen atom, as substance P antagonists.
Substance P antagonists having improved activity and fewer side effects are desired.
BRIEF DESCRIPTION OF THE INVENTION
The present invention provides piperidinylaminomethyl trifluoromethyl cyclic ether compounds of the following chemical formula (I):
and their pharmaceutically acceptable salts, wherein
R
1
is C
1
-C
6
alkyl;
R
2
is hydrogen, C
1
-C
6
alkyl, halo C
1
-C
6
alkyl or phenyl;
R
3
is hydrogen or halo; and
R
4
and R
5
are independently hydrogen, C
1
-C
6
alkyl or halo C
1
-C
6
alkyl.
The compounds of formula (I) contain at least two chiral centers and therefore exist as at least two diastereoisomeric pairs of optical isomers including epimers. This invention includes both the individual isomers of the compounds of formula (I) and mixtures of two or more of such isomers.
The compounds of formula (I) of the invention preferably have the (2S,3S) configuration with respect to the piperidine ring.
Embodiments of the invention are compounds of formula (I) wherein R
1
is C
1
-C
3
alkyl; R
2
is hydrogen, C
1
-C
3
alkyl, halo C
1
-C
3
alkyl or phenyl; R
3
is hydrogen or fluorine; and R
4
and R
5
are independently hydrogen, C
1
-C
3
alkyl or halo C
1
-C
3
alkyl.
Other embodiments of the invention are compounds of formula (I) wherein R
1
is methyl; R
2
is hydrogen, methyl, trifluoromethyl or phenyl; R
3
is hydrogen; and R
4
and R
5
area hydrogen.
A specific preferred compound of the formula (I) is (2S,3S)-3-(6-methoxy-1-methyl-1-trifluoromethylisochroman-7-yl)methylamino-2-phenylpiperidine or a pharmaceutically acceptable salt thereof.
The compounds of the invention are useful as substance P antagonists, and thus useful for treating a disorder or condition selected from dysthymia, major depressive disorder, pediatric depression, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, phobias such as social phobia and agoraphobia; post traumatic stress disorder, borderline personality disorder, acute pain, chronic pain, migraine, angiogenesis, sunburn, urinary incontinence, inflammatory disorders such as rheumatoid arthritis, osteoarthritis, psoriasis, asthma and allergic disorders; emesis, including acute, delayed and anticipatory emesis wherein the emetic agent or condition is chemotherapy, radiation, surgery, motion, migraine or any other emetic agent or condition; disorders caused by
Helicobacter pylori,
cardiovascular disorders, ophthalmic disorders, inflammation of the urinary tract, psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, movement disorders such as Tourette's syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia and other dyskinesias; cognitive disorders such as dementias (including age related dementia and senile dementia of the Alzheimer's type) and memory disorders (e.g., amnestic disorders), eating disorders such as anorexia nervosa and bulimia nervosa, attention deficit hyperactivity disorder, chronic fatigue syndrome, premature ejaculation, premenstrual syndrome, premenstrual dysphoric disorder, chemical dependencies and addictions, stress related somatic disorders, neuralgia, peripheral neuropathy, gastroesophageal reflux disease, reflex sympathetic dystrophy such as shoulder/hand syndrome; hypersensitivity disorders such as to poison ivy; fibromyalgia, angina, Reynaud's disease, rheumatic diseases such as fibrositis; eczema, rhinitis, allergies, post-herpetia neuralgia, cystitis, inflammatory bowel disease, irritable bowel syndrome, colitis, fibrosing and collagen disorders such as scleroderma and eosinophilic fascioliasis; blood flow disorders due to vasodilatation, and disorders related to immune enhancement or suppression such as systemic lupus erythematosus in a mammal, especially a human. These compounds are especially useful as anti-inflammatory or anti-emetic agents, or agents for treating CNS disorders.
The compounds of the invention are particularly useful in the treatment of emesis, including acute, delayed or anticipatory emesis such as emesis or nausea induced by chemotherapy, radiation, surgery, pregnancy, motion, vestibular disorders, toxins, migraine, and variations in intracranial pressure. Most specifically, these compounds are of use in the treatment of emesis induced by antineoplastic agents, including those used in cancer therapy, and emesis induced by other pharmacological agents such as rolipram or morphine. These compounds are also useful for chronic and acute pain including hyper-analgesic pain, neuropathic pain, post-operative pain and pain associated with nerve damage.
The present invention also relates to a pharmaceutical composition for treating a disorder or condition for which antagonist activity toward substance P is needed, in an mammal, which comprises an amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition, and a pharmaceutically acceptable carrier.
The invention also relates to a method of treating a disorder or condition for which antagonist activity toward substance P is needed, in a mammal, which comprises administering to a mammal in need of such treatment an amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition.
The invention also relates to a pharmaceutical composition for treating a disorder or condition selected from dysthymia, major depressive disorder, pediatric depression, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, phobias such as social phobia and agoraphobia; post traumatic stress disorder, borderline personality disorder, acute pain, chronic pain, migraine, angiogenesis, sunburn, urinary incontinence, inflammatory disorders such as rheumatoid arthritis, osteoarthritis, psoriasis, asthma and allergic disorders; emesis, including acute, delayed and anticipatory emesis wherein the emetic agent or condition is chemotherapy, radiation, surgery, motion, migraine or any other emetic agent or condition; disorders caused by
Helicob
Obach R. Scott
Scully Douglas Alan
Chang Ceila
Ginsburg Paul H.
Pfizer Inc
Richardson Peter C.
Waldron Roy F.
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