Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2001-12-05
2004-05-11
Morris, Patricia L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C546S177000
Reexamination Certificate
active
06734306
ABSTRACT:
TECHNICAL FIELD
This invention relates to novel N-benzenesulfonyl L-proline compounds. These compounds are useful as antagonists of bradykinin, and are thus useful in the treatment of inflammation, asthma, allergic rhinitis, pain or the like in mammalian, especially humans. The present invention also relates to a pharmaceutical composition comprising the above compounds.
BACKGROUND ART
Bradykinin (“BK”) is generated under normal conditions in mammalia by the action of various plasma enzymes such as kallikrein on high molecular weight kininogens. It is widely distributed in mammals, and relates its two receptor subtypes, B
1
and B
2
. The actions of BK at the B
2
receptor include mainly contraction of arterial and venous preparations, although it can cause relaxation of peripheral resistance vessels as well.
Many of the more important functions of BK, such as increases in vascular permeability, pain, and vasodilatation, however, are mediated by the B
2
receptor. These effects at the B
2
receptor are believed to be responsible for BK's role in numerous diseases, such as inflammation, cardiovascular disease, pain, and the common cold. Hence antagonists at the B
2
receptor should find considerable therapeutic applications. Most of the efforts in this area thus far have been directed at peptidic analogues of the BK structure, some of which have been studied as analgesics and antiinflammatory agents.
Numerous N-benzenesulfonyl L-proline compounds as a B
2
antagonist have been synthesized, and disclosed in a number of patent publications such as international publication Nos. WO 97/41104, WO 96/13485, WO 99/00387, WO 98/24783, WO 98/03503, WO 97/24349, WO 97/07115 and WO 96/40639.
International Publication Number WO 98/24783, WO 98/03503, WO 97/24349, WO 97/07115 disclose a variety of N-benzenesulfonyl L-proline compounds as antagonists of bradykinin.
It would be desirable if there were provided a non-peptide antagonist of the B
2
receptor, having an improved B
2
antagonistic activity and a good metabolic stability against human liver microsomes.
BRIEF DISCLOSURE OF THE INVENTION
The present invention provides a compound of the following formula:
or the pharmaceutically acceptable salts thereof wherein
X
1
and X
2
are independently halo or C
1-4
alkyl;
R
1
and R
2
are independently hydrogen or C
1-4
alkyl;
R
3
and R
4
are independently hydrogen or halo; and
R
5
is
(a) —C
3-9
diazacycloalkyl optionally substituted with C
5-11
azabicycloalkyl;
(b) —C
3-9
azacycloalkyl-NH—(C
5-11
, azabicycloalkyl optionally substituted with C
1-4
alkyl);
(c) —NH—C
1-3
alkyl-C(O)—C
5-11
diazabicycloalkyl;
(d) —NH—C
1-3
alkyl-C(O)—NH—C
5-11
azabicycloalkyl, the C
5-11
azabicycloalkyl being optionally substituted with C
1-4
alkyl;
(e) —C
3-9
azacycloalkyl optionally substituted with C
3-9
azacycloalkyl; or
(f) —NH—C
1-5
alkyl-NH—C(O)—C
4-9
cycloalkyl-NH
2
.
The N-benzenesulfonyl L-proline compounds of this invention have an antagonistic action towards bradykinin and are thus useful in therapeutics, particularly for the treatment of inflammation, rheumatoid arthritis, cystitis, post-traumatic and post ischemic cerebral edema, liver cirrhosis, Alzheimer's disease, cardiovascular disease, pain, common cold, allergies, asthma, pancreatitis, burns, virus infection, head injury, multiple trauma, rhinitis, hepatorenal failure, diabetes, metastasis, pancreatitis, neovascularization, corneal haze, glaucoma, ocular pain, ocular hypertension or the like in mammalian, especially humans.
The N-benzenesulfonyl L-proline compounds of this invention have an antagonistic action towards bradykinin and are thus useful in therapeutics, particularly for the treatment of Amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, multiple sclerosis, stroke, head trauma, post-surgical brain edema, brain edema (general), cytotoxic brain edema (such as that associated with brain tumors, stroke, head trauma, etc.), brain edema associated with metabolic diseases (renal failure, pediatric metabolic diseases, etc.), rheumatoid arthritis, osteoarthritis, migraine, neuropathic pain, pruritis, brain tumor, pseudotumor cerebri, glaucoma, hydrocephalus, spinal cord trauma, spinal cord edema, neurodegenerative diseases, respiratory diseases, diuresis, natriuresis calciuresis, COPD (chronic obstructive pulmonary disease), post-traumatic brain injury, itching, sepsis or the like in mammalian, especially humans.
The present invention provides a pharmaceutical composition for the treatment of disease conditions mediated by bradykinin, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
Further, the present invention also provides a pharmaceutical composition for the treatment of inflammation, rheumatoid arthritis, cystitis, post-traumatic and post ischemic cerebral edema, liver cirrhosis, Alzheimer's disease, cardiovascular disease, pain, common cold, allergies, asthma, pancreatitis, burns, virus infection, head injury, multiple trauma, rhinitis, hepatorenal failure, diabetes, metastasis, pancreatitis, neovascularization, corneal haze, glaucoma, ocular pain, ocular hypertension or the like, which comprises a therapeutically effective amount of the N-benzenesulfonyl L-proline compound of formula (I) or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier.
Further, the present invention also provides a pharmaceutical composition for the treatment of Amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, Multiple sclerosis, Stroke, head trauma, Post-surgical brain edema, Brain edema (general), Cytotoxic brain edema (such as that associated with brain tumors, stroke, head trauma, etc.), Brain edema associated with metabolic diseases (renal failure, pediatric metabolic diseases, etc.), Rheumatoid arthritis, Osteoarthritis, Migraine, Neuropathic Pain, Pruritis, Brain Tumor, Pseudotumor cerebri, Glaucoma, Hydrocephalus, Spinal cord trauma, Spinal cord edema, neurodegenerative diseases, respiratory diseases, diuresis, natriuresis calciuresis, COPD (chronic obstructive pulmonary disease), post-traumatic brain injury, itching or Sepsis, which comprises a therapeutically effective amount of a compound of formual (I) or its pharmaceutically acceptable carrier.
Also, the present invention provides a method for the treatment of disease conditions mediated by bradykinin, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
Further, the present invention provides a method for the treatment of inflammation, rheumatoid arthritis, cystitis, post-traumatic and post ischemic cerebral edema, liver cirrhosis, Alzheimer's disease, cardiovascular disease, pain, common cold, allergies, asthma, pancreatitis, burns, virus infection, head injury, multiple trauma, rhinitis, hepatorenal failure, diabetes, metastasis, pancreatitis, neovascularization, corneal haze, glaucoma, ocular pain, ocular hypertension or the like, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term “halo” is fluoro, chloro, bromo or iodo (preferably fluoro or chloro).
As used herein, the term “alkyl” means straight or branched chain saturated radicals, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, secondary-butyl, tertiary-butyl.
As used herein, the term “C
4-9
cycloalkyl” means monocyclic alkyl having 4 to 9 carbon atoms, such as cyclobutyl, cyclopentyl, cycloheptyl, cyclohexyl, and the like.
As used herein, the term “C
3-9
azacycloalkyl, C
3-9
diazacycloalkyl, C
5-11
azabicycloalkyl or C
5-11
diazabicycloalkyl ” means a group wherein one or two carbons of mono- or bicyclic alkyl ring components are substituted by nitrogen atoms, included, but not limited to, azetidinyl, piperazinyl, piperidino, piperidinyl, pyrr
Katsu Yasuhiro
Kawai Makoto
Koike Hiroki
Nukui Seiji
Ashbrook Charles W.
Kurlandsky David R.
Morris Patricia L.
Pfizer Inc.
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