Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-05-06
2004-11-30
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S253100, C514S253110
Reexamination Certificate
active
06825200
ABSTRACT:
TECHNICAL FIELD
This invention relates to new peptide compounds and pharmaceutically acceptable salts thereof which are useful as medicament.
BACKGROUND ART
Some peptide compounds have been known as described in, for example, EP 0 394 989 A2, WO96/16981 and JP-A-10-81671.
DISCLOSURE OF INVENTION
This invention relates to new peptide compounds.
One object of this invention is to provide the new and useful peptide compounds and pharmaceutically acceptable salts thereof that possess a strong inhibitory activity on the production of nitric oxide (NO).
Another object of this invention is to provide a process for the preparation of the peptide compounds and salts thereof.
A further object of this invention is to provide a pharmaceutical composition comprising said peptide compound or a pharmaceutically acceptable salt thereof.
Still further object of this invention is to provide a use of said peptide compounds or pharmaceutically acceptable salts thereof as a medicament for prophylactic and therapeutic treatment of NO-mediated diseases including respiratory diseases such as adult respiratory distress syndrome (ARDS) and asthma; cardiovascular diseases such as cardiovascular ischemia, myocarditis, heart failure, hypotension and atherosclerosis; endocrine diseases such as diabetes (e.g., insulin-dependent diabetes mellitus, etc.), complications of diabetes mellitus (e.g., diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, etc.) and gout; renal diseases such as glomerulonephritis and renal failure; gastrointestinal diseases such as peptic ulcer and inflammatory bowel disease (e.g., ulcerative colitis, chronic colitis, etc.); pancreatic diseases such as pancreatitis; hepatic diseases such as hepatitis and liver cirrhosis; diseases of bone or joint such as synovitis, arthritis, osteoarthritis, osteoporosis; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis; dermal diseases such as dermatitis and eczema; cancer such as solid tumors and metastasis; rejection by organ transplantation; shock (e.g., septic shock, etc.); sepsis-induced systemic inflammatory response syndrome; and sexual dysfunction such as male sexual dysfunction (e.g., erectile dysfunction) and female sexual dysfunction (e.g., orgasmic dysfunction related to clitoral disturbances) in human being and animals.
The object peptide compounds of the present invention are novel and can be represented by the following general formula (I):
wherein
R
1
is benzofuranyl substituted by halogen, or styryl substituted by halogen,
R
2
is phenyl, pyridyl, thienyl or thiazolyl, each of which is optionally substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen and trihalo(lower)alkyl, or lower alkyl optionally substituted by one or more halogen atoms,
R
3
is hydrogen or lower alkoxy,
R
4
and R
5
are the same or different and each is hydrogen, lower alkyl or optionally protected hydroxy(lower)alkyl, and
R
6
is hydrogen or lower alkyl.
Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and include, for example, a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, etc.); an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); an organic carboxylic or sulfonic acid addition salt (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, citrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); and a salt with a basic or acidic amino acid (e.g., arginine, aspartic acid, gultamic acid, etc.).
In the above and subsequent descriptions of the present specification, suitable examples and illustration of the various definitions which the present invention intends to include within the scope thereof are explained in detail as follows.
The term “lower” is used to intend a group having 1 to 6, preferably 1 to 4, carbon atom(s), unless otherwise provided.
Suitable “halogen” includes, for example, fluorine, bromine, chlorine and iodine.
“Styryl substituted by halogen” means styryl which has halogen atom as a substituent on the benzene ring. Suitable examples of “styryl substituted by halogen” include 2-(2-chlorophenyl)ethenyl, 2-(3-chlorophenyl)ethenyl, 2-(4-chlorophenyl)ethenyl, 2-(2-bromophenyl)ethenyl, 2-(3-bromophenyl)ethenyl, 2-(4-bromophenyl)ethenyl, 2-(2-fluorophenyl)ethenyl, 2-(3-fluorophenyl)ethenyl, 2-(4-fluorophenyl)ethenyl, and the like.
Suitable “lower alkyl” and “lower alkyl” moiety in the terms “trihalo(lower)alkyl” and “hydroxy(lower)alkyl” include straight or branched alkyl having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl and hexyl, in which more preferred one is C
1
-C
4
alkyl.
Suitable “lower alkoxy” includes straight or branched alkoxy having 1 to 6 carbon atom(s), such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, tert-pentyloxy and hexyloxy, in which more preferred one is C
1
-C
4
alkoxy.
Suitable examples of “trihalo(lower)alkyl” include trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl and 3,3,3-trifluoropropyl, in which more preferred one is trifluoromethyl.
“Lower alkyl optionally substituted by one or more halogen atoms” includes lower alkyl and halo(lower)alkyl. Suitable “halo(lower)alkyl” includes lower alkyl substituted by 1 to 3 halogen atoms such as trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl and 3,3,3-trifluoropropyl, in which more preferred one is trihalo(lower)alkyl.
“Optionally protected hydroxy(lower)alkyl” includes hydroxy(lower)alkyl and protected hydroxy(lower)alkyl. Suitable examples of hydroxy-protecting group include lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, etc.), acyl such as lower alkanoyl optionally substituted by one to three halogen atoms (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, trichloroacetyl, trifluoroacetyl, etc.), optionally substituted phenyl(lower)alkyl, for example, mono(or di or tri)phenyl(lower)alkyl optionally substituted by nitro or lower alkoxy (e.g., benzyl, 4-nitrobenzyl, 4-methoxybenzyl, benzhydryl, trityl, etc.), trisubstituted silyl [e.g., tri(lower)alkylsilyl (e.g., trimethylsilyl, tert-butyldimethylsilyl, etc.), etc.], tetrahydropyranyl and the like.
Suitable “hydroxy(lower)alkyl” includes hydroxy(C
1
-C
6
)alkyl such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl and 6-hydroxyhexyl.
Suitable “protected hydroxy(lower)alkyl” includes lower alkoxy(lower)alkyl such as (C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl, for example, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1-methoxypropyl, 2-methoxypropyl, 3-methoxypropyl, ethoxymethyl, 2-ethoxyethyl, 3-ethoxypropyl and propoxymethyl.
Phenyl, pyridyl, thienyl or thiazolyl at R
2
is optionally substituted by one or more, preferably one to three, substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen and trihalo(lower)alkyl.
Suitable “amino-protecting group” includes, for example, acyl and conventional protecting group such as mono(or di or tri)aryl(lower)alkyl, for example, mono(or di or tri)phenyl (lower)alkyl (e.g., benzyl, trityl, etc.). Suitable examples of said acyl include aliphatic acyl such as lower alkanoyl which may be substituted by one to three halogen atoms (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimeth
Imamura Kenichiro
Ishibashi Naoki
Ohkawa Takehiko
Ohne Kazuhiko
Sato Kentaro
Bernhardt Emily
Fujisawa Pharmaceutical Co. Ltd.
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