Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-05-16
2002-04-23
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S524000
Reexamination Certificate
active
06376484
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to tetrazole compounds. More particularly, this invention relates to:
(1) tetrazole compounds having interleukin-1&bgr; converting enzyme inhibitory activity of the following formula (I):
wherein all of the symbols have the same meanings as described hereinafter, or a non-toxic salt thereof, an acid addition salt thereof or a hydrate thereof;
(2) processes for the preparation thereof; and
(3) pharmaceutical agents containing such devivative as an active ingredient.
BACKGROUND OF THE INVENTION
Interleukin 1 (IL-1) is a key cytokine that directly or indirectly participates in the regulation of, for example, the immune system, hemopoietic system and neuroendocrine system, and thus, has a crucial physiological role. There are two types of IL-1, which have different isoelectric points (IL-1&agr;: pl=5, IL-1&bgr;: pl=7). Both of these are produced as a precursor having molecular weight of 31 Kd. The IL-1&bgr; precursor does not bind to the IL receptor nor exerts a biological function. The IL-1&bgr; converting enzyme (ICE) cleaves the precursor protein between Asp 116 and Ala 117 and converts into an active IL-1&bgr; mature form having a molecular weight of 17 Kd. Following the cleavage, IL-1&bgr; is secreted, binds to the receptor and triggers various biological activities (Ref. The New England Journal of Medicine, 328, 106 (1993)).
The inhibition of ICE enzymatic activity leads to prevention of conversion of the IL-1&bgr; precursor into the mature form and hence results in blockage of IL-1 biological activity. There are many possible target diseases for ICE inhibitors, for example, prevention and/or treatment of insulin dependent diabetes (type 1), autoimmune diseases, including multiple sclerosis, immune diseases, such as acute or delayed type hypersensitivity, infectious diseases, infection complications, septic shock, acute or chronic inflammatory diseases, such as arthritis, colitis, glomelular nephritis, hepatitis, pancreatitis, reperfusion injury, cholangeitis, encephalitis, endocarditis, myocarditis and vasculitis, neural diseases, such as Alzheimer's disease and Parkinson's disease, bone or cartilage-resorption diseases, Crohn's disease, osteo arthritis etc.
It is believed that ICE and/or ICE-like cystein proteases play important roles in cell death by apoptosis. Therefore it is possible that an ICE inhibitor may be used in the prevention and/or treatment of diseases resulting from apoptosis disorders, such as infection, reduction or enhancement of immune or central nervous system function, neoplasm etc. Diseases associated with apoptosis disorders are as follows; AIDS, ARC (AIDS related complex), adult T cell leukemia, hairy cell (pilocytic) leukemia, myelosis, respiratory dysfunction, arthropathy, HIV or HTLV-I related diseases, such as uveitis, virus related diseases, such as hepatitis C, neoplasm, diffuse collagen diseases, such as systemic lupus erythematosis or rheumatoid arthritis, autoimmune diseases, such as ulcerative colitis, Sjogren's syndrome, primary binary cirrhosis, idiopathic thrombocytopnic purpura, autoimmonohaemolytic anemia, severe myasthenia, insulin dependent (type I) diabetes, osteodysplasia syndrome, periodic thrombocytopenia, aplastic anemia, idiopathic thrombocytopenia, various diseases which accompany thrombocytopenia, such as disseminated intravascular coagulation, hepatic diseases, including hepatitis (type C, A, B, or F virus borne or drug mediated) and hepatic cirrhosis, Alzheimer's disease, dementia, such as Alzheimer type senile dementia, cerebral vascular disturbance, neuro-degenerative diseases, adult dyspnea syndrome, infection, hyperplasia of the prostate, myoma of the uterus, asthma bronchiole, arteriosclerosis, various kinds of congenital teratoma, nephritis, senile cataract, chronic fatigue syndrome, myodystrophy, peripheral nervous disturbance, and so on (Ref. The New England Journal of Medicine, 328, 106-113 (1993), Arthritis & Rheumatism, 39, 1092 (1996)).
RELATED ARTS
Compounds having an inhibitory activity on IL-1&bgr; converting enzyme (ICE) are known. The sequence of the ICE cleavage site of pre-IL-1&bgr; (Tyr-Val-His-Asp) has high affinity with ICE. Substrate analog inhibitors which are chemically modified and based on the above substrate sequence, for example, a compound of formula (X):
wherein
Y
X
is
,or
R
1X
is
(a) a substituted C1-12 alkyl (in which a substituent is hydrogen, hydroxy etc.) or
(b) an aryl C1-6 alkyl (in which aryl is phenyl, naphthyl, pyridyl, furyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, benzoimidazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, benzothienyl, pyrazolyl, indolyl, purinyl or isooxazolyl), wherein the aryl can be mono-substituted or di-substituted (in which a substituent is a C1-6 alkyl, halogen, hydroxyl, C1-6 alkylcarbonyl etc.);
R
2X
is
(a) hydrogen,
(in which R
3X
is
(1) a substituted C1-12 alkyl (in which a substituent is hydrogen, hydroxy etc.), or
(2) an aryl C1-6 alkyl or substituted aryl C1-6 alkyl as hereinbefore defined (in which an aryl may be mono-substituted or di-substituted by C1-6 alkyl, halogen, hydroxyl, C1-6 alkylcarbonyl etc.);
R
4X
and R
5X
are each hydrogen, hydroxyl etc.; and
R
6X
is
(1) hydrogen,
(2) a substituted C1-6 alkyl (in which a substituent is hydrogen, hydroxyl etc.),
(3) an aryl C1-6 alkyl (in which alkyl is substituted by hydrogen, oxo, C1-3 alkyl etc., aryl has the same meaning as hereinbefore defined, said aryl is mono-substituted or di-substituted, said substituent is C1-6 alkyl, halogen, hydroxyl, C1-6 alkylcarbonyl etc.),
(4) a C1-6 alkylaminocarbonyl C1-6 alkyl or C1-6 alkylcarbonylamino C1-6 alkyl,
(5) an arylaminocarbonyl C1-6 alkyl or arylcarbonylamino C1-6 alkyl (in which aryl has the same meaning as hereinbefore defined, said aryl is mono-substituted or di-substituted, said substituent is C1-6 alkyl, halogen, hydroxyl, C1-6 alkylcarbonyl etc.) or
(6) an aryl C1-6 alkylaminocarbonyl C1-6 alkyl or aryl C1-6 alkylcarbonylamino C1-6 alkyl (in which aryl has the same meaning as hereinbefore defined, said aryl is mono-substituted or di-substituted, said substituent is C1-6 alkyl, halogen, hydroxyl, C1-6 alkylcarbonyl etc.) etc.;
AA
1X
is a bond etc.;
AA
2X
is a bond or; and
AA
3X
is a bond or
(wherein R
8X
and R
9X
is
(a) hydrogen,
(b) a substituted C1-6 alkyl (in which a substituent is hydrogen, hydroxyl etc.) or
(c) an aryl C1-6 alkyl (in which aryl has the same meaning as hereinbefore defined, said aryl is mono-substituted or di-substituted, said substituent is C1-6 alkyl, halogen, hydroxyl, C1-6 alkylcarbonyl, etc.)) (with the proviso that, definitions not related are omitted) are disclosed as having an inhibitory activity on ICE (see EP 519748).
The compounds of formula (Y):
R
Y
—[A
1Y
—A
2Y
]
nY
—A
3Y
—A
4Y
—X
Y
—A
5Y
(Y)
wherein
R
Y
is hydrogen, an amino protecting group or benzyloxy, which may be optionally substituted by a ring;
nY is 0 or 1;
A
1Y
is Val, Leu, Ala, Ile or trimethylsilyl-Ala;
A
2Y
is Phe or Tyr;
A
3Y
is Val, Leu, Ala, Ile, trimethylsilyl-Ala or a divalent radical group:
(in which ring A
Y
may be optionally substituted by hydroxy or C1-4 alkoxy); A
4Y
is a bond or
(in which R
1Y
is hydrogen or C1-4 alkyl, and
Y
1Y
is a residue bonded to the &agr;-carbon atom of an optionally protected &agr;-amino acid);
wherein
A
3Y
and A
4Y
together may form:
(wherein Y
1Y
has the same meaning as hereinbefore defined, and R
1Y
and R
1aY
are combined to form —(CH
2
)
mY
—(in which mY is 2, 3, 4 or 5));
X
Y
is a divalent radical group:
(wherein R
6Y
is hydrogen or C1-4 alkyl); and
A
5Y
is hydrogen, CF
3
, —Z
1Y
—Z
2Y
—Y
2Y
(in which Z
1Y
and Z
2Y
is each, independently, a bond or an &agr;-amino acid residue and Y
2Y
is NH
2
, C1-4 alkylamino, di-(C1-4 alkyl)amino or hetero ring bonded to the Z
2Y
nitrogen), —CH
2
—X
1Y
—Y
3Y
(in which X
1Y
is O or S and Y
3Y
is heteroaryl) or —CH
2
—Y
3Y
wherein Y
3Y
is as previously defined)
(with the proviso that, de
Miyazaki Tohru
Ohmoto Kazuyuki
Ohno Hiroyuki
Tanaka Makoto
Lambkin Deborah C.
Ono Pharmaceutical Co. Ltd.
Sughrue Mion Zinn Macpeak & Seas, PLLC
LandOfFree
Tetrazole compounds and pharmaceutical agents containing... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Tetrazole compounds and pharmaceutical agents containing..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Tetrazole compounds and pharmaceutical agents containing... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2895978