Substituted amides, sulfonamides and ureas useful for...

Details Substituted amides, sulfonamides and ureas useful for... Substituted amides, sulfonamides and ureas useful for...

2002-07-09

2004-08-17

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C548S491000, C514S415000, C514S419000, C514S616000

Reexamination Certificate

active

06777577

ABSTRACT:

FIELD OF THE INVENTION
The present invention discloses novel substituted amide compounds, specifically carboxamides, sulfonamides, and urea compounds having enzyme inhibiting properties, especially for inhibiting protein tyrosine kinases.
BACKGROUND OF THE INVENTION
The novel compounds of the present invention may have general therapeutic value for the treatment of such diseases as cancer, including bone, colon or breast cancer; immunodeficiency disorders and diabetes; atherosclerosis, osteoporosis, leukemia and other conditions such as coronary heart disease, congestive heart failure, renal failure and diseases of the central nervous system where the compounds exert a beneficial effect. The inventive compounds have been found to inhibit the Src protein tyrosine kinase, a member of the Src family.
The Src family consists of nine members—Src. Yes, Fgr, Yrk. Fyn. Lyn, Hck, Lck and Blk—which share the same domain structure. The N-terminal, unique domain contains a myristylation site and frequently a palmitoylation site. It is followed by the regulatory SH3 and SH2 domains, a catalytic domain that is bilobal and has its active site wedged between the two lobes, and a C-terminal regulatory tail that contains the hallmark regulatory tyrosine residue (Tyr527 in Src). Kinase activity is reduced when the latter is phosphorylated and bound to the SH2 domain. The SH2 and SH3 domains bind phosphotyrosyl and proline-rich peptides, respectively: through these interactions, they participate in intra- and intermolecular regulation of kinase activity, as well as localization and substrate recognition.
There is a wealth of evidence that tyrosine phosphorylation plays a crucial role in many cell regulatory processes. Fahad Al-Obeidi et al.,
Biopolymers
(Peptide Science) 47, 197-223 (1998). Researchers have found that functional perturbation of the kinases results in many diseases. Thus, there has been a great deal of effort applied in attempts to develop potent and selective inhibitors for these enzymes.
The Src protein tyrosine kinase plays a role in osteoporosis and other bone diseases. Osteoporosis is defined as a systemic skeletal disease which is characterized by low bone mass and microarchitectural deterioration of bone tissue resulting in an increase in bone fragility and susceptibility to fracture, W. A. Peck, et al.,
Am. J. Med
., 94, 646, (1993) Conference Report. It is estimated that osteoporosis causes 1.5 million fractures annually with a total medical cost of $13.8 billion. National Osteoporosis Foundation, August, 1997. The most typical sites of such fractures are the hip, spine, wrist, and ribs. It is also estimated that one out of every two women and one in eight men will have an osteoporosis related fracture in their lifetime. Osteoporosis is most commonly associated with postmenopause and age-related bone tissue loss. In addition, osteoporosis can occur secondarily to various drugs and diseases such as corticosteroids, anticonvulsants, alcohol, malabsorption syndromes, primary biliary cirrhosis, myeloma, thalassemia, thyrtoxicosis, Cushing's syndrome, Turner's syndrome, and primary hyperparathyroidism. Drugs used in the treatment of osteoporosis are generally classified as antiresorptive or formation stimulating. In normal bone tissue, there is a balance between bone formation by osteoblasts and bone resorption by osteoclasts. When the balance of this ongoing process is upset, bone resorption can exceed bone formation resulting in quantitative bone loss. Most of the treatments have involved those that act through inhibition of bone resorption, such as calcium supplements, estrogen, calcitonin, and vitamin D, L. Riggs,
West. J Med
., 154, 63 (1991).
Examples of treatments which act though stimulation of bone formation are sodium fluoride, low intermittent dosage of parathyroid hormone, M. Missbach, et al.,
Rech. Chimie Med
., July, 1997, London.
Several reports have disclosed compelling evidence that the protein tyrosine kinase (PTK)p60c-Src (sometimes referred to as c-Src) plays a critical role in osteoclastic function, M. Missbach, et al., ibid. It was reported that, in vitro, kinase inhibitors of c-Src are capable of reducing osteoclastic bone resorption, Ibid. Osteoclasts are bone marrow cells that are responsible for breaking down or remodeling bone. Once an osteoclast comes into contact with the bone surface, it adheres tightly to the bone, flattens out, and begins the process of secreting materials which results in dissolution of the bone. This fundamental action of osteoclasts is dependent on Src kinase. In this case it is clear that at least one of the roles for Src kinase is in the regulation of cytoskeletal changes involved in establishing the close bone cell interface and in polarizing cellular secretion toward the bone surface. Thus, animals genetically engineered to lack Src kinase show abnormalities that indicate a general inability to resorb bone.
In addition, osteoclasts derived from these animals are unable the to flatten on bone, nor are they able to dissolve it. Consistent with these results, small molecule inhibitors of Src kinase have been shown to be useful in countering bone loss in animal models of osteoporosis, such as IL-1-induced hypercalcemia, and bone loss in ovariectomized rats. Src kinase inhibitors would be useful for the treatment of disorders marked by inappropriate bone resorption like osteoporosis.
SUMMARY OF THE INVENTION
The present invention provides novel carboxamides, sulfonamides and ureas having inhibitory activity against osteoporosis and related bone tissue loss.
In one embodiment, this invention provides novel carboxamide compounds having such desirable therapeutically inhibitory activity. The inventive carboxamides have the general structure shown in Formula I, including enantiomers, stereolsomers and tautomers thereof, or pharmaceutically acceptable salts or solvates of said compound, said compound having the general structure shown in Formula I:
wherein:
m is an integer from 0 to 4;
n is an integer from 1 to 6;
R′ is a C
1
-C
4
alkyl;
R
1
is:
R
3
is selected from the group consisting of H, C
1
-C
4
straight chain alkyl and C
1
-C
4
branched alkyl;
R
2
is selected from the group consisting of —(CH
2
)
p
—NH—C(═NH)NH
2
; —(CH
2
)
p
—R
4
; and —(CH
2
)
q
—Ar
1
, wherein p is an integer from 1 to 4; q is 0 or 1; R
4
is C
5
-C
7
cycloalkyl; and Ar
1
is selected from the group consisting of:
wherein R
5
is —NH
2
or phenyl.
In another embodiment, this invention provides novel substituted urea and sulfonamide compounds having inhibitory activity against osteoporosis and related bone tissue loss. The inventive compounds have the general structure shown in Formula II, including enantiomers, stereoisomers and tautomers thereof, as well as its pharmaceutically acceptable salts or solvates:
wherein R
1
is selected from the group consisting of H, straight chain C
1
-C
6
alkyl; branched C
1
-C
6
alkyl; —(CH
2
)
p
—Ar
1
; and —(CH
2
)
p
—R
4
, wherein p is 1 or 2;
Ar
1
is phenyl or naphthyl optionally substituted with a straight chain or branched
C
1
-C
6
alkyl group; and
R
4
is C
5
-C
7
cycloalkyl;
R
2
is selected from the group consisting of:
R
5
is selected from the group consisting of H, straight chain C
1
-C
6
alkyl;
branched C
1
-C
6
alkyl;
R
3
is —(CH
2
)
q
—Ar
2
or —(CH═CH)-Phenyl, wherein q is an integer from 0 to 4; and Ar
2
is selected from the group consisting of:
Y is selected from the group consisting of:
with the proviso that when Y is any of the moieties:
then R
1
is H.
When used herein, unless otherwise defined, the following terms have the given meanings:
alkyl (including the alkyl portions of lower alkoxy)—represents a straight or branched, saturated hydrocarbon chain having from 1 to 10 carbon atoms, preferably from 1 to 6;
aryl—represents a carbocyclic group having from 6 to 14 carbon atoms and having at least one benzenoid ring, with all available substitutable aromatic carbon atoms of the carbocyclic group being intended as possible points of attachment. Pr

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