Aryloxy-alkyl-dialkylamines

Details Aryloxy-alkyl-dialkylamines Aryloxy-alkyl-dialkylamines

1999-12-10

2001-07-31

Higel, Floyd D. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S215000, C548S342100, C548S373100, C548S400000, C549S061000, C549S505000, C558S419000

Reexamination Certificate

active

06268504

ABSTRACT:

BACKGROUND OF THE INVENTION
Matrix metalloproteinases (MMPs) are a group of enzymes that have been implicated in the pathological destruction of connective tissue and basement membranes [Woessner, J. F., Jr.
FASEB J.
1991, 5, 2145; Birkedal-Hansen, H.; Moore, W. G. I.; Bodden, M. K.; Windsor, L. J.; Birkedal-Hansen, B.; DeCarlo, A.; Engler, J. A.
Crit. Rev. Oral Biol. Med.
1993, 4, 197; Cawston, T. E.
Pharmacol. Ther.
1996, 70, 163; Powell, W. C.; Matrisian, L. M.
Cur. Top. Microbiol. and Immunol.
1996, 213, 1]. These zinc containing endopeptidases consist of several subsets of enzymes including collagenases, stromelysins and gelatinases. Of these classes, the gelatinases have bee shown to be the MMPs most intimately involved with the growth and spread of tumors, while the collagenases have been associated with the pathogenesis of osteoarthritis [Howell, D. S.; Pelletier, J.-P. In
Arthritis and Allied Conditions;
McCarthy, D. J.; Koopman, W. J., Eds.; Lea and Febiger: Philadelphia, 1993; 12th Edition Vol. 2, pp. 1723; Dean, D. D.
Sem. Arthritis Rheum.
1991, 20, 2; Crawford, H. C; Matrisian, L. M.
Invasion Metast.
1994-95, 14, 234; Ray, J. M.; Stetler-Stevenson, W. G.
Exp. Opin. Invest. Drugs,
1996, 5, 323].
The use of hormone replacement therapy for bone loss prevention in post-menopausal women is well precedented. The normal protocol calls for estrogen supplementation using such formulations containing estrone, estriol, ethynyl estradiol or conjugated estrogens isolated from natural sources (i.e. Premarin® conjugated estrogens from Wyeth-Ayerst). In some patients, therapy may be contraindicated due to the proliferative effects unopposed estrogens (estrogens not given in combination with progestins) have on uterine tissue. This proliferation is associated with increased risk for endometrosis and/or endometrial cancer. The effects of unopposed estrogens on breast tissue is less clear, but is of some concern. The need for estrogens which can maintain the bone sparing effect while minimizing the proliferative effects in the uterus and breast is evident. Certain nonsteroidal antiestrogens have been shown to maintain bone mass in the ovariectomized rat model as well as in human clinical trials. Tamoxifen (sold as Novadex® brand tamoxifen citrate by Zeneca Pharmaceuticals, Wilmington, Del.), for example, is a useful palliative for the treatment of breast cancer and has been demonstrated to exert an estrogen agonist-like effect on the bone, in humans. However, it is also a partial agonist in the uterus and this is cause for some concern. Raloxifene, a benzthiophene antiestrogen, has been shown to stimulate uterine growth in the ovariectomized rat to a lesser extent than Tamoxifen while maintaining the ability to spare bone. A suitable review of tissue selective estrogens is seen in the article “Tissue-Selective Actions Of Estrogen Analogs”,
Bone
Vol. 17, No. 4, October 1995, 181S-190S.
The present invention provides novel intermediates which may be used in the production of pharmaceutical compounds for anti-estrogenic and MMP-inhibiting utilities. The use of 4-carbamoylmethoxy-methoxy-benzyl chloride compounds of tie structures:
are taught NL 6402393; 1964; and Chem. Abstr. 1965, 62, 7698.
The use of 4-(2-dialkylamino-ethoxy)benzoyl chloride compounds of the structures:
are disclosed in Sharpe, C. J. et. al. J. Med. Chem. 1972, 15, 523 and Jones, C. D. et. al. J. Med. Chem. 1984, 27, 1057. Similarly, the use of 4-(2-quinolinylmethoxy)benzyl chloride
is disclosed by Huang, F-C. et. al. J. Med. Chem. 1990, 33, 1194.
SUMMARY OF THE INVENTION
The present invention provides new compounds, as well as methods for the production thereof, which can be used in the production of pharmaceutically active compounds. The compounds of this invention can particularly be used as intermediates in the production of pharmaceutical compounds, such as low molecular weight, non-peptide inhibitors of matrix metalloproteinases (e.g. gelatinases, stromelysins and collagenases) and TNF-_ converting enzyme (TACE, tumor necrosis factor-_ converting enzyme) which are useful for the treatment of diseases in which these enzymes are implicated such as arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system and HIV infection. In addition, the compounds of this invention can be used to produce compounds which behave like estrogen agonists by lowering cholesterol and preventing bone loss. Therefore, these compounds are useful for treating many maladies including osteoporosis, prostatic hypertrophy, infertility, breast cancer, endometrial hyperplasia and cancer, cardiovascular disease, contraception, Alzheimer's disease and melanoma.
The present invention includes novel compounds of formula (I):
wherein:
R
1
and R
2
are, independently, selected from H; C
1
-C
12
alkyl, preferably C
1
-C
6
alkyl; or C
1
-C
6
perfluorinated alkyl, preferably —CF
3
;
X is a leaving group, such as halogen, —O—SO
2
—CH
3
, —O—SO
2
—CF
3
, or a moiety of the structure:
Z is selected from —NO
2
, halogen, —CH
3
or —CF
3
;
A is selected from —O— or —S—, —SO— or —SO
2
—;
m is an integer from 0 to 3, preferably 1;
R
3
, R
4
, R
5
, and R
6
are independently selected from H, halogen, —NO
2
, alkyl (preferably C
1
-C
12
alkyl, more preferably C
1
-C
6
alkyl), alkoxy (preferably C
1
-C
12
alkoxy, more preferably C
1
-C
6
alkoxy), C
1
-C
6
perfluorinated alkyl (preferably —CF
3
), OH or the C
1
-C
4
esters or allyl ethers thereof, —CN, —O—R
1
, —O—Ar, —S—R
1
, —S—Ar, —SO—R
1
, —SO—Ar, —SO
2
—R
1
, —SO
2
—Ar, —CO—R
1
, —CO—Ar, —CO
2
—R
1
, or —CO
2
—Ar;
Y is selected from:
a) the moiety:
wherein R
7
and R
8
are independently selected from the group of H, C
1
-C
6
alkyl, or phenyl.
b) a five-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NH—, —N(C
1
C
4
alkyl)—, —N═, and —S(O)
n−
, wherein n is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C
1
-C
4
alkyl, trihalomethyl, C
1
-C
4
alkoxy, trihalomethoxy, C
1
-C
4
acyloxy, C
1
-C
4
alkylthio, C
1
-C
4
alkylsulfinyl, C
1
-C
4
alkylsulfonyl, hydroxy (C
1
-C
4
)alkyl, phenyl optionally substituted with 1-3 (C
1
-C
4
)alkyl, —CO
2
H, —CN, —CONHR
1
, —NH
2
, C
1
-C
4
alkylamino, C
1
-C
4
dialkylamino, —NHSO
2
R
1
, —NHCOR
1
, —NO
2
;
c) a six-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NH—, —N(C
1
C
4
alkyl)—, —N═, and —S(O)
n−
, wherein n is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C
1
-C
4
alkyl, trihalomethyl, C
1
-C
4
alkoxy, trihalomethoxy, C
1
-C
4
acyloxy, C
1
-C
4
alkylthio, C
1
-C
4
alkylsulfinyl, C
1
-C
4
alkylsulfonyl, hydroxy (C
1
-C
4
)alkyl, phenyl optionally substituted with 1-3 (C
1
-C
4
)alkyl, —CO
2
H, —CN, —CONHR
1
, —NH
2
, C
1
-C
4
alkylamino, C
1
-C
4
dialkylamino, —NHSO
2
R
1
, —NHCOR
1
, —NO
2
;
d) a seven-membered saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NH—, —N(C
1
C
4
alkyl)—, —N═, and —S(O)
n−
, wherein n is an integer of from 0-2, optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C
1
-C
4
alkyl, trihalomethyl, C
1
-C
4
alkoxy, trihalomethoxy, C
1
-C
4
acyloxy, C
1
-C
4
alkylthio, C
1
-C
4
alkylsulfinyl, C
1
-C
4
alkylsulfonyl, hydroxy (C
1
-C
4
)alkyl, phenyl optionally substituted with 1-3 (C
1
-C
4
)alkyl, —CO
2
H, —CN, —CONHR
1
, —NH
2
, C
1
-C
4
alkylamino, C
1
-C
4
dialkylamino, —NHSO
2
R
1
, —

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