Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-01-21
1998-10-06
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5462714, 546256, A61K 3144, C07D41304
Patent
active
058176802
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to novel compounds which have hemoregulatory activities and can be used to inhibit the myelopoietic system of humans and animals.
BACKGROUND OF THE INVENTION
A variety of regulatory messengers and modifiers such as colony stimulating factors, interferons, and different types of peptides are responsible for the regulation of myelopoiesis.
We have now found certain compounds which have an inhibitory effect on myelopoietic cells in vitro. They may be used to prevent quiescent cells from entering into cell division. Cells entering into cell division are susceptible to attack by cytotoxic anti-cancer drugs. In addition to providing a protective function in therapy using cytotoxic drugs, the compounds may also be used to arrest proliferation of cancer cells related to the myelopoietic system, i.e. myeloid leukemia.
SUMMARY OF THE INVENTION
This invention comprises compounds, hereinafter represented as formula (I), which have hemoregulatory activities and can be used to inhibit haematopoiesis.
The compounds are useful in providing a protective function in therapy using irradiation and/or cytotoxic drugs, and may also be used to arrest proliferation of cancer cells related to the myelopoietic system, for example, in the treatment of myeloid leukemia. The compounds may also be used in many clinical situations where it is desirable to alter haematopoiesis.
These compounds may also be used in combination with the dimers of co-pending U.S. application Ser. No.08/001,905, incorporated by reference herein, to provide alternating peaks of high and low activity in the bone marrow cells, thus augmenting the natural circadian rhythm of haematopoiesis. In this way, cytostatic therapy can be given at periods of low bone marrow activity, thus reducing the risk of bone marrow damage, while regeneration will be promoted by the succeeding peak of activity. This invention is also a pharmaceutical composition, which comprises a compound of formula (I) and a pharmaceutically acceptable carrier.
This invention further constitutes a method for inhibiting the myelopoietic system of an animal, including humans, which comprises administering to an animal in need thereof, an effective amount of a compound of formula (I).
DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention are illustrated by the Formula (I): ##STR1## wherein
R.sub.1 and R.sub.2 are independently hydrogen, C.sub.1-6 alkyl, phenyl, napthyl, benzyl, pyridyl, furyl, oxazolyl or thiazolyl;
R.sub.3 and R.sub.4 are independently hydrogen, --CO.sub.2 H, --(CH.sub.2).sub.n OH, --C(O)NH.sub.2, tetrazole, --CO.sub.2 (C.sub.1-3 alkyl), C(O)C.sub.1-3 alkyl, CSNH.sub.2, C.sub.1-6 alkyl or --(CH.sub.2).sub.n CO.sub.2 H; n is 1, 2 or 3;
provided at least one of R.sub.1 and R.sub.2 and one of R.sub.3 and R.sub.4 is not hydrogen;
or a pharmaceutically acceptable salt thereof.
Also included in this invention are pharmaceutically acceptable salt complexes of the compounds of this invention.
Preferred compounds are:
The present invention provides compounds of Formula (I) above ##STR2## which can be prepared by a process that comprises:
a) reacting a compound of Formula (2) ##STR3## with a substituted amino-alcohol of Formula (3) ##STR4## wherein R.sub.1 and R.sub.2 are independently selected from H, C.sub.1-6 alkyl, phenyl, napthyl, benzyl, pyridyl, furyl, oxazolyl or thiazolyl. R.sub.3 and R.sub.4 are independently selected from H, CONH.sub.2, CSNH.sub.2, (CH.sub.2).sub.n OH, (CH.sub.2).sub.n CO.sub.2 H, tetrazole, --COO(C.sub.1-3 alkyl), --C(O)C.sub.1-3 alkyl or C.sub.1-6 alkyl in a suitable solvent such as DMF with a coupling reagent such as N-Ethyl-N'(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and a tertiary amine such as triethyl amine to provide a compound of Formula (4). ##STR5##
Cyclization of compound (4) in the presence of Burgess Reagent (methoxycarbonylsulfamoyl)-triethylammonium hydroxide, inner salt, in refluxing THF provides oxazolines of Formula (5). ##STR6##
The treatment of compounds
REFERENCES:
Brunner, et al., "Asymmetric catalysis. XLV. Enantioselective (1989), Chemical Abstracts, vol. 17, No. 17, abstract no. 154196, Chem. Ber. (1989), 122(3), 499-507.
Haidukewych, et al., "Mild conversion of carboxylic acids to 2-oxazolines and their utility as a crboxyl masking group against lithium aluminum hydride", (1972), Chemical Abstracts, vol. 77, No. 17, see abstract no. 114288, Tetrahedron Lett. (1972) (30), 3031-4.
Bhatnagar Pradip Kumar
Heerding Dirk
Hall Linda E.
Rotman Alan L.
Smithkline Beecham Corportion
Venetianer Stephen A.
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