3′,3′-N-bis-desmethyl-3′-N-cycloalkyl...

Details 3′,3′-N-bis-desmethyl-3′-N-cycloalkyl... 3′,3′-N-bis-desmethyl-3′-N-cycloalkyl...

1998-08-26

2002-05-14

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007200, C536S007400, C536S018500

Reexamination Certificate

active

06387885

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a class of macrolide compounds which are antagonists of lutenizing hormone-releasing hormone (LHRH), to pharmaceutical compositions comprising the compounds, to methods of using the compounds and to the process of making the same. More particularly, the present invention relates to 3′,3′-N-bis-desmethyl-3′-N-cycloalkyl-6-O-methyl-11-deoxy-11,12-cyclic carbamate erythromycin A derivatives which are antagonists of LHRH.
BACKGROUND OF THE INVENTION
The gonadotropins, follicle stimulating hormone (FSH), lutenizing hormone (LH), and chorionic gonadotropin (CG) are required for ovulation, spermatogenesis, and the biosynthesis of sex steroids. A single hypothalamic hormone, gonadotropin-releasing hormone GnRH also known as LHRH is responsible for regulating the secretion of both FSH and LH in mammals.
LHRH is a decapeptide having the structure:
pyro-Glu
1
-His
2
-Trp
3
-Ser
4
-Tyr
5
-Gly
6
-Leu
7
-Arg
8
-Pro
9
-Gly
10
-NH
2
where the superscripts designate the position of each aminoacyl residue in the decapeptide chain.
LHRH is released from the hypothalamus and binds to a receptor on the pituitary gland, causing the release of LH and FSH which subsequently act on the gonads to stimulate the synthesis of steroid sex hormones. The pulsatile release of LHRH, and thereby the release of LH and FSH, controls the reproductive cycle in animals and man. Acute doses of LHRH agonists increase the levels of LH and steroidal sex hormones in both animals and humans. Paradoxically, chronic doses of LHRH agonists suppress the level of LH and steroidal sex hormones. Consequently, the effect of multiple doses of LHRH agonists is to suppress estrogen formation in females and testosterone production in males. The same effect is observed in both animals and humans after administration of either acute or chronic doses of LHRH antagonists.
In recent years considerable research effort has been expended on finding antagonists of LHRH. These efforts have produced a number of peptide LHRH antagonists, which suppress LH and reproductive hormones in mammals upon administration. See for example, M. J. Karten in “Modes of Action of GnRH and GnRH analogs”, edited by W. F. Crowley and P. M. Conn, p. 277 (1992). The literature has reported that LHRH antagonists are useful in the treatment of a variety of conditions in which the suppression of sex steroids plays a key role including contraception, delay of puberty, treatment of benign prostatic hyperplasia, palliative treatment or remission of hormonal-dependent tumors of the prostate, the treatment of cryptorchidism, hirustism in women, gastric motility disorders, dysmenorrhea, and endometriosis.
Current LHRH antagonists are decapeptides which, because of their low oral bioavailability, are administered either intravenously or subcutaneously. Non-peptide heterocyclic antagonists have been reported in the literature, see for example, WO 95/280405, WO 95/29900, WO 97/22707, WO 97/21704 and WO 97/2103. Non-peptide LHRH antagonists have the possible advantage of improved oral bioavailability and are smaller molecules.
However, there are no known reports of macrolide compounds as LHRH antagonists in the literature. Macrolide antibiotics and macrolide prokinetic agents are known. For example, macrolide antibiotics derived from erythromycin which contain 11,12-cyclic carbamate moieties are disclosed in EP 248 279 A2. The 3′-N substituted erythromycin derivatives, which are effective antibacterial agents are described in EP 0 559 896 A1. Macrocyclic lactone (macrolide) prokinetic agents are known. See J. S. Gidda et al., in European Patent Application No. 0349100, published Jan. 3, 1990, which discloses 12-membered macrolides for use as gastrointestinal motility enhancers. S. Omura and Z. Itoh, in U.S. Pat. No. 4,677,097, issued Jun. 30, 1987; European Application No. 215,355, published Mar. 25, 1987; and European Application No. 213,617, published Mar. 11, 1987, disclose derivatives of erythromycins A, B, C and D which are useful as stimulants of digestive tract contractile motion. Additionally, T. Sunazuka, et al.,
Chem. Pharm. Bull
. 37(10): 2701-2709 (1989) discloses quaternary derivatives of 8,9-anhydroerythromycin A 6,9-hemiacetal and 9,9-dihydro-erythromycin A 6,9-epoxide with gastrointestinal motor stimulating activity.
None of these references disclose novel 3′, 3′-N-bis-desmethyl-3′-N-cycloalkyl-6-O-methyl-11-deoxy-11,12-cyclic carbamate erythromycin A derivatives of the present invention, which are effective as LHRH antagonists.
SUMMARY OF THE INVENTION
In one aspect, the present invention relates to a compound having the formula:
or a pharmaceutically acceptable salt or ester thereof, wherein
A is selected from the group consisting of:
(a) —C,
(b) —N, and
(c) —O;
X and Y are independently at each occurrence selected from the group consisting of:
(a) hydrogen,
(b) halide,
(c) alkoxy,
(d) alkyl,
(e) aryl, and
(f) substituted aryl;
R and R
1
are independently selected at each occurrence from the group consisting of:
(a) alkyl,
(b) cycloalkyl,
(c) heterocylic,
(d) substituted heterocyclic,
(e) alkylcycloalkyl,
(f) substituted alkylcycloalkyl,
(g) alkylaryl,
(f) alkylheterocyclic,
(g) alkenyl,
(h) alkynyl,
m is 1, 2 or 3
R
2
and R
3
are independently at each occurrence
(a) hydrogen,
(b) methyl, or
R
2
and R
3
together form a cycloalkyl moiety, when A is C; and
n=1, 2 or 3.
In another aspect, the present invention relates to a process for preparing the compound formula I. The process comprises the steps of:
(a) reacting a compound of formula:
 with sodium hexamethyldisilazide and carbonyldiimidazole to afford a compound of the formula:
(b) reacting the compound obtained in step (a) with an amino compound of the formula:
 and deprotection to afford a compound of the formula:
c) stepwise bisdesmethylating the 3′-amino by treating the compound obtained in step (b) twice with iodine in presence of a base to afford a compound of the formula:
(d) alkylating the 3′,3′-N-bisdesmethylated compound obtained in step (c) with an alkylating agent.
The compounds of the invention exhibit little or no antibacterial activity, but they bind to the LHRH receptors and are effective LHRH antagonists. Thus, these compounds are effective in the treatment of prostate cancer, endometriosis, precocious puberty and other types of diseases which are related to sex hormones.
Accordingly, in another aspect of the invention, the present invention relates to pharmaceutical compositions which are useful as LHRH antagonists and suppress LH and testosterone and estrogen in mammals.
In still another aspect, the present invention relates to a method of suppressing levels of sex hormones in male or female mammals comprising administering to a host in need of such treatment a therapeutically effective amount of an LHRH compounds in combination with a therapeutically effective amount of an antiandrogenic agent.
DETAILED DESCRIPTION OF THE INVENTION
The terms “loweralkyl” or “alkyl” as used herein refer to straight or branched chain alkyl radicals containing from1 to 20 carbon atoms, sometimes represented as Cx-Cy-alkyl where x and y respectively represent the minimum and maximum number of carbon atoms in the alkyl radical. Examples of loweralkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
The term “alkoxy” or “lower alkoxy” as used herein refers to a loweralkyl group, as defined above, which is bonded to an oxygen atom in an ether linkage. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, isopropoxy, n-pentyloxy, t-butoxy, n-octyloxy and the like. This alkoxy radical can also contain a ring which include, but are not limited to, five or six atom ring composed of carbons, one or two heteroatoms such as nitrogen, oxygen.
The term “alkenyl” as used herein refers to a branched or straight hyd

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