Process for the synthesis of gonadotropin releasing hormone...

Details Process for the synthesis of gonadotropin releasing hormone... Process for the synthesis of gonadotropin releasing hormone...

2002-04-05

2003-09-16

Rotman, Alan L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S277400, C546S164000, C546S193000, C548S511000, C514S339000

Reexamination Certificate

active

06620824

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to a process for preparing a gonadotropin releasing hormone antagonist having an arylindole core.
BACKGROUND OF THE INVENTION
The gonadotropin-releasing hormone (GnRH), also referred to as luteinizing hormone-releasing hormone (LHRH), is a decapeptide that plays a key role in human reproduction. The hormone is released from the hypothalamus and acts on the pituitary gland to stimulate the biosynthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH released from the pituitary gland is primarily responsible for the regulation of gonadal steroid production in both sexes, whereas FSH regulates spermatogenesis in males and follicular development in females.
GnRH agonists and antagonists have proven effective in the treatment of certain conditions which require inhibition of LH/FSH release. In particular, GnRH-based therapies have proven effective in the treatment of endometriosis, uterine fibroids, polycystic ovarian disease, precocious puberty and several gonadal steroid-dependent neoplasia, most notably cancers of the prostate, breast and ovary. GnRH agonists and antagonists have also been utilized in various assisted fertilization techniques and have been investigated as a potential contraceptive in both men and women. They have also shown possible utility in the treatment of pituitary gonadotrophe adenomas, sleep disorders such as sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hyperplasia, hirsutism, as an adjunct to growth hormone therapy in growth hormone deficient children, and in murine models of lupus.
Current GnRH antagonists are GnRH-like decapeptides which are generally administered intravenously or subcutaneously presumably because of negligible oral activity. These have amino acid substitutions usually at positions one, two, three, six and ten.
Non-peptide GnRH antagonists offer the possible advantage of oral administration. Non-peptide GnRH antagonists have been described in European Application 0 219 292 and in De, B. et al., J. Med. Chem., 32, 2036-2038 (1989), in WO 95/28405, WO 95/29900 and EP 0679642 all to Takeda Chemical Industries, Ltd.
Substituted indoles known in the art include those described in the following patents and patent applications. Fisher et al. (U.S. Pat. No. 5,030,640) discloses alpha-heterocyclic ethanol aminoalkyl indoles which are potent &bgr;-agonists.
Manning et al. (U.S. Pat. No. 4,544,663) is directed to indolamine derivatives which can be used as male anti-fertility agents.
Youngdale et al (WO 90/0572) discloses alpha-amino-indole-3-acetic acids useful as anti-diabetic, anti-obesity and anti-atherosclerotic agents.
Boch et al. (French pat. No. 2,181,559) discloses indole derivatives with sedative, neuroleptic, analgesic, hypotensive, antiserotonin and adrenolytic activity.
Belgian patent 879381 discloses 3-aminoalkyl-1H-indole-5-thioamide and carboxamide derivatives as cardiovascular agents used to treat hypertension, Raynaud's disease and migraine.
An object of the present invention is to develop an efficient synthetic route to prepare the class of GnRH antagonist compounds having regioselectivity and enantioselectivity, specifically the class of compound known as chiral tryptamines.
SUMMARY OF THE INVENTION
The present invention is directed a process for preparing a compound of Formula I,
or its pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
p is: 1-4;
R
1
is:
(1) hydrogen,
(2) (C
1
-C
6
)-alkyl, or
(3) aryl;
R
2
, R
3
, and R
4
are independently:
(1) hydrogen,
(2) (C
1
-C
6
)-alkyl,
(3) (C
2
-C
6
)-alkenyl,
(4) CN,
(5) nitro,
(6) (C
1
-C
3
)-perfluoroalkyl,
(7) (C
1
-C
3
)-perfluoroalkoxy, or
(8) aryl;
R
5
is:
(1) hydrogen,
(2) (C
1
-C
6
)-alkyl,
(3) aryl,
(4) (C
1
-C
3
)-perfluoroalkyl,
(5) CN,
(6) NO
2
, or
(7) halogen;
R
6
and R
7
are independently:
(1) hydrogen, or
(2) (C
1
-C
6
)-alkyl;
R
8
is:
(1) (C
1
-C
6
)-alkyl; or
(2) aryl; and
R
9
is:
(1) (C
1
-C
6
)-alkoxy, or
(2) NHR
10
R
11
, wherein R
10
and R
11
are independently:
(a) hydrogen,
(b) (C
1
-C
6
)-alkyl, or
(c) aryl,
 wherein R
10
and R
11
taken together form a monocyclic ring, bicyclic ring or bridged ring containing from 3 to 7 carbon atoms, and the ring may be optionally substituted by R
2
, R
3
, and R
4
; and
R
12
is:
(1) (C
1
-C
6
)-alkyl,
(2) halo, wherein halo is F, Cl, Br or I,
(3) (C
1
-C
4
)-perfluoroalkyl,
(4) (CH
2
)
n
NMe
3
+
wherein n is 1 to 6, or
(5) aryl wherein aryl is optionally substituted with one, two, or three substituents selected from the group consisting of NO
2
, (C
1
-C
6
)-alkyl, and halo as defined above;
comprising the steps of:
(1) reacting a compound of formula (a),
 with an aziridine compound of formula
 in the presence of a Lewis-acid in an aprotic solvent to produce a compound of formula (b)
 wherein R
9a
is (C
1
-C
6
)-alkoxy, hydrolyzing the compound of formula (b) in the presence of a base and a protic solvent to give an acid form of the compound of formula (b) wherein R
9a
is hydroxyl;
(2) reacting the acid form of the compound of formula (b) with an amine in an aprotic solvent to produce a compound of formula (c)
(3) reacting the compound of formula (c) with amine, NHR
10
R
11
in the presence of a base in an aprotic solvent to give an amide compound of formula (d),
(4) reacting the compound of formula (d) with
 in the presence of an acid in an aprotic solvent to give the compound of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the synthesis of a gonadotropin releasing hormone antagonist in an efficient way, which involves preparation of key intermediates: 2-arylindole core; a chiral aziridine, in particular chiral nosyl aziridine; and an amine salt. The key step in the process is the coupling reaction of 2-arylindole and nosyl aziridine using boron trifluoride catalysis. The process of the present invention provides the compound of Formula I with unprecedented regioselectivity and enantioselectivity.
The present invention relates to a process for preparing a compound of Formula I,
or its pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
p is: 1-4;
R
1
is:
(1) hydrogen,
(2) (C
1
-C
6
)-alkyl, or
(3) aryl;
R
2
, R
3
, and R
4
are independently:
(1) hydrogen,
(2) (C
1
-C
6
)-alkyl,
(3) (C
2
-C
6
)-alkenyl,
(4) CN,
(5) nitro,
(6) (C
1
-C
3
)-perfluoroalkyl,
(7) (C
1
-C
3
)-perfluoroalkoxy, or
(8) aryl;
R
5
is:
(1) hydrogen,
(2) (C
1
-C
6
)-alkyl,
(3) aryl,
(4) (C
1
-C
3
)-perfluoroalkyl,
(5) CN,
(6) NO
2
, or
(7) halogen;
R
6
and R
7
are independently:
(1) hydrogen, or
(2) (C
1
-C
6
)-alkyl;
R
8
is:
(1) (C
1
-C
6
)-alkyl; or
(2) aryl; and
R
9
is:
(1) (C
1
-C
6
)-alkoxy, or
(2) NHR
10
R
11
, wherein R
10
and R
11
are independently:
(a) hydrogen,
(b) (C
1
-C
6
)-alkyl, or
(c) aryl,
 wherein R
10
and R
11
taken together form a monocyclic ring, bicyclic ring or bridged ring containing from 3 to 7 carbon atoms, and the ring may be optionally substituted by R
2
, R
3
, and R
4
; and
R
12
is:
(1) (C
1
-C
6
)-alkyl,
(2) halo, wherein halo is F, Cl, Br or I,
(3) (C
1
-C
4
)-perfluoroalkyl,
(4) (CH
2
)
n
NMe
3
+
wherein n is 1 to 6, or
(5) aryl wherein aryl is optionally substituted with one, two, or three substituents selected from the group consisting of NO
2
, (C
1
-C
6
)-alkyl, and halo as defined above;
comprising the steps of:
(1) reacting a compound of formula (a),
 with an aziridine compound of formula
 in the presence of a Lewis-acid in an aprotic solvent to produce a compound of formula (b)
 wherein R
9a
is (C
1
-C
6
)-alkoxy, hydrolyzing the compound of formula (b) in the presence of a base and a protic solvent to give an acid form of the compound of formula (b) wherein R
9a
is hydroxyl;
(2) reacting the acid form of the compound of formula (b) with an amine in an aprotic solvent to produce a compound of formula (c)
(3) reacting the compound of formula (c) with amine, NHR
10
R
11
in the presence of a base in a

Affiliated with

Also associated with

Rating

Process for the synthesis of gonadotropin releasing hormone... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for the synthesis of gonadotropin releasing hormone..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the synthesis of gonadotropin releasing hormone... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3098860