Method for synthesizing caspase inhibitors

Details Method for synthesizing caspase inhibitors Method for synthesizing caspase inhibitors

2000-10-13

2003-05-06

Gerstl, Robert (Department: 1626)

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

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

Reexamination Certificate

active

06559304

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The invention relates to a process for simultaneously N(2)-acylating piperazic acid or an ester thereof and forming a bicyclic ring structure. The invention also relates to the use of that process step in a method of synthesizing a bicyclic compound useful as an intermediate for the production of an inhibitor of a caspase, particularly an inhibitor of interleukin-1&bgr; converting enzyme (“ICE”).
BACKGROUND OF THE INVENTION
Compounds containing a bicyclic aza-containing ring systems have been prepared as conformationally restricted dipeptide surrogates for a variety of medically important compounds. In particular, such ring systems are present in angiotensin converting enzyme (ACE) inhibitors, such as Cilazapril®, and in caspase inhibitors, such as inhibitors of interleukin-1&bgr; converting enzyme (ICE).
Current methods for synthesizing compounds containing these byciclic aza-containing ring systems have many disadvantages. The typical methods of forming this ring system have been described [EP 94,095, WO 95/35308, WO 97/22619, U.S. Pat. Nos. 5,656,627, 5,716,929 and 5,756,486 and J. P. Kim, et al.,
Tetrahedron Letters,
38, pp. 4935-4938 (1997)].
These methods involve multiple steps wherein an N(1)-protected piperazate must be provided. An appropriately protected amino acid, usually a &ggr;-ester of glutamic acid, is coupled to the piperazate. After deprotection, the bicyclic system is then formed via an acid chloride coupling at the N(1) position.
The main disadvantages to such methods are the use of expensive reagents and the number of steps required for protection and deprotection making the overall process extremely time consuming. Moreover, these methods are often useful for research purposes but are not amenable to large scale production.
In order to be more commercially feasible, it would be desirable to produce compounds containing a byciclic aza-containing ring system in an easier, less expensive manner than has been previously described.
SUMMARY OF THE INVENTION
Applicant has solved this problem by providing a new method of simultaneously N(2)-acylating an N(1)-protected piperazic acid or an ester thereof and creating a bicyclic ring structure comprising that acylated piperazic acid or ester. Until now, formation of said bicylcic compound had not been achieved via N(2)-acylation.
This method involves the formation of the desired bicyclic system in two simple steps. This method also utilizes inexpensive reagents, require no selective protection/deprotection and is amenable to large scale production. Moreover, this method produces very little contaminating by-products. And this method preserves chirality between the N(1)-protected piperazic acid or an ester thereof and the resulting byciclic aza-containing ring system.
This method is particularly useful for producing an intermediate that may be subsequently converted into a caspase inhibitor, particularly an inhibitor of ICE, through additional steps known in the art.
DETAILED DESCRIPTION OF THE INVENTION
The following abbreviations are used throughout this application:
t-Bu=tert-butyl
Et=ethyl
Cbz=carboxybenzyl
DMF=N,N-dimethylformamide
THF=tetrahydrofuran
MTBE=methyl tert-butyl ether
DCC=dicyclohexylcarbodiimide
EDC=1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
Ac=acetyl.
DBU=1,8-Diazabicyclo[5.4.0]undec-7-ene
Fmoc=9-Fluorenylmethoxycarbonyl
According to one embodiment, the invention provides a process for converting compound G to compound H:
wherein:
R
1
is a C
2-4
straight chain alkyl substituted at the carbon alpha to the COOH moiety with N(R
4
)(R
4
), NO
2
or N
3
and optionally substituted at any other carbon with one or more substituents independently selected from C
1-6
straight or branched alkyl, C
2-4
straight or branched alkenyl or alkynyl, O—[C
1-6
straight or branched alkyl], O—[C
2-6
straight or branched alkenyl or alkynyl], oxo, or halo; wherein
each R
4
is independently selected from H or an amino protecting group, with the proviso that both R
4
are not simultaneously hydrogen;
R
2
is selected from hydrogen, C
1-6
straight or branched alkyl, C
2-6
straight or branched alkenyl or alkynyl, or Ar, wherein said alkyl, alkenyl or alkynyl is optionally substituted with Ar; wherein
Ar is a saturated, partially saturated or unsaturated monocyclic or bicyclic ring structure, wherein each ring contains 5 to 7 ring atoms and each ring optionally contains from 1 to 3 heteroatoms selected from O, N and S; and
Ar is optionally substituted at one or more ring atoms with one or more substituents independently selected from C
1-6
straight or branched alkyl, C
2-6
straight or branched alkenyl or alkynyl, O—[C
1-6
straight or branched alkyl], O—[C
2-6
straight or branched alkenyl or alkynyl], oxo, halo, NO
2
, N(R
4
)(R
4
), or CN;
n is 0 or 1;
any substitutable ring carbon is optionally substituted by Q
1
; wherein
each Q
1
is independently selected from —Ar
1
, —T
1
—R
9
, or (CH
2
)
1-3
—T
1
—R
9
; provided that when —Ar
1
is substituted with a Q
1
which comprises one or more additional —Ar
1
groups, said additional —Ar
1
groups are not substituted with Q
1
; wherein
Ar
1
is a saturated, partially saturated or unsaturated monocyclic or bicyclic ring structure, wherein each ring contains 5 to 7 ring atoms and each ring optionally contains from 1 to 3 heteroatoms selected from O, N and S; and
wherein each Ar
1
is optionally singly or multiply substituted at any ring atom by —N(R
9
)(R
9
), halo, —NO
2
, —CN, ═O, —OH, -perfluoro C
1-3
alkyl,
 or —Q
1
;
wherein each R
9
is a C
1-6
straight or branched alkyl group optionally substituted with one or more substituents independently selected from —F, ═O or Ar
1
, wherein any R
9
may be substituted with a maximum of two Ar
1
;
T
1
is selected from a valence bond, —CH═CH—, —O—, —S—, —SO—, —SO
2
—, —NR
10
—, —NR
10
—C(O)—, —C(O)—, —O—C(O)—, —C(O)—O—, —C(O)—NR
10
—, O—C(O)—NR
10
—, —NR
10
—C(O)—O—, —NR
10
—C(O)—NR
10
—, —S(O)
2
—NR
10
—, —NR
10
—S(O)
2
—, or —NR
10
—S(O)
2
—NR
10
—; and
each R
10
is independently selected from —H or C
1-6
straight or branched alkyl;
The term “amino protecting group”, as used herein, means a moiety that prevents chemical reactions from occurring on the nitrogen atom to which that protecting group is attached. An amino protecting group must also be removable by a chemical reaction. Amino protecting groups that are acid cleavable include t-butoxycarbonyl. Examples of amino protecting groups that are base cleavable include Fmoc and alkyl carbamates. Amino protecting groups that are cleaved by hydrogenolysis include Cbz and allyloxycarbonyl. The phthalimide protecting group is typically removed by treatment with hydrazine.
In a preferred embodiment, R
1
is substituted at the terminal carbon (i.e., the one bound to the N(1) ring nitrogen) with oxo, making R
1
an acyl-containing moiety. More preferred is when R
1
contains both the protected amine substituent and the oxo substituent. One of the most preferred R
1
groups is:
In another preferred embodiment, n is 1.
In yet another preferred embodiment, R
2
is t-butyl.
The method of this invention comprises the steps of:
(a) combining compound G with an organic solvent selected from dichloroethane, dichloromethane, toluene, chlorobenzene, chloroform, monoglyme, diglyme, THF, or CCl
4
;
(b) adding less than about 0.2 equivalents of DMF;
(c) adjusting the temperature of the resulting mixture to between 20° C. and 100° C.;
(d) adding about 2 or more equivalents of SOCl
2
to said mixture over a period of between 2 and 24 hours.
Not all organic solvents may be used in step (a). The list of solvents set forth above are known to work. Other similar organic solvents may also work in the reaction and are to be considered part of the present invention. Preferably, the organic solvent is toluene or dichloroethane.
In step (b), it is preferred to use about 0.1 equivalent of D

Affiliated with

Also associated with

Rating

Method for synthesizing caspase inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Method for synthesizing caspase inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for synthesizing caspase inhibitors will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3028190