Thiazole derivatives

Details Thiazole derivatives Thiazole derivatives

2001-06-11

2002-02-05

Aulakh, C. S. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S269700, C544S333000

Reexamination Certificate

active

06344562

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention is concerned with novel thiazole derivatives that inhibit binding of adhesive proteins to the surface of cells by influencing cell-cell and cell-matrix interactions.
SUMMARY OF THE INVENTION
The subject invention provides compounds having the formula:
wherein
R
1
is
R
2
is
R
3
is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, carboxy, alkyl-O—CO—, or aralkyl-O—CO—;
R
4
is hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl;
R
5
and R
6
are each independently hydrogen, alkyl, cycloalkyl, or heteroaryl;
R
7
and R
8
are each independently hydrogen, alkyl, cycloalkyl, or aralkyl, or R
7
and R
8
together with the N atoms to which they are attached form a 5- to 8-membered heterocyclic ring that is either unsubstituted or substituted with alkyl;
R
9
is hydrogen, alkyl, or cycloalkyl;
R
10
is aryl, aralkyl, heterocyclyl, heterocyclylalkyl, hydroxy, hydrogen, or alkyl, or R
10
is carboxy, carboxyalkyl, alkyl-O—CO—, aralkyl-O—CO—, alkyl-CO—, aralkyl-CO—, heteroarylalkyl-CO—, alkylsulphonyl, arylsulphonyl or heteroarylsulphonyl and k is zero, or R
10
is an &agr;-amino acid bonded via the amino group and l is zero and k is 1;
A is carbonyl or sulphonyl;
B is hydrogen, alkyl, or cycloalkyl;
a is an integer from 0 to 2 but not being zero when R
1
is —NH
2
; b is an integer from 0 to 4; c, d, f, g, k, l and m are each independently an integer from 0 to 1, whereby c, f and g
are not simultaneously 0 and whereby m is not 0 when f or g is 1; i is an integer from 0 to 1, whereby k and l are also 0 when i is 0; e is an integer from 0 to 3; h is an integer from 0 to 5; j is an integer from 0 to 2; and the sum of e, h and j is an integer from 2 to 7;
and the pharmaceutically usable salts and esters thereof. Although recited as a single grouping, all combinations of the mentioned substituents are envisioned.
It is preferred that f and g are not both 1. It is also preferred where R
2
is
and R
9
, R
10
, A, B, c and f to l are as defined above, or
and R
10
, A, B and f to l are as defined above, or
and R
9
, R
10
, A, d, e and h to l are as defined in claim
1
, or
and R
9
, R
10
, c, e, g and h to l are as defined above, and c and g cannot simultaneously equal 0.
It is favored when arylene is phenylene or phenylene that is substituted with one or more substituents selected from the group consisting of alkoxy, aralkoxy, halogen, and alkoxy-alkoxy. Especially favored is where arylene is meta- or para-phenylene or substituted meta- or para-phenylene, with the substituents of the phenylene previously given by the definition of R
2
standing meta- or para- to one another and with the substituted phenylene carrying an additional substituent on the ring selected from the group of alkoxy, alkoxy-alkoxy, halogen or aralkoxy.
R
3
is preferably hydrogen, alkyl, cycloalkyl, alkyl-O—CO—, carboxy or unsubstituted or substituted phenyl, with the substituted phenyl being substituted by one or more substituents selected from halogen, nitro and amino. R
4
is preferably hydrogen, alkyl, cycloalkyl, phenyl, or pyridyl. R
5
and R
6
are preferably hydrogen or pyridyl and R
7
and R
8
are hydrogen, or R
5
and R
6
are each hydrogen or pyridyl and R
7
and R
8
together with the N atoms to which they are attached form a 5- or 6-membered ring. R
10
is preferably piperidyl, pyridylmethyl, pyridyl, benzyl, alkyl, hydrogen or substituted or unsubstituted phenyl, with the substituted phenyl being mono- or multiply-substituted by halogen, alkoxy, alkoxycarbonyl, carboxy or hydroxy, or R
10
is alkyl-O—CO-methyl, carboxymethyl, alkylsulphonyl, alkyl-CO—, benzyl-O—CO— or alkyl-O—CO—, with k being equal to zero, or R
10
is L-valine, L-phenylalanine, L-phenylglycine, L-leucine, L-isoleucine, L-serine, L-threonine, 3-(1-naphthyl)-L-alanine, 3-(2-naphthyl)-L-alanine, N-isopropyl-glycine, &bgr;-cyclohexyl-L-alanine or L-proline, with k being equal to 1 and l being equal to zero.
Other preferred compounds include where R
9
is hydrogen or cycloalkyl and where R
2
is bonded to position 5 of the thiazole ring and R
3
is bonded to position 4 of the thiazole ring.
A favored subgenus is where compound of formula I is a compound having the formula:
wherein R
1′
is
R
2′
is
A is carbonyl or sulphonyl;
c, d, f, g, k, l and m are each independently an integer from 0 to 1, whereby c, f and g are not simultaneously 0 and whereby m is not 0 when f or g is 1; i is an integer from 0 to 1, whereby k and l are also 0 when i is 0; e is an integer from 0 to 3; h is an integer from 0 to 5; j is an integer from 0 to 2; and the sum of e, h and j is an integer from 2 to 7; and
R
10
′ is phenyl; phenyl substituted with halogen, hydroxy, or alkoxy; carboxy; carboxy alkyl, alkyl, or pyridine;
R
3′
is hydrogen or alkyl.
A preferred group of compounds is where R
1′
is
and R
3′
is alkyl, e.g. methyl or tert-butyl, A is carbonyl, and R
10′
is phenyl, phenyl substituted with chlorine, phenyl substituted with methoxy, or pyridine.
An alternative preferred group of compounds is where A is sulphonyl.
Another preferred group of compounds is where R
1′
is
In such a group, it is preferred that R
1′
is hydrogen and R
10′
is phenyl, alkyl, or pyridine.
The subject invention provides a process for manufacturing compounds of formula I (as used for the remainder of the Summary of the Invention, the phrase “the compounds of formula I” also includes the pharmaceutically usable salts and esters of the formula I) which comprises reacting a compound of the formula:
with an amine of the formula:
wherein R
1
, R
3
, R
9
, R
10
, A, B and d to m are as above, c is equal to 1 and R
03
is alkyl or aralkyl.
Novel intermediates in this process include compounds of the formula:
wherein R
1
is
R
3
is alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, carboxy, alkyl-O—CO—, or aralkyl-O—CO—, wherein R
3
is not hydrogen or methyl when R
1
is
a is an integer from 0 to 2 but not being 0 when R
1
is —NH
2
.
Pharmaceutical compositions provided by the subject invention include an effective amount of a compound of formula I and a pharmaceutically acceptable carrier.
The subject invention further provides a method for treating or preventing illnesses which are caused by a malfunction of the binding of adhesive proteins to vitronectin receptors, which comprises administering to a subject in need of such treating or preventing an effective amount of a compound of formula I.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to be construed as limiting the invention.
The invention is concerned especially with thiazole derivatives of formula I
wherein
R
1
is
R
2
is
R
3
is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, carboxy, alkyl-O—CO— or aralkyl-O—CO—;
R
4
is hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;
R
5
and R
6
are each independently hydrogen, alkyl, cycloalkyl or heteroaryl;
R
7
and R
8
are each independently hydrogen, alkyl, cycloalkyl or aralkyl or R
7
and R
8
together with the N atoms to which they are attached form a 5- to 8-membered heterocyclic ring which can be alkyl-substituted;
R
9
is hydrogen, alkyl or cycloalkyl;
R
10
is aryl, aralkyl, heterocyclyl, heterocyclylalkyl, hydroxy, hydrogen or alkyl, or R
10
is carboxy, carboxyalkyl, alkyl-O—CO—, aralkyl-O—CO—, alkyl-CO—, aralkyl-CO—, heteroarylalkyl-CO—, alkylsulphonyl, arylsulphonyl or heteroarylsulphonyl and k is zero, or R
10
is an &agr;-amino acid bonded via the amino group and l is zero and k is 1;
A is carbonyl or sulphonyl;
B is hydrogen, alkyl or cycloalkyl;
a to m are zero or whole positive numbers, with a being zero to 2 but not being zero when R
1
is —NH
2
; b being zero to 4; c, d, f, g, k, l and m each independently being zero or 1, whereby c, f and g are not simultaneously zero and whereby m is not zero when f or g is 1; i is zero or 1, whereby k and l are also zero when i is

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