Claims
- 1. A compound of formula I ##STR25## wherein: X.sub.1 and X.sub.2 are independently selected from C.dbd.O, C.dbd.NH and CH.sub.2 ;
- X.sub.3 is selected from CH.sub.2, C.dbd.O, CHOH, ##STR26## wherein n=2 or 3, and C.dbd.N(R.sub.9) wherein R.sub.9 is hydroxy or amino-aryl;
- R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are independently selected from hydrogen, hydroxyl, C.sub.1-16 alkyl, C.sub.1-16 alkoxyl, C.sub.3-8 cycloalkoxyl, halogen, amino which may be unsubstituted or mono- or di-substituted by acyl, trifluoroacyl, aralkyl or aryl groups, and OSO.sub.2 (R.sub.10) wherein R.sub.10 is alkyl or aryl;
- R.sub.5 and R.sub.8 are independently selected from hydrogen, hydroxyl, C.sub.1-16 alkoxyl, halogen, amino which may be unsubstituted or mono- or di-substituted by acyl, trifluoroacyl, aralkyl or aryl groups, and OSO.sub.2 (R.sub.10) wherein R.sub.10 is as above defined;
- R.sub.6 is selected from the group consisting of hydrogen, R.sub.B --CH.sub.2 -- (wherein R.sub.B is an aryl or heterocyclyl group), a group of formula R.sub.C --CH.dbd.CH--, (wherein Rc is hydrogen or C.sub.1-5 alkyl), C.sub.1-16 alkyl, C.sub.2-8 alkenyl, C.sub.3-8 cycloalkyl, acyl of formula --C(R.sub.11).dbd.O (wherein R.sub.11 is selected from hydrogen, C.sub.1-16 alkyl, C.sub.3-8 cycloalkyl, hydroxyalkyl, heterocyclyl, aryl araloxyalkyl, and acyloxyalkyl) and an acyl residue of a naturally occurring or a synthetic amino acid or di- or tri-peptide;
- R.sub.7 is selected from the group consisting of hydrogen, methyl, CH.sub.2 OH, CH.sub.2 O--R.sub.12 (wherein R.sub.12 is the group tetrahydropyranyl (THP), or a saccharide of the formula ##STR27## in which R.sub.13 is amino or aminoacyl, R.sub.14 and R.sub.15 are both hydrogen or one of R.sub.14 and R.sub.15 is hydrogen and the other of R.sub.14 and R.sub.15 is hydroxy or alkoxy or halogen or a group OSO.sub.2 (R.sub.10) as defined above), CH.sub.2 --O--Ph--(amino) (wherein the amino may be unsubstituted or mono- or di-substituted by alkyl, acyl, trifluoroacyl, aralkyl or aryl) and CH.sub.2 -amino (wherein the amino is mono- or di-substituted by an alkyl, acyl, trifluoroacyl, aralkyl or aryl group or the amino is within an heterocyclic ring optionally substituted with C.sub.1-16 alkyl or C.sub.1-16 alkyloxy or aryloxy),
- or a pharmaceutically acceptable salt thereof.
- 2. A compound according to claim 1, in which
- X.sub.1 and X.sub.2 are independently selected from C.dbd.O and C.dbd.NH;
- X.sub.3 is selected from CH.sub.2 ; C.dbd.O, CHOH and C.dbd.N(R.sub.9) wherein R.sub.9 is hydroxy or amino-aryl;
- R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are independently selected from hydrogen, hydroxyl, C.sub.1-4 alkoxyl, C.sub.3-8 cycloalkoxyl, O-mesyl (O--SO.sub.3 CH.sub.3), amino and amino-benzyl;
- R.sub.5 and R.sub.8 are independently selected from hydrogen, hydroxyl, C.sub.1 -C.sub.4 alkoxyl, halogen, amine, amino-benzyl; and amino-trifluoroacetyl;
- R.sub.6 is selected from hydrogen R.sub.B --CH.sub.2, wherein R.sub.B is as defined in claim 1, C.sub.1-10 alkyl, C.sub.2-6 alkenyl, acyl of formula --C(R.sub.11).dbd.O (where in R.sub.11 is selected from the group consisting of C.sub.1-10 alkyl, hydroxylalkyl, heterocyclyl, aryl araloxyalkyl, and acyloxyalkyl) and an acyl residue of a naturally occurring or synthetic amino acid or di- or tri-peptide; and
- R.sub.7 is selected from the group consisting of hydrogen, methyl, CH.sub.2 OH, CH.sub.2 O--R.sub.12 (wherein R.sub.12 is the group tetrahydropyranyl (THP), or a saccharide of the formula ##STR28## in which R.sub.13 is amino or aminotrifluoroacetyl or amino-acetyl, R.sub.15 is hydrogen and R.sub.14 is hydroxy, iodine, O-mesyl, or CH.sub.2 --O--Ph--NH--COR wherein R is alkyl, aralkyl or aryl), and CH.sub.2 -amino (wherein the amino is within an heterocyclic ring optionally substituted with C.sub.1-10 alkyl or C.sub.1-5 alkyloxy or aryloxy); or a pharmaceutically acceptable salt thereof.
- 3. A compound according to claim 1, in which:
- X.sub.1 and X.sub.2 are independently selected from C.dbd.O and C.dbd.NH;
- X.sub.3 is selected from CH.sub.2, C.dbd.O and CHOH,
- R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are independently selected from hydrogen, hydroxyl, methyl, methoxy, O-mesylate, amino, amino-benzyl, fluorine and chlorine;
- R.sub.5 and R.sub.8 are independently selected from hydrogen, hydroxyl, methoxy, ethoxy, amino and amino-trifluoroacetyl;
- R.sub.6 is selected from hydrogen, benzyl, allyl, 3,4-dimethoxybenzyl, pyridinemethyl, (N-methyl-dihydropyridine)-methyl, nicotyl, glycyl and isoleucyl; and
- R.sub.7 is selected from the group consisting of hydrogen, methyl, CH.sub.2 OH, CH.sub.2 O--R,.sub.12 (wherein R.sub.12 is the group tetrahydropyranyl (THP), or a saccharide of the formula ##STR29## in which R.sub.13 is amino or aminotrifluoroacetyl or aminoacetyl, R.sub.15 is hydrogen and R.sub.14 is iodine), and CH.sub.2 -amino wherein the amino is within a morpholino ring;
- or a pharmaceutically acceptable salt thereof.
- 4. A compound according to claim 1, in which
- X.sub.1 and X.sub.2 are both C.dbd.O;
- X.sub.3 is C.dbd.O;
- R.sub.1, R.sub.2 and R.sub.3 are each hydrogen and R.sub.4 is hydrogen, hydroxy or methoxy;
- R.sub.5 and R.sub.8 are independently selected from hydrogen, hydroxyl, methoxy and amino;
- R.sub.6 is selected from hydrogen, pyridinemethyl, (N-methyl-dihydropyridine)-methyl, nicotyl, glycyl and isoleucyl; and
- R.sub.7 is methyl;
- or a pharmaceutically acceptable salt thereof.
- 5. A process for producing a compound of formula I, as defined in claim 1, which process comprises:
- (a) reacting a compound of formula 2: ##STR30## wherein X.sub.1, X.sub.2 and R.sub.1 to R.sub.7 are as defined in claim 1, and W represents a leaving group, with an amine of the formula
- H.sub.2 N--CH.sub.2 --R.sub.B
- wherein R.sub.B is as defined in claim 1, to give a compound of formula I wherein R.sub.6 is R.sub.B --CH.sub.2 --;
- (b) if desired, converting the thus obtained compound of formula (I) into another compound of formula (I); and/or
- (C) if desired, converting the compound of formula (I) to a pharmaceutically acceptable salt thereof.
- 6. A process according to claim 5, wherein step (a) is carried out with a 1 to 10 fold excess of amine, in an organic solvent therefor, in the presence of an organic base for from 6 to 48 hours, at from -10.degree. C. to room temperature.
- 7. A process according to claim 5 wherein, in step (b), the compound of formula (I) wherein R.sub.6 is R.sub.B --CH.sub.2 -- is converted to a compound of the formula I in which R.sub.6 is hydrogen.
- 8. A process according to claim 7, wherein R.sub.B is a 3,4-dimethoxyphenyl or vinyl group and the conversion is carried out by oxidation.
- 9. A process according to claim 8, wherein R.sub.B is a 3,4-dimethoxyphenyl group and the oxidation is conducted using 2,3 dichloro-5,6 dicyano 1,4-benzoquinone.
- 10. A process according to claim 7, which further comprises converting the compound of formula (I) in which R.sub.6 is hydrogen into a compound of formula I wherein R.sub.6 is C.sub.1-16 alkyl, C.sub.2-8 alkenyl, C.sub.3-8 cycloalkyl, an acyl group of formula --C(R.sub.11).dbd.O, wherein R.sub.11 is as defined above, or an acyl residue of an amino acid or of a di-or tri-tripeptide.
- 11. A process according to claim 5, wherein step (b) comprises the reduction of a compound of formula (I) wherein X.sub.3 is C.dbd.O to give a compound of formula I wherein X.sub.3 is CHOH or CH.sub.2.
- 12. A pharmaceutical composition which comprises, as active ingredient, a compound of formula 1 as defined in claim 1, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier or diluent.
- 13. A method of treating amyloidosis, comprising administering to a patient in need thereof an effective amount of a compound of formula 1 as defined in claim 1 or a pharmaceutically acceptable salt thereof.
Priority Claims (1)
Number |
Date |
Country |
Kind |
9516349 |
Aug 1995 |
GBX |
|
Parent Case Info
This application is a 371 of PCT/EP96/03237, filed Jul. 23, 1996. Priority is based upon application no. GB 9516349.9, having a filing date of Aug. 9, 1995, which application is incorporated herein by reference in the entirety.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
102e Date |
371c Date |
PCT/EP96/03237 |
7/23/1996 |
|
|
2/9/1998 |
2/9/1998 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO97/06165 |
2/20/1997 |
|
|
US Referenced Citations (3)
Number |
Name |
Date |
Kind |
5637572 |
Merlini et al. |
Jun 1997 |
|
5731313 |
Suarato et al. |
Mar 1998 |
|
5744454 |
Suarato et al. |
Apr 1998 |
|
Non-Patent Literature Citations (1)
Entry |
J. Med. Chem., vol. 31(2), pp. 433-444, Grunewald, 1988. |