2-{N-(2-amino-3-(heteroaryl or aryl)propionyl)-aminoacyl}-amino}-alkylboronic acid derivatives

• US 6,933,290 B2
• Filed: 05/29/2002
• Issued: 08/23/2005
• Est. Priority Date: 05/30/2001
• Status: Expired due to Fees

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Furet, Pascal, Guagnano, Vito, Imbach, Patricia, Lang, Marc
• Primary Examiner(s): AULAKH, CHARANJIT
• Application Number:
  US10/478,794
• Publication Number:
  US 20040167337A1
• Time in Patent Office: 1,182 Days
• Field of Search: 514/64, 514/19, 514/18, 530/331, 549/213, 562/7
• US Class Current: 514/64
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 5/06191 containing heteroatoms different from O, S, or N

Abstract

Disclosed are derivatives of 2-{[N-(2-amino-3-(heteroaryl or aryl)propionyl)-aminoacyl]-amino}-alkylboronic acid, processes for the preparation of such compounds, pharmaceutical preparations, and the use of such derivatives in the preparation of pharmaceutical compositions for the therapeutic treatment of warm-blooded animals, including humans

Claims

1. A compound of the formula I

wherein

R₁ is unsubstituted or substituted aryl;

arylalkylcarbonyl, wherein the aryl moiety is unsubstituted or substituted;

unsubstituted or substituted heterocyclyl;

or heterocyclylalkylcarbonyl, wherein the heterocyclyl moiety is unsubstituted or substituted;

R₂ is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl;

R₃ is hydrogen, unsubstituted or substituted aryl or alkyl which is unsubstituted or substituted by

unsubstituted or substituted cycloalkyl,

unsubstituted or substituted aryl, or

unsubstituted or substituted heteroaryl comprising at least one nitrogen atom;

R₄ is a moiety of the formula IA,

wherein A₁ and A₂ are hydroxy or substituted hydroxy, or together with the binding boron atom and the two binding oxygen atoms form a ring of the formula IA*,

wherein W is alkylene, substituted alkylene, unsubstituted or substituted cycloalkylene, unsubstituted or substituted bicycloalkylene or unsubstituted or substituted tricycloalkylene;

and R₅ is unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, or unsubstituted or substituted cycloalkyl;

or a salt thereof.

2. A compound of the formula I according to claim 1, wherein the stereochemistry is as depicted in formula I*

wherein the shown configuration represents the absolute configuration and wherein R₁, R₂, R₃, R₄ and R₅ are as defined for formula I in claim 1,

or a salt thereof.

3. A compound of the formula I according to claim 1, wherein

R₁ is either substituted aryl-lower alkylcarbonyl or unsubstituted or substituted aryl,

R₂ is substituted aryl or unsubstituted or substituted heterocyclyl,

R₃ is lower alkyl, unsubstituted or substituted aryl or lower alkyl which is substituted by unsubstituted or substituted aryl,

R₄ is a moiety of the formula IA wherein A₁ and A₂ are hydroxy, lower alkyloxy, aryloxy with unsubstituted or substituted aryl or cycloalkyloxy with unsubstituted or substituted cycloalkyl, or wherein A₁ and A₂, together with the binding boron atom and the two binding oxygen atoms form a ring of the formula IA* wherein W is unsubstituted or substituted lower alkylene bound via two different carbon atoms that are spatially nearby or vicinal, especially in vicinal or, relatively to each other, in “

1,3”

-position, and

R₅ is lower alkyl,

or a salt thereof.

4. A compound of the formula I according to claim 1, wherein

R₁ is phenyloxyphenyl-lower alkylcarbonyl;

phenyl-lower alkoxyphenyl-lower alkylcarbonyl;

pyridyloxyphenyl-lower alkylcarbonyl;

phenyl-lower alkylcarbonyl substituted by lower alkoxy, halogen, halogen-lower alkyl, or unsubstituted or substituted phenyl or naphthyl, wherein in both cases the substituents if present are independently one or more, especially one to three, substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, formyl, lower alkanoyl, amino, N-lower alkylamino, N,N-di-lower alkylamino, mercapto, sulfo, lower alkyl-thio, carbamoyl, N-lower alkyl-carbamoyl;

N,N-di-lower alkyl-carbamoyl, phenyl, naphthyl, pyridyl, cyano and nitro, more preferably lower alkoxy;

R₂ is phenyl substituted by one or more moieties independently selected from the group consisting of hydroxy, lower alkoxy, halogen, and halogen-lower alkyl;

R₃ is lower alkyl, isobutyl, phenyl or phenyl substituted by one or more, up to three substituents independently selected from the group consisting of hydroxy, lower alkoxy, halogen, and halogen-lower alkyl;

R₄ is —

B(OH)₂ or 2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl;

(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl; and

R₅ is lower alkyl;

or a salt thereof.

5. A compound of formula I according to claim 1, wherein

R₁ is phenyloxyphenylacetyl, benzyloxyphenylacetyl, pyridyloxyphenylacetyl, biphenylyl, pyridylphenyl, lower alkylphenyl or substituted phenylpropionyloxy wherein the phenyl substituents are up to three substituents independently selected from the group consisting of methoxy;

fluoro, chloro and trifluoromethyl;

R₂ is phenyl substituted with up to three methoxy substituents, especially 2,3,4-trimethoxyphenyl or 3,4,5-trimethoxyphenyl;

R₃ is isobutyl or phenyl that is unsubstituted or substituted with up to three moieties independently selected from hydroxy, fluoro and methoxy;

R₄ is (1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl or —

B(OH)₂; and

R₅ is isopropyl;

or a salt thereof.

6. A compound of formula I according to claim 1, wherein

R₁ is biphenylyl, lower alkyl-phenyl, phenyl-lower alkyl-carbonyl, phenoxy-phenyl-lower alkyl-carbonyl, phenyl-lower alkoxy-phenyl-lower alkyl-carbonyl or pyridyl-phenyl;

R₂ is either phenyl substituted by 1 to 3 lower alkoxy radicals or phenyl-lower alkoxy-phenyl;

R₃ is lower alkyl or phenyl-lower alkyl;

R₄ is 4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl, (1S,2S,6R8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl or —

B(OH)₂; and

R₅ is lower alkyl;

or a salt thereof.

7. A compound of formula I according to claim 1 selected from the group consisting of

(R)-1-{(S)-2-[(S)-2-(biphenyl-3-ylamino)-(3-(3,4,5-trimethoxy-phenyl)-propionylamino]-3-methyl-butyrylamino}-3-methyl-butylboronic acid,

(R)-3-methyl-1-{(S)-3-methyl-2-[(S)-2-[2-(3-phenoxy-phenyl)-acetylamino]-3-(2,3,4-trimethoxy-phenyl)-propionylamino]-butyrylamino}-butylboronic acid and

(R)-3-methyl-1-{(S)-3-methyl-2[(S)-2-(3-phenyl-propionylamino)-3-(2,3,4-trimethoxy-phenyl)-propionylamino]-butyrylamino}-butylboronic acid,

or a pharmaceutically acceptable salt thereof.

8. A compound of formula I according to claim 1 selected from the group consisting of

(S)-2-[(S)-2-(biphenyl-3-ylamino)-3-(3,4,5-trimethoxy-phenyl)-propionylamino]-3-methyl-N-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl)-butyl]-butyramide,

(S)-3-methyl-N-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl)-butyl]-2-[(S)-2-[2-(3-phenoxy-phenyl)-acetylamino]-3-(2,3,4-trimethoxy-phenyl)-propionylamino]-butyramide, and

(S)-3-methyl-N-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl)-butyl]-2-[(S)-2-(3-phenyl-propionyl-amino)-3-(2,3,4-trimethoxy-phenyl)-propionylamino]-butyramide,

or a pharmaceutically acceptable salt thereof.

9. A compound of formula I according to claim 1 selected from the group consisting of

(R)-1-{(S)-2-[(S)-2-(biphenyl-3-ylamino)-3-(4-methoxy-phenyl)-propionylamino]-3-methyl-butyrylamino}-3-methyl-butylboronic acid,

(R)-1-{(S)-2-[(S)-2-(biphenyl-3-ylamino)-3-(3,4-dimethoxy-phenyl)-propionylamino]-3-methyl-butyrylamino}-3-methyl-butylboronic acid,

(R)-1-{(S)-2-[(S)-2-(3-isopropyl-phenylamino)-3-(3,4,5-trimethoxy-phenyl)-propionylamino]-3-methyl-butyrylamino}-3-methyl-butylboronic acid,

(R)-3-methyl-1-{(S)-3-methyl-2-[(S)-2-(3-pyridin-2-yl-phenylamino)-3-(3,4,5-trimethoxy-phenyl)-propionylamino]-butyrylamino}-butylboronic acid,

(R)-1-{(S)-2-[(S)-2-(biphenyl-3-ylamino)-3-(2,3,4-trimethoxy-phenyl)-propionylamino]-3-methyl-butyrylamino}-3-methyl-butylboronic acid,

(R)-1-{(S)-2-[(S)-3-(4-benzyloxy-phenyl)-2-(biphenyl-3-ylamino)-propionylamino]-3-methyl-butyrylamino}-3-methyl-butylboronic acid,

(R)-1-{(R)-2-[(S)-2-(biphenyl-3-ylamino)-3-(3,4,5-trimethoxy-phenyl)-propionylamino]-3-methyl-butyrylamino}-3-methyl-butylboronic acid,

(R)-1-{(S)-2-[(R)-2-(biphenyl-3-ylamino)-3-(3,4,5-trimethoxy-phenyl)-propionylamino]-3-methyl-butyrylamino}-3-methyl-butylboronic acid,

1-{(S)-2-[(S)-2-(biphenyl-3-ylamino)-3-(3,4,5-trimethoxy-phenyl)-propionylamino]-3-methyl-butyrylamino}-3-methyl-butylboronic acid,

(R)-1-((S)-2-{(S)-3-(3,4-dimethoxy-phenyl)-2-[2-(3-phenoxy-phenyl)-acetylamino]-propionylamino}-3-methyl-butyrylamino)-3-methyl-butylboronic acid,

(R)-3-methyl-1-{(S)-3-methyl-2-[(S)-2-[2-(3-phenoxy-phenyl)-acetylamino]-3-(3,4,5-trimethoxy-phenyl)-propionylamino]-butyrylamino}-butylboronic acid,

(R)-1-((S)-2-{(S)-3-(4-benzyloxy-phenyl)-2-[2-(3-benzyloxy-phenyl)-acetylamino]-propionylamino}-3-methyl-butyrylamino)-3-methyl-butylboronic acid,

(R)-1-{(S)-2-[(S)-2-(biphenyl-3-ylamino)-3-(3,4,5-trimethoxy-phenyl)-propionylamino]-4-methyl-pentanoylamino}-3-methyl-butylboronic acid,

(R)-1-{(S)-2-[(S)-2-(biphenyl-3-ylamino)-3-(3,4,5-trimethoxy-phenyl)-propionylamino]-4-methyl-pentanoylamino}-3-methyl-butylboronic acid,

(R)-1-{(S)-2-[(S)-2-(biphenyl-3-ylamino)-3-(4-methoxy-phenyl)-propionylamino]-4-methyl-pentanoylamino}-3-methyl-butylboronic acid,

(R)-1-{(S)-2-[(S)-2-(biphenyl-3-ylamino)-3-(3,4,5-trimethoxy-phenyl)-propionylamino]-propionylamino}-3-methyl-butylboronic acid,

(R)-1-{(S)-2-[(S)-2-(biphenyl-3-ylamino)-3-(2,3,4-trimethoxy-phenyl)-propionylamino]-propionylamino}-3-methyl-butylboronic acid,

(R)-1-{(S)-2-[(S)-2-(biphenyl-3-ylamino)-3-(4-methoxy-phenyl)-propionylamino]-propionylamino}-3-methyl-butylboronic acid,

(R)-1-{(S)-2-[(S)-2-(biphenyl-3-ylamino)-3-(3,4-dimethoxy-phenyl)-propionylamino]-propionylamino}-3-methyl-butylboronic acid,

(R)-1-{(S)-2-[(S)-2-(3-isopropyl-phenylamino)-3-(3,4,5-trimethoxy-phenyl)-propionylamino]-propionylamino}-3-methyl-butylboronic acid,

(R)-3-methyl-1-{(S)-2-[(S)-2-(3-phenyl-propionylamino)-3-(2,3,4-trimethoxy-phenyl)-propionylamino]-propionylamino}-butylboronic acid,

(R)-1-{(S)-2-[(S)-2-(biphenyl-3-ylamino)-3-(3,4,5-trimethoxy-phenyl)-propionylamino]-3-methyl-butyrylamino}-2-phenyl-ethylboronic acid, and

(R)-1-{(S)-2-[(S)-2-(biphenyl-3-ylamino)-3-(4-methoxy-phenyl)-propionylamino]-3-methyl-butyrylamino}-2-phenyl-ethylboronic acid,

or a pharmaceutically acceptable salt thereof.

10. A compound of formula I according to claim 1 selected from the group consisting of

(S)-2-[(S)-2-(biphenyl-3-ylamino)-3-(4-methoxy-phenyl)-propionylamino]-3-methyl-N-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl)-butyl]-butyramide,

(S)-2-[(S)-2-(biphenyl-3-ylamino)-3-(3,4-dimethoxy-phenyl)-propionylamino]-3-methyl-N-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl)-butyl]-butyramide,

(S)-2-[(S)-(3-isopropyl-phenylamino)-3-(3,4,5-trimethoxy-phenyl)-propionylamino]-3-methyl-N-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl)-butyl]-butyramide,

(S)-3-methyl-N-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl)-butyl]-2-[(S)-2-(3-pyridin-2-yl-phenylamino)-3-(3,4,5-trimethoxy-phenyl)-propionylamino]-butyramide,

(S)-2-[(S)-2-(biphenyl-3-ylamino)-3-(2,3,4-trimethoxy-phenyl)-propionylamino]-3-methyl-N-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl)-butyl]-butyramide,

(S)-2-[(S)-3-(4-benzyloxy-phenyl)-2-(biphenyl-3-ylamino)-propionylamino]-3-methyl-N-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl)-butyl]-butyramide,

(R)-2-[(S)-2-(biphenyl-3-ylamino)-3-(3,4,5-trimethoxy-phenyl)-propionylamino]-3-methyl-N-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl)-butyl]-butyramide,

(S)-2-(biphenyl-3-ylamino)-3-(3,4,5-trimethoxy-phenyl)-propionylamino]-3-methyl-N-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl)-butyl]-butyramide,

(S)-2-[(S)-2-(biphenyl-3-ylamino)-3-(3,4,5-trimethoxy-phenyl)-propionylamino]-3-methyl-N-[3-methyl-1-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-butyl]-butyramide,

(S)-2-{(S)-3-(3,4-dimethoxy-phenyl)-2-[2-(3-phenoxy-phenyl)-acetylamino]-propionylamino}-3-methyl-N-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl)-butyl]-butyramide,

(S)-3-methyl-N-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl)-butyl]-2-[(S)-2-[2-(3-phenoxy-phenyl)-acetylamino]-3-(3,4,5-trimethoxy-phenyl)-propionylamino]-butyramide,

(S)-2-{(S)-3-(4-benzyloxy-phenyl)-2-[2-(3-benzyloxy-phenyl)-acetylamino]-propionylamino}-3-methyl-N-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl)-butyl]-butyramide,

(S)-2-[(S)-2-(biphenyl-3-ylamino)-3-(3,4,5-trimethoxy-phenyl)-propionylamino]-4-methyl-pentanoic acid [(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl)-butyl]-amide,

(S)-2-[(S)-2-(biphenyl-3-ylamino)-3-(3,4-dimethoxy-phenyl)-propionylamino]-4-methyl-pentanoic acid [(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl)-butyl]-amide,

(S)-2-[(S)-2-(biphenyl-3-ylamino)-3-(4-methoxy-phenyl)-propionylamino]-4-methyl-pentanoic acid [(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl)-butyl]-amide,

(S)-2-(biphenyl-3-ylamino)-N-{(S)-1-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl)-butylcarbamoyl]-ethyl}-3-(3,4,5-trimethoxy-phenyl)-propionamide,

(S)-2-(biphenyl-3-ylamino)-N-{(S)-1-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl)-butylcarbamoyl]-ethyl}-3-(2,3,4-trimethoxy-phenyl)-propionamide,

(S)-2-(biphenyl-3-ylamino)-3-(4-methoxy-phenyl)-N-{(S)-1-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl)-butylcarbamoyl]-ethyl}-propionamide,

(S)-2-(biphenyl-3-ylamino)-3-(3,4-dimethoxy-phenyl)-N-{(S)-1-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl)-butylcarbamoyl]-ethyl}-propionamide,

(S)-2-(3-isopropyl-phenylamino)-N-{(S)-1-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl)-butylcarbamoyl]-ethyl}-3-(3,4,5-trimethoxy-phenyl)-propionamide,

(S)-N-{(S)-1-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl)-butylcarbamoyl]-ethyl}2-(3-phenyl-propionylamino)-3-(2,3,4-trimethoxy-phenyl)-propionamide,

(S)-2-[(S)-2-(biphenyl-3-ylamino)-3-(3,4,5-trimethoxy-phenyl)-propionylamino]-3-methyl-N-[(R)-2-phenyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl)-ethyl]-butyramide, and

(S)-2-[(S)-2-(biphenyl-3-ylamino)-3-(4-methoxy-phenyl)-propionylamino]-3-methyl-N-[(R)-2-phenyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^2,6]dec-4-yl)-ethyl]-butyramide,

or a pharmaceutically acceptable salt thereof.

11. A compound of formula I according to claim 1 which is (R)-1-{(S)-2-[(S)-2-(biphenyl-3-ylamino)-3-(4-methoxy-phenyl)-propionylamino]-3-methyl-butyrylamino}-3-methyl-butylboronic acid,

or a pharmaceutically acceptable salt thereof.

12. A compound of formula I according to claim 1 which is (R)-1-((S)-2-{(S)-3-(3,4-dimethoxy-phenyl)-2-[2-(3-phenoxy-phenyl)-acetylamino]-propionylamino}-3-methyl-butyrylamino)-3-methyl-butylboronic acid,

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutically acceptable salt of a compound of formula I according to claim 1.

14. A pharmaceutical composition comprising a compound of formula I according to claim 1 or a pharmaceutically acceptable salt of such a compound together with a pharmaceutically acceptable carrier.

15. A pharmaceutical composition for the treatment of a proliferative disease in warm-blooded animals, comprising, in a dose effective against said disease, a compound of formula I according to claim 1, or a pharmaceutically acceptable salt of such a compound, together with a pharmaceutically acceptable carrier, wherein the proliferative disease is selected from, colon tumors, breast tumors, lung tumors and prostate tumor.

16. A method of treating warm-blooded animals, which comprises administering to such a warm-blooded animal suffering from a proliferative disease a therapeutically effective amount of a compound of formula I according to claim 1 or of a pharmaceutically acceptable salt of such a compound, wherein the proliferative disease is selected from, colon tumors, breast tumors, lung tumors and prostate tumor.

17. A process for the preparation of a compound of formula I according to claim 1 or of a salt of such a compound, comprising

a) reacting a dipeptide analogue of the formula II,

wherein R₃, R₄ and R₅ have the meanings as defined in claim 1, with a carbonic acid of the formula III,

or a reactive derivative thereof, wherein R₁ and R₂ have the meanings as defined in claim 1;

b) optionally reacting readily removable protecting groups with functional groups on a compound of formula II and/or III, where the functional groups reacted are not groups participating in the reaction of step a);

c) removing protecting groups from the compound resulting from step b); and

d) optionally converting the resulting compound of formula I into another compound of formula I, converting an obtained free compound of formula I into a salt, converting an obtained salt of a compound of formula I into a different salt or into its free form, and/or separating a mixture of isomeric compounds of formula I into the individual isomers.

18. A process for the preparation of a compound of formula I according to claim 1 or of a salt of such a compound, wherein R₁ is arylalkylcarbonyl or heterocyclylalkylcarbonyl and the other moieties R₂ to R₅ have the meanings as defined in claim 1, comprising

a) reacting an amino compound of the formula IV,

with a carbonic acid of the formula V,

or a reactive derivative thereof, wherein R₁ is arylalkylcarbonyl or heterocyclylalkylcarbonyl;

b) optionally reacting readily removable protecting groups with functional groups on a compound of formula II and/or III, where the functional groups reacted are not groups participating in the reaction of step a);

c) removing protecting groups from the compound resulting from step b); and

d) optionally converting the resulting compound of formula I into another compound of formula I, converting an obtained free compound of formula I into a salt, converting an obtained salt of a compound of formula I into a different salt or into its free form, and/or separating a mixture of isomeric compounds of formula I into the individual isomers.