4-Amino-5-phenyl-7-cyclohexyl-pyrrolo 2,3-d pyrimidine derivatives

• US 20060058324A1
• Filed: 11/11/2003
• Published: 03/16/2006
• Est. Priority Date: 11/12/2002
• Status: Abandoned Application

• Current Assignee: Carlos Garcia-Echeverria, Hans-Georg Capraro, Pascal Furet
• Original Assignee: Carlos Garcia-Echeverria, Hans-Georg Capraro, Pascal Furet
• Inventors: Furet, Pascal, Garcia-Echeverria, Carlos, Capraro, Hans-Georg
• Application Number:
  US10/534,427
• Publication Number:
  US 20060058324A1
• Time in Patent Office: Days
• US Class Current: 514/265.100
• 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: C07D 487/04 Ortho-condensed systems

Abstract

The invention relates to new 4-amino-5-phenyl-7-cyclohexyl-pyrrolo[2,3-d]pyrimidine derivatives, processes for the preparation thereof, the application thereof in a process for the treatment of the human or animal body, the use thereof, alone or in combination with one or more other pharmaceutically active compounds, for the treatment of a disease, especially a proliferative disease, such as a tumour disease, a method for the treatment of such diseases in mammals, especially in humans, and the use of such a compound, alone or in combination with one or more other pharmaceutically active compounds, for the preparation of a pharmaceutical composition (medicament) for the treatment especially of a proliferative disease, such as a tumour.

Claims

1. A compound of formula I

wherein

n is from 0 to 4,

R₁ is hydrogen, unsubstituted or substituted lower alkyl or halogen,

R₂ is hydroxy;

unsubstituted, mono- or disubstituted amino;

a heterocyclic radical containing at least one nitrogen ring atom and being-attached to the cyclohexane ring of the molecule of formula I via a nitrogen ring atom;

a radical R₅—

(C═

Y)—

NH—

, wherein R₅ is unsubstituted or substituted lower alkyl, unsubstituted, mono- or disubstituted amino, a heterocyclic radical, or etherified hydroxy, and Y is oxygen, sulfur or imino;

or a radical R₆-sulfonylamino, wherein

R₆ is unsubstituted or substituted lower alkyl, unsubstituted, mono- or disubstituted amino or phenyl optionally substituted by lower alkyl, lower alkoxy or nitro,

R₃ is lower alkyl, hydroxy-, amino- or halogen-substituted lower alkyl, hydroxy, cyano, lower alkoxy, lower alkanoyl, lower alkanoyloxy, amino, mono- or di-lower alkylamino, lower alkanoylamino, carboxy, lower alkoxycarbonyl or halogen, wherein the R₃ substituents can be selected independently of one another if n>

1,

R₄ is a radical R₇—

CR₈(R₉)—

, wherein R₇ is cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, pyrrolyl, thienyl or pyridyl, said R₇ substitutents being optionally substituted by one or more radicals selected from lower alkyl and halogen, and R₈ and R₉ are independently of each other hydrogen, lower alkyl or halogen, and

X is selected from —

O—

, —

NH— and

—

S—

,

or a salt thereof.

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

n is from 0 to 4,

R₁ is hydrogen, unsubstituted or substituted lower alkyl or halogen,

R₂ is hydroxy;

unsubstituted, mono- or disubstituted amino;

a heterocyclic radical containing at least one nitrogen ring atom and being attached to the cyclohexane ring of the molecule of formula I via a nitrogen ring atom;

a radical R₅—

(C═

Y)—

NH—

, wherein R₅ is unsubstituted or substituted lower alkyl, unsubstituted, mono- or disubstituted amino, a heterocyclic radical, or etherified hydroxy, and Y is oxygen, sulfur or imino;

or a radical R₆-sulfonylamino, wherein

R₆ is unsubstituted or substituted lower alkyl, unsubstituted, mono- or disubstituted amino or phenyl optionally substituted by lower alkyl, lower alkoxy or nitro,

R₃ is lower alkyl or lower alkoxy, wherein the R₃ substituents can be selected independently of one another if n>

1,

R₄ is a radical R₇—

CR₈(R₉)—

, wherein R₇ is cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, pyrrolyl, thienyl, pyridyl or phenyl substituted by one or more radicals selected from lower alkyl and halogen, and R₈ and R₉ are independently of each other hydrogen, lower alkyl or halogen, and

X is selected from —

O—

, —

NH— and

—

S—

,

or a salt thereof.

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

n is 0,

R₁ is hydrogen, unsubstituted or substituted lower alkyl or halogen,

R₂ is hydroxy;

unsubstituted, mono- or disubstituted amino;

a heterocyclic radical containing at least one nitrogen ring atom and being attached to the cyclohexane ring of the molecule of formula I via a nitrogen ring atom;

a radical R₅—

(C═

Y)—

NH—

, wherein R₅ is unsubstituted or substituted lower alkyl, unsubstituted, mono- or disubstituted amino, a heterocyclic radical, or etherified hydroxy, and Y is oxygen, sulfur or imino;

or a radical R₆-sulfonylamino, wherein

R₆ is unsubstituted or substituted lower alkyl, unsubstituted, mono- or disubstituted amino or phenyl optionally substituted by lower alkyl, lower alkoxy or nitro,

R₄ is benzyl, and

X is selected from —

O—

, —

NH— and

—

S—

,

or a salt thereof.

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

n is 0,

R₁ is hydrogen, unsubstituted or substituted lower alkyl or halogen,

R₂ is hydroxy;

unsubstituted, mono- or disubstituted amino;

a heterocyclic radical having from 4 to 8 ring members and from 1 to 3 heteroatoms whereby at least one heteroatom is nitrogen and the binding of the heterocyclic radical to the cyclohexane ring of the molecule of formula I occurs via a nitrogen ring atom;

a radical R₅—

(C═

Y)—

NH—

, wherein R₅ is lower alkyl, unsubstituted, mono- or disubstituted amino, etherified hydroxy, a heterocyclic radical having from 4 to 8 ring members and from 1 to 3 heteroatoms whereby at least one heteroatom is nitrogen and the binding of the heterocyclic radical occurs via a nitrogen ring atom, lower alkyl substituted by said heterocyclic radical or by one or more radicals selected independently of one another from the group consisting of amino, N-lower alkylamino, N,N-di-lower alkylamino, N-lower alkanoylamino, N,N-di-lower alkanoylamino, hydroxy, lower alkoxy, lower alkoxy-lower alkoxy, lower alkanoyl, lower alkanoyloxy, cyano, nitro, carboxy, lower alkoxycarbonyl, carbamoyl, amidino, guanidino, ureido, mercapto, lower alkylthio and halogen, and Y is oxygen, sulfur or imino;

or a radical R₆-sulfonylamino, wherein R₆ is unsubstituted or substituted lower alkyl, unsubstituted, mono- or disubstituted amino or phenyl optionally substituted by lower alkyl, lower alkoxy or nitro,

R₄ is benzyl, and

X is selected from —

O—

, —

NH— and

—

S—

,

or a salt thereof.

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

n is 0,

R₁ is hydrogen, lower alkyl or halogen,

R₂ is hydroxy;

unsubstituted, mono- or disubstituted amino;

a heterocyclic radical having from 4 to 8 ring members and from 1 to 3 heteroatoms whereby at least one heteroatom is nitrogen and the binding of the heterocyclic radical to the cyclohexane ring of the molecule of formula I occurs via a nitrogen ring atom;

a radical R₅—

(C═

Y)—

NH—

, wherein R₅ is lower alkyl, unsubstituted or monosubstituted amino, etherified hydroxy, or lower alkyl substituted by a heterocyclic radical having from 4 to 8 ring members and from 1 to 3 heteroatoms whereby at least one heteroatom is nitrogen and the binding of the heterocyclic radical occurs via a nitrogen ring atom, and Y is oxygen or imino;

or a radical R₆-sulfonylamino, wherein R₆ is lower alkyl or disubstituted amino,

R₄ is benzyl, and

X is selected from —

O—

, —

NH— and

—

S—

,

or a salt thereof.

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

n is 0,

R₁ is hydrogen, lower alkyl or halogen,

R₂ is hydroxy, amino, N,N-di-lower alkylamino, pyrimidinyl-amino, 1,4,5,6-tetrahydro-pyrimidinyl-amino, 4,5-dihydro-1H-imidazolyl-amino, azetidin-1-yl, pyrrolidin-1-yl, 1-piperidyl, lower alkyl-piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl;

a radical R₅—

(C═

Y)—

NH—

, wherein R₅ is lower alkyl, lower alkoxy, amino, N-lower alkylamino, N-(phenyl-lower alkyl)-amino, N-(lower alkyl-phenyl-lower alkyl)-amino, N-(lower alkoxy-phenyl-lower alkyl)-amino, N-(morpholin-4-yl-lower alkyl)-amino, N-(N′

,N′

-di-lower alkylamino-lower alkyl)-amino, lower alkoxy-lower alkoxy, 1-piperidyl-lower alkyl, morpholin-4-yl-lower alkyl or lower alkyl-piperazin-1-yl-lower alkyl, and Y is oxygen or imino;

or a radical R₆-sulfonylamino, wherein

R₆ is lower alkyl or N,N-di-lower alkylamino,

R₄ is benzyl, and

X is —

O—

,

or a salt thereof.

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

cis-4-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexanol;

trans-4-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexanol;

cis-5-(3-benzyloxy-phenyl)-7-(4-piperidin-1-yl-cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;

trans-5-(3-benzyloxy-phenyl)-7-(4-piperidin-1-yl-cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;

cis-5-(3-benzyloxy-phenyl)-7-(4-pyrrolidin-1-yl-cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;

trans-5-(3-benzyloxy-phenyl)-7-(4-pyrrolidin-1-yl-cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;

cis-5-(3-benzyloxy-phenyl)-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;

trans-5-(3-benzyloxy-phenyl)-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;

cis-5-(3-benzyloxy-phenyl)-7-(4-morpholin-4-y-cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;

trans-5-(3-benzyloxy-phenyl)-7-(4-morpholin-4-yl-cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;

cis-7-(4-azetidin-1-yl-cyclohexyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;

trans-7-(4-azetidin-1-yl-cyclohexyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;

cis-5-(3-benzyloxy-phenyl)-7-(4-thiomorpholin-4-yl-cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;

trans-5-(3-benzyloxy-phenyl)-7-(4-thiomorpholin-4-yl-cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;

trans-5-(3-benzyloxy-phenyl)-7-(4-diethylamino-cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;

cis-7-(4-amino-cyclohexyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;

trans-7-(4-amino-cyclohexyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;

cis-{4-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexyl}-carbamic acid methyl ester;

cis-1-{4-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexyl}-3-methyl-urea;

cis-N-{4-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexyl}-2-piperidin-1-yl-acetamide;

cis-N-{4-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexyl)-2-morpholin-4-yl-acetamide;

cis-N-{4-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexyl}-2-(4-methyl-piperazin-1-yl)-acetamide;

cis-5-(3-benzyloxy-phenyl)-7-[4-(pyrimidin-2-ylamino)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;

cis-5-(3-benzyloxy-phenyl)-7-[4-(1,4,5,6-tetrahydro-pyrimidin-2-ylamino)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;

cis-5-(3-benzyloxy-phenyl)-7-[4-(4,5-dihydro-1H-imidazol-2-ylamino)-cyclohexyl]-7H-pyrrolo[

2,3-d]pyrimidin-4-ylamine;

cis-N-{4-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexyl}-methanesulfonamide;

cis-N-{4-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexyl}-N,N-dimethylaminosulfonamide;

cis-5-(3-benzyloxy-phenyl)-7-(4-dimethylamino-cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;

N-4-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexyl}-acetamide;

cis-1-{4-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexyl}-3-ethyl-urea;

cis-1-{4-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexyl}-3-isopropyl-urea;

cis-1-{4-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexyl}-3-propyl-urea;

cis-1-{4-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexyl}-3-butyl-urea;

cis-1-{4-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexyl}-3-(3-methyl-benzyl)-urea;

cis-1-{4-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexyl}-3-benzyl-urea;

cis-1-{4-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexyl}-3-(4-methoxy-benzyl)-urea;

cis-1-{4-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexyl}-3-tert-butyl-urea;

cis-N-{4-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexyl}-guanidine;

cis-1-{4-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexyl}-3-(2-dimethylamino-ethyl)-urea;

cis-1-{4-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexyl}-3-(2-morpholin-4-yl-ethyl)-urea;

cis-1-{4-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexyl}-3-(3-morpholin-4-yl-propyl)-urea;

cis-{4-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexyl}-carbamic acid 2-methoxy-ethyl ester;

cis-4-[4-amino-5-(3-benzyloxy-phenyl)-6-bromo-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexanol;

trans-4-[4-amino-5-(3-benzyloxy-phenyl)-6-bromo-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexanol;

cis-4-[4-amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexanol;

trans-4-[4-amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclohexanol;

trans-5-(3-benzyloxy-phenyl)-6-methyl-7-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;

trans-5-(3-benzyloxy-phenyl)-7-(4-dimethylamino-cyclohexyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;

trans-5-(3-benzyloxy-phenyl)-7-(4-diethylamino-cyclohexyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;

trans-5-(3-benzyloxy-phenyl)-6-methyl-7-(4-pyrrolidin-1-yl-cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;

trans-5-(3-benzyloxy-phenyl)-6-methyl-7-(4-morpholin-4-yl-cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;

trans-7-(4-azetidin-1-yl-cyclohexyl)-5-(3-benzyloxy-phenyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;

and pharmaceutically acceptable salts thereof.

8. A compound of formula I, or a pharmaceutically acceptable salt thereof, according to claim 1 for use in a method for the treatment of the human or animal body.

9. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, together with at least one pharmaceutically acceptable carrier.

10. A method for the treatment of a disease which responds to an inhibition of IGF-IR-dependent cell proliferation comprising administering a compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof.

11. A method for the treatment of a disease which responds to an inhibition of IGF-IR tyrosine kinase comprising administering a compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof.

12. A process for the preparation of a compound of formula I according to claim 1 or of a salt of such a compound, characterized in that

a) in order to prepare a compound of formula I, in which R₂ is hydroxy, a compound of formula II

wherein n, R₁, R₃, R₄ and X have the meanings as defined for a compound of formula I, is reacted with methanesulfonic acid hydroxy-cyclohexyl ester;

b) in order to prepare a compound of formula I, in which R₂ is amino, a compound of formula II, wherein n, R₁, R₃, R₄ and X have the meanings as defined for a compound of formula I, is reacted in a first step with a compound of formula III

wherein PG is an amino protecting group which is removed in a second step;

c) in order to prepare a compound of formula I, in which R₂ is mono- or disubstituted amino or a heterocyclic radical containing at least one nitrogen ring atom and being attached to the cyclohexane ring of the molecule of formula I via a nitrogen ring atom, a compound of formula IV,

wherein n, R₁, R₃, R₄ and X have the meanings as defined for a compound of formula I and —

O—

Z is a leaving group, is reacted with a compound of the formula R₁₀—

H in which R₁₀ is mono- or disubstituted amino or a heterocyclic radical containing at least one nitrogen ring atom wherein the heterocyclic radical is attached to the hydrogen atom of R₁₀—

H via a nitrogen ring atom;

d) in order to prepare a compound of formula I, in which R₂ is a radical R₅—

(C═

Y)—

NH—

wherein R₅ is unsubstituted or substituted lower alkyl and Y is oxygen, a compound of formula I, in which R₂ is amino, is reacted with a compound of the formula R₅—

(C═

O)-Halogen wherein R₅ is unsubstituted or substituted lower alkyl;

e) in order to prepare a compound of formula I, in which R₂ is a radical R₅—

(C═

Y)—

NH—

wherein R₅ is lower alkyl substituted by a heterocyclic radical containing at least one nitrogen ring atom whereby the binding of the heterocyclic radical to lower alkyl occurs via a nitrogen ring atom, and Y is oxygen, a compound of formula V

wherein n, R₁, R₃, R₄ and X have the meanings as defined for a compound of formula I, is reacted with a compound of the formula R₁₁—

H in which R₁₁ is a heterocyclic radical containing at least one nitrogen ring atom wherein the heterocyclic radical is attached to the hydrogen atom of R₁, —

H via a nitrogen ring atom;

f) in order to prepare a compound of formula I, in which R₂ is a radical R₅—

(C═

Y)—

NH—

wherein R₅ is unsubstituted, mono- or disubstituted amino or a heterocyclic radical containing at least one nitrogen ring atom whereby the binding of the heterocyclic radical occurs via a nitrogen ring atom and Y is oxygen, a compound of formula I, in which R₂ is a radical R₅—

(C═

Y)—

NH—

wherein R₅ is imidazol-1-yl and Y is oxygen, is reacted with a compound of the formula R₅—

H, in which R₅ is unsubstituted, mono- or disubstituted amino, or a heterocyclic radical which contains at least one nitrogen ring atom;

g) in order to prepare a compound of formula I, in which R₂ is a radical R₅—

(C═

Y)—

NH—

wherein R₅ is unsubstituted or monosubstituted amino and Y is oxygen or sulfur, a compound of formula I, in which R₂ is amino, is reacted with a compound of the formula R₁₂—

N═

C═

Y wherein Y is oxygen or sulfur, the radical R₁₂—

NH—

corresponding to unsubstituted or monosubstituted amino R₅;

h) in order to prepare a compound of formula I, in which R₂ is a radical R₅—

(C═

Y)—

NH—

wherein R₅ is lower alkylamino wherein the lower alkyl moiety is substituted by unsubstituted, mono- or disubstituted amino or by a heterocyclic radical containing at least one nitrogen ring atom whereby the binding of the heterocyclic radical to the lower alkyl moiety occurs via a nitrogen ring atom and Y is oxygen or sulfur, a compound of formula VI

wherein Y is oxygen or sulfur and n, R₁, R₃, R₄ and X have the meanings as defined for a compound of formula I, is reacted with a compound of the formula R₁₃—

H, in which R₁₃ is unsubstituted, mono- or disubstituted amino or a heterocyclic radical containing at least one nitrogen ring atom wherein the heterocyclic radical is attached to the hydrogen atom of R₁₃—

H via a nitrogen ring atom;

i) in order to prepare a compound of formula I, in which R₂ is a radical R₅—

(C═

Y)—

NH—

wherein R₅ is etherified hydroxy and Y is oxygen, a compound of formula I, in which R₂ is amino, is reacted with a compound of the formula R₅—

(C═

O)-Halogen wherein R₅ is etherified hydroxy;

j) in order to prepare a compound of formula I, in which R₂ is a radical R₅—

(C═

Y)—

NH—

wherein R₅ is lower alkoxy substituted by unsubstituted, mono- or disubstituted amino or by a heterocyclic radical containing at least one nitrogen ring atom whereby the binding of the heterocyclic radical to the lower alkyl moiety of lower alkoxy occurs via a nitrogen ring atom and Y is oxygen, a compound of formula VII

wherein n, R₁, R₃, R₄ and X have the meanings as defined for a compound of formula I, is reacted with a compound of the formula R₁₄—

H, in which R₁₄ is unsubstituted, mono- or disubstituted amino or a heterocyclic radical containing at least one nitrogen ring atom wherein the heterocyclic radical is attached to the hydrogen atom of R₁₄—

H via a nitrogen ring atom;

k) in order to prepare a compound of formula I, in which R₂ is a radical R₆-sulfonylamino wherein R₆ has the meanings as defined above under formula I, a compound of formula I, in which R₂ is amino, is reacted with R₆-sulfonyl halide;

l) in order to prepare a compound of formula I, in which R₁ is halogen, a compound of formula I, in which R₁ is hydrogen, is reacted with N-halosuccinimide;

m) in order to prepare a compound of formula I, in which R₁ is lower alkyl, a compound of formula I, in which R₁ is halogen, is reacted with tetra(lower alkyl) tin;

n) in order to prepare a compound of formula I, a compound of formula II, wherein n, R₁, R₃, R₄ and X have the meanings as defined for a compound of formula I, is reacted with a compound of formula VIII

wherein R₂ has the meanings as defined for a compound of formula I;

wherein functional groups which are present in the starting compounds of processes a) to n) and are not intended to take part in the reaction, are present in protected form if necessary, and protecting groups that are present are cleaved, wherein said starting compounds may also exist in the form of salts provided that a salt-forming group is present and a reaction in salt form is possible,

and, if so desired, a compound of formula I thus obtained is converted into another compound of formula I, a free compound of formula I is converted into a salt, an obtained salt of a compound of formula I is converted into the free compound or another salt, and/or a mixture of isomeric compounds of formula I is separated into the individual isomers.