# US 7,612,064 B2 · Sulfopyrroles

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- Number: US 7,612,064 B2
- Document ID: US7612064B2
- Status: Granted
- Kind: B2
- Application number: 10/557,664
- Filed: 2004-05-24
- Published: 2007-03-15
- Granted: 2009-11-03
- Earliest claimed: 2003-05-26
- Assignees: Takeda Pharmaceutical Company Limited
- Inventors: Martin Eberle; Philipp Ermert; Daniel Obrecht; Frank Lach; Anatol Luther; Felix Bachmann; Allessandro Strebel
- Web page: https://patentgrep.com/patent/US7612064B2

## CPC

- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 7/06: Antianaemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 17/14: for baldness or alopecia
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/16: Otologicals
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 207/48: Sulfur atoms
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/14: containing three or more hetero rings
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention relates to compounds of formula (I) wherein R1 represents aryl, aralkyl or heteroaryl, R2 is aryl or heteroaryl and R3 is aryl, heteroaryl or optionally substituted aminomethyl, to methods of synthesis of such compounds, to pharmaceutical compositions containing compounds of formula (I), to the use of a compounds of formula (I) for the preparation of a pharmaceutical composition for the treatment of neoplastic and autoimmune diseases, and to methods of treatment of neoplastic and autoimmune diseases using compounds of formula (I) or of pharmaceutical compositions containing same.

## Claims

### Claim 1

A compound of formula (I)
wherein
R1 represents C5-10 aryl, C5-10 aryl-C1-4 alkyl, C5-10 aryl-C2-4 alkenyl or 5 or 6-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from at least one of nitrogen, sulfur, and oxygen, wherein the aryl and the heteroaryl may be substituted by one to five substituents independently selected from C1-4 alkyl, halo-C1-4 alkyl, C1-4 alkoxy, di C1-7 alkylamino, halogen, and nitro;
and wherein two adjacent substituents together with atoms of the aryl or the heteroaryl may form a 5 membered heterocyclic ring containing at least one oxygen atom;
R2 is C5-10 aryl or 5 or 6-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from at least one of nitrogen, sulfur, and oxygen, wherein the aryl or the heteroaryl may be substituted by one to five substituents independently selected from
C1-4 alkyl, C1-4 alkoxy, and halogen;
and wherein two adjacent substituents together with atoms of the aryl or the heteroaryl may form a 5 membered heterocyclic ring containing two oxygen atoms;
R3 represents a group CH2NR6R7;
R6 represents hydrogen, C1-7 alkyl, phenyl-C1-4 alkyl optionally substituted by C1-4 alkoxy, or amino-C1-7 alkyl, wherein a nitrogen of the amino-C1-7 alkyl can be substituted by up to two substituents selected from C1-4 alkyl;
C5-10 aryl substituted by one substituent selected from 5 or 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from at least one of nitrogen, sulfur, and oxygen, heterocyclyl containing 4-10 atoms compromising 1, 2, or 3 heteroatoms selected from at least one of nitrogen, sulfur, and oxygen, and a sulfamoyl group SO2NR4R5, wherein said substituent on the aryl may be directly linked or linked via a spacer selected from C1-4 alkylidene; and optionally one or two further substituents selected from C1-4 alkyl;
C5-10 aryl substituted by cyano; or
5 or 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from at least one of nitrogen, sulfur, and oxygen;
R4 represents hydrogen;
R5 represents hydrogen; and
R7 represents hydrogen, C1-4 alkyl, or C1-4 alkylcarbonyl;
or salts thereof.

### Claim 2 (depends on 1)

A compound of formula (I) according to claim 1, wherein
R1 represents C5-10 aryl or 5 or 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from at least one of nitrogen, sulfur, and oxygen, wherein the aryl and the heteroaryl may be substituted by one to five substituents independently selected from C1-4 alkyl, halo-C1-4 alkyl, C1-4 alkoxy, di C1-7 alkylamino, halogen, and nitro;
R2 is C5-10 aryl or 5 or 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from at least one of nitrogen, sulfur, and oxygen, wherein the aryl or the heteroaryl may be substituted by one to five substituents independently selected from C1-4 alkyl, C1-4 alkoxy, and halogen;
and wherein two adjacent substituents together with atoms of the aryl or the heteroaryl may form a 5membered heterocyclic ring containing two oxygen atoms;
R3 represents a group CH2NR6R7;
R6 represents hydrogen, C1-7 alkyl, phenyl-C1-4 alkyl optionally substituted by C1-4 alkoxy, or amino-C1-7 alkyl, wherein a nitrogen of the amino-C1-7 alkyl can be substituted by up to two substituents selected from C1-4 alkyl; or
C5-10 aryl substituted by one substituent selected from 5 or 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from at least one of nitrogen, sulfur, and oxygen, heterocyclyl containing 4-10 atoms comprising 1, 2, or 3 heteroatoms selected from at least one of nitrogen, sulfur, and oxygen, and a sulfamoyl group SO2NR4R5, wherein said substituent on the aryl may be directly linked or linked via a spacer selected from C1-4 alkylidene; and optionally one or two further substituents selected from C1-4 alkyl, or
C5-10 aryl substituted by cyano; or
5 or 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from at least one of nitrogen, sulfur, and oxygen;
R4 represents hydrogen;
R5 represents hydrogen; and
R7 represents hydrogen, C1-4 alkyl, or C1-4 alkylcarbonyl;
or salts thereof.

### Claim 3 (depends on 1)

A compound of formula (I) according to claim 1, wherein
R1 represents C5-10 aryl or 5 or 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from at least one of nitrogen, sulfur, and oxygen, wherein the aryl and the heteroaryl may be substituted by one to five substituents independently selected from C1-4 alkyl, halo-C1-4 alkyl, C1-4 alkoxy, di C1-7 alkylamino, and halogen;
R2 is C5-10 aryl or 5 or 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from at least one of nitrogen, sulfur, and oxygen, wherein the aryl or the heteroaryl may be substituted by one to five substituents independently selected from
C1-4 alkyl, C1-4 alkoxy, and halogen;
and wherein two adjacent substituents together with atoms of the aryl or the heteroaryl may form a 5 membered heterocyclic ring containing two oxygen atoms;
R3 represents a group CH2NR6R7;
R6 represents hydrogen, C1-7 alkyl, phenyl-C1-4 alkyl optionally substituted by C1-4 alkoxy, or amino-C1-7 alkyl, wherein a nitrogen of the amino-C1-7 alkyl can be substituted by up to two substituents selected from C1-4 alkyl; or
phenyl substituted by one substituent selected from 5 or 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from at least one of nitrogen, sulfur, and oxygen, heterocyclyl containing 4-10 atoms comprising 1, 2 or 3 heteroatoms selected from at least one of nitrogen, sulfur, and oxygen, and a sulfamoyl group SO2NR4R5, wherein said substituent on the phenyl may be directly linked or linked via a spacer selected from C1-4 alkylidene; and optionally one or two further substituents selected from C1-4 alkyl; or
phenyl substituted by cyano; or
pyridyl;
R4 represents hydrogen;
R5 represents hydrogen; and
R7 represents hydrogen, C1-4 alkyl, or C1-4 alkylcarbonyl;
or salts thereof.

### Claim 4 (depends on 1)

A compound of formula (I) according to claim 1, wherein
R1 represents C5-10 aryl or 5 or 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from at least one of nitrogen, sulfur, and oxygen, wherein the aryl and the heteroaryl may be substituted by one to five substituents independently selected from C1-4 alkyl, halo-C1-4 alkyl, C1-4 alkoxy, di C1-7 alkylamino, and halogen;
R2 is C5-10 aryl or 5 or 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from at least one of nitrogen, sulfur, and oxygen, wherein the aryl or the heteroaryl may be substituted by one to five substituents independently selected from
C1-4 alkyl, and halogen;
and wherein two adjacent substituents together with atoms of the aryl or the heteroaryl may form a 5 membered heterocyclic ring containing two oxygen atoms;
R3 represents a group CH2NR6R7;
R6 represents hydrogen, C1-4 alkyl, or amino-C1-7 alkyl, wherein a nitrogen of the amino-C1-7 alkyl can be substituted by up to two substituents selected from C1-4 alkyl; or
phenyl substituted by one substituent selected from 5 or 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from at least one of nitrogen, sulfur, and oxygen, heterocyclyl containing 4-10 atoms comprising 1, 2 or 3 heteroatoms selected from at least one of nitrogen, sulfur, and oxygen, and a sulfamoyl group SO2NR4R5, wherein said substituent on the phenyl may be directly linked or linked via a spacer selected from C1-4 alkylidene; and optionally one or two further substituents selected from C1-4 alkyl; or
phenyl substituted by cyano; or
pyridyl;
R4 represents hydrogen;
R5 represents hydrogen; and
R7 represents hydrogen, C1-4 alkyl;
or salts thereof.

### Claim 5 (depends on 1)

A compound of formula (I) according to claim 1, wherein
R1 represents phenyl substituted by up to two substituents independently selected from C1-4 alkyl, C1-4 alkoxy, and halogen;
R2 is C5-10 aryl optionally substituted by one to three substituents independently selected from C1-4 alkyl, and halogen;
and wherein two adjacent substituents together with atoms of the aryl may form a 5 membered heterocyclic ring containing two oxygen atoms;
R3 represents a group CH2NR6R7;
R6 represents phenyl substituted by one substituent selected from 5 or 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from at least one of nitrogen, sulfur, and oxygen heterocyclyl containing 4-10 atoms comprising 1, 2 or 3 heteroatoms selected from at least one of nitrogen, sulfur, and oxygen, and a sulfamoyl group SO2NR4R5, wherein said substituent on the phenyl may be directly linked or linked via a spacer selected from C1-4 alkylidene; or
pyridyl;
R4 represents hydrogen;
R5 represents hydrogen; and
R7 represents hydrogen or C1-4 alkyl;
or salts thereof.

### Claim 6 (depends on 1)

A compound of formula (I) according to claim 1 selected from the group consisting of
(p-1-imidazolylphenyl)-(1-[p-toluenesulfonyl]-2-[3,4,5-trimethoxyphenyl]-4-pyrrolylmethyl)-amine;
(p-1,2,4-triazolylphenyl)-(1-[p-toluenesulfonyl]-2-[3,4,5-trimethoxyphenyl]-4-pyrrolylmethyl)-amine;
(p-morpholinophenyl)-(1-[p-toluenesulfonyl]-2-[3,4,5-trimethoxyphenyl]-4-pyrrolylmethyl)-amine; and
(p-morpholinophenyl)-(1-[p-toluenesulfonyl]-2-[3,4,5-trimethoxyphenyl]-4-pyrrolylmethyl)-amine.

### Claim 7 (depends on 1)

A compound of formula (I) according to claim 1 selected from the group consisting of
(p-1-imidazolylphenyl)-(1-[p-toluenesulfonyl]-2-[3,4,5-trimethoxyphenyl]-4-pyrrolylmethyl)-amine; and
(p-morpholinophenyl)-(1[p-methoxyphenyl]-2-[3,4,5-trimethoxyphenyl]-4-pyrrolylmethyl)-amine.

### Claim 8 (depends on 1)

The compound of formula (I) according to claim 1 which is (p-1-imidazolylphenyl)-(1-[p-toluenesulfonyl]-2-[3,4,5-trimethoxyphenyl]-4-pyrrolylmethyl)-amine.

### Claim 9 (depends on 1)

A pharmaceutical composition comprising a compound of formula (I) according to claim 1 and a pharmaceutically acceptable carrier.