IP Library › Granted Patent US 7,253,158

Granted Patent B2

US 7,253,158 · App. 11/179,703 · Granted Aug 7, 2007

Sulfonamides

Assignee: Hoffmann-La Roche Inc.

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Quick Facts

Patent No.: US 7,253,158
App. No.: 11/179,703
Granted: Aug 7, 2007
Kind: B2

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Abstract

The invention relates to compounds of the general formula in which R 1 , R 2 , R3, R 4 , R 2′ , R3′, R 4′ , R 5 , and X is —CHR— are as defined in the specification. The invention also provides pharmaceutically acceptable acid addition salts, optically pure enantiomers, racemates and diastereomeric mixtures of such compounds. The invention further provides methods for the treatment of Alzheimer's disease or common cancers.

Claims (276)

1. A compound of formula I

wherein

R 1 is aryl or is heteroaryl selected from the group consisting of pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, tetrazolyl, [1,2,4]triazolyl, [1,2,4]oxadiazolyl, oxazolyl, indanyl, benzo[1,3]dioxolyl, benzofuranyl and isoxazolyl, each of which is unsubstituted or substituted by one or more substituents selected from the group consisting of

halogen,

lower alkyl,

lower alkyl substituted by halogen,

—O-lower alkyl substituted by halogen,

NO 2 and

CN;

R 2 , R 3 , R 4 , R 2′ , R 3′ , and R 4′ are each independently lower alkyl, phenyl or lower alkyl substituted by halogen;

R 5 is aryl or is heteroaryl selected from the group consisting of pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, tetrazolyl, [1,2,4]triazolyl, [1,2,4]oxadiazolyl, oxazolyl, indanyl, benzo[1,3]dioxolyl, benzofuranyl and isoxazolyl, each of which is unsubstituted or substituted by one or more substituents selected from the group consisting of

halogen,

lower alkyl,

lower alkoxy,

CN,

nitro,

amino,

hydroxy,

lower alkyl substituted by hydroxy, and

lower alkyl substituted by halogen,

or is aryl or is heteroaryl selected from the group consisting of pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, tetrazolyl, [1,2,4]triazolyl, [1,2,4]oxadiazolyl, oxazolyl, indanyl, benzo[1,3]dioxolyl, benzofuranyl and isoxazolyl, each of which is substituted by

—C(O)—NR″ 2 ,

—(CR 2 ) m —C(O)—R′,

—(CH 2 ) m -heterocycloalkyl wherein heterocycloalkyl is selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl;

—(CH 2 ) m -heteroaryl wherein heteroaryl is selected from the group consisting of pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, tetrazolyl, [1,2,4]triazolyl, [1,2,4]oxadiazolyl, oxazolyl, indanyl, benzo[1,3]dioxolyl, benzofuranyl and isoxazolyl which is unsubstituted or substituted by —(CH 2 ) m -lower alkoxy, lower alkyl, —(CH 2 ) m —O-benzyl or CH 2 OH,

—O—C(O)-lower alkyl,

—O—C(O)—NR 2 ,

—O—(CH 2 ) m —C(O)OH,

—O-lower alkinyl,

—O-lower alkyl substituted by halogen,

—O—(CH 2 ) m -heterocyclyl,

—O—(CH 2 ) m -phenyl which is unsubstituted or substituted by hydroxy,

—O—(CH 2 ) m -heteroaryl wherein heteroaryl is selected from the group consisting of pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, tetrazolyl, [1,2,4]triazolyl, [1,2,4]oxadiazolyl, oxazolyl, indanyl, benzo[1,3]dioxolyl, benzofuranyl and isoxazolyl which is unsubstituted or substituted by lower alkyl,

—(CH 2 ) m —NH—C(O)R′,

—(CH 2 ) m —NH—S(O) 2 —R′,

—S(O) 2 -lower alkyl,

—S(O) 2 -heterocyclyl, or

—S(O) 2 NH-cycloalkyl,

or is cycloalkyl;

R′ is hydrogen,

lower alkyl,

lower alkinyloxy,

hydroxy,

cycloalkyl, heterocycloalkyl selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, which is unsubstituted or substituted by one or more substituents selected from

COOH,

—C(O)O-lower alkyl,

—CH 2 C(O)O-lower alky,

halogen and

lower alkyl,

or is phenyl,

benzyl,

heteroaryl selected from the group consisting of pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, tetrazolyl, [1,2,4]triazolyl, [1,2,4]oxadiazolyl, oxazolyl, indanyl, benzo[1,3]dioxolyl, benzofuranyl and isoxazolyl,

—(CH 2 ) m -lower alkoxy or

—(CHR) m —C(O)O-lower alkyl;

R″ is hydrogen,

cycloalkyl which is unsubstituted or substituted by one or more halogen atoms,

lower alkyl,

lower alkyl substituted by halogen,

lower alkyl substituted by hydroxy,

—(CH 2 ) m -heterocycloalkyl, wherein heterocycloalkyl is selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl,

—NR 2 ,

benzyl or

—(CHR) m —C(O)O-lower alkyl;

R is hydrogen or lower alkyl;

R 6 is hydrogen or lower alkyl;

X is —CHR—; and

m is 0, 1, 2 or 3;

or a pharmaceutically acceptable acid addition salt, optically pure enantiomer, racemate or diastereomeric mixture thereof.

2. A compound of formula II

wherein

R 2 , R 3 , R 4 , R 2′ , R 3′ , and R 4′ are each independently hydrogen, lower alkyl or CF 3 ;

R 5 is cycloalkyl, aryl or heteroaryl selected from the group consisting of pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, tetrazolyl, [1,2,4]triazolyl, [1,2,4]oxadiazolyl, oxazolyl, indanyl, benzo[1,3]dioxolyl, benzofuranyl and isoxazolyl, wherein cycloalkyl, aryl or heteroaryl are unsubstituted or substituted by one or more substituents selected from the group consisting of

halogen,

lower alkyl,

CHO,

CN,

hydroxy,

lower alkyloxy,

lower alkinyloxy,

—OCF 3 ,

OCHF 2 ,

OCH 2 F,

—OC(O)-lower alkyl,

—OC(O)—NR′R″,

—O—(CH 2 ) n -heterocycloalkyl wherein heterocycloalkyl is selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl,

—O—(CH 2 ) n -heteroaryl wherein heteroaryl is selected from the group consisting of pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, tetrazolyl, [1,2,4]triazolyl, [1,2,4]oxadiazolyl, oxazolyl, indanyl, benzo[1,3]dioxolyl, benzofuranyl and isoxazolyl which is unsubstituted or substituted by lower alkyl,

—O—(CH 2 ) n -aryl,

—(CH 2 ) n —C(O)NR′R″,

—(CH 2 ) n —C(O)O-lower alkyl,

—(CH 2 ) n —C(O)OH,

—(CH 2 ) n —C(O)O-lower alkinyl,

—C(O)-heterocycloalkyl wherein heterocycloalkyl is selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl optionally substituted by COOH,

—C(O)-cycloalkyl,

—C(O)-aryl,

—NR′R″,

nitro,

—S(O) 2 -lower alkyl,

—S(O) 2 -cycloalkyl,

—S(O) 2 -heterocycloalkyl wherein heterocycloalkyl is selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl,

—S(O) 2 -aryl, and

—S(O) 2 —NR′R″,

or is

R′ and R″ are each independently hydrogen,

lower alkyl,

cycloalkyl,

heterocycloalkyl selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl,

di-lower alkylamino,

—CH 2 CF 3 ,

—CH 2 CHF 2 ,

—CH 2 CH 2 F,

—C(O)-lower alkyl,

—C(O)O-lower alkyl or

—C(O)-cycloalkyl;

X is a bond, lower alkyl or lower alkenyl; and

n is 0, 1, 2 or 3;

or a pharmaceutically acceptable acid addition salt, optically pure enantiomer, racemate or diastereomeric mixture thereof.

3. A compound of claim 1 , wherein

R 1 is phenyl substituted by halogen and R 5 is phenyl substituted by —C(O)—NR″ 2 .

4. A compound of claim 1 , wherein R 1 is phenyl substituted by halogen or by lower alkyl substituted by halogen and R 5 is phenyl substituted by halogen, by lower alkyl substituted by halogen, by CH 2 OH, or by halogen and lower alkoxy.

5. A compound of claim 1 , wherein R 1 is phenyl substituted by halogen and R 5 is phenyl substituted by —(CR 2 ) m —C(O)—R′ or by —(CR 2 ) m —C(O)—R′ and halogen.

6. A compound of claim 1 , wherein R 1 is phenyl substituted by halogen and R 5 is phenyl substituted by hydroxy.

7. A compound of claim 1 , wherein R 1 is phenyl substituted by halogen and R 5 is phenyl substituted by NH 2 .

8. A ompound of claim 1 , wherein R 1 is heteroaryl, selected from the group consisting of pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, tetrazolyl, [1,2,4]triazolyl, [1,2,4]oxadiazolyl, oxazolyl, indanyl, benzo[1,3]dioxolyl, benzofuranyl and isoxazolyl, unsubstituted or substituted by one or more substituents as described in claim 1 .

9. A compound of claim 1 , wherein X is —CH 2 —.

10. A compound of claim 1 , wherein R 1 is aryl and R 5 is aryl.

11. A pharmaceutical composition comprising a compound of formula I

wherein

halogen,

lower alkyl,

lower alkyl substituted by halogen,

—O-lower alkyl substituted by halogen,

NO 2 , and

CN;

R 2 , R 3 , R 4 , R 2′ , R 3′ , and R 4′ are each independently hydrogen, lower alkyl, phenyl or lower alkyl substituted by halogen;

halogen,

lower alkyl,

lower alkoxy,

CN,

nitro,

amino,

hydroxy,

lower alkyl substituted by hydroxy, and

lower alkyl substituted by halogen,

—C(O)—NR″ 2 ,

—(CR 2 ) m —C(O)—R′,

—(CH 2 ) m -heterocycloalkyl,

—O—C(O)-lower alkyl,

—O—C(O)—NR 2 ,

—O—(CH 2 ) m —C(O)OH,

—O-lower alkinyl,

—O-lower alkyl substituted by halogen,

—O—(CH 2 ) m -heterocyclyl,

—O—(CH 2 ) m -phenyl which is unsubstituted or substituted by hydroxy,

—(CH 2 ) m —NH—C(O)R′,

—(CH 2 ) m —NH—S(O) 2 —R′,

—S(O) 2 -lower alkyl,

—S(O) 2 -heterocyclyl, or

—S(O) 2 NH-cycloalkyl,

or is cycloalkyl;

R′ is hydrogen,

lower alky,

lower alkinyloxy,

hydroxy,

cycloalkyl,

heterocycloalkyl selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, which is unsubstituted or substituted by one or more substituents selected from COOH, —C(O)O-lower alkyl, —CH 2 C(O)O-lower alky, halogen and lower alkyl,

or is phenyl,

benzyl,

—(CH 2 ) m -lower alkoxy or

—(CHR) m —C(O)O-lower alkyl;

R″ is hydrogen,

cycloalkyl, which is unsubstituted or substituted by one or more halogen atoms,

lower alkyl,

lower alkyl substituted by halogen,

lower alkyl substituted by hydroxy,

—NR 2 ,

benzyl or

—(CHR) m —C(O)O-lower alkyl;

R is hydrogen or lower alkyl;

R 6 is hydrogen or lower alkyl;

X is —CHR—; and

m is 0, 1, 2 or 3;

or a pharmaceutically acceptable acid addition salt, optically pure enantiomer, racemate or diastereomeric mixture thereof

and a pharmaceutically acceptable carrier.

12. A process for preparing a compound of formula I

wherein

halogen,

lower alky,

lower alkyl substituted by halogen,

—O-lower alkyl substituted by halogen,

NO 2 and

CN;

R 2 , R 3 , R 4 , R 2′ , R 3′ , and R 4′ are each independently lower alkyl, phenyl or lower alkyl substituted by halogen;

halogen,

lower alkyl,

lower alkoxy,

CN,

nitro,

amino,

hydroxy,

lower alkyl substituted by hydroxy, and

lower alkyl substituted by halogen,

—C(O)—NR′ 2 ,

—(CR 2 ) m —C(O)—R′,

—(CH 2 ) m -heterocycloalkyl,

—(CH 2 ) m -heteroaryl wherein heteroaryl is selected from the group consisting of pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, tetrazolyl, [1,2,4]triazolyl, [1,2,4]oxadiazolyl, oxazolyl, indanyl, benzo[1,3]dioxolyl, benzofuranyl and isoxazolyl, which is unsubstituted or substituted by —(CH 2 ) m -lower alkoxy, lower alkyl, —(CH 2 ) m —O-benzyl or CH 2 OH,

—O—C(O)-lower alkyl,

—O—C(O)—NR 2 ,

—O—(CH 2 ) m —C(O)OH,

—O-lower alkinyl,

—O-lower alkyl substituted by halogen,

—O—(CH 2 ) m -heterocyclyl,

—O—(CH 2 ) m -phenyl which is unsubstituted or substituted by hydroxy,

—O—(CH 2 ) m -heteroaryl wherein heteroaryl is selected from the group consisting of pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, tetrazolyl, [1,2,4]triazolyl, [1,2,4]oxadiazolyl, oxazolyl, indanyl, benzo[1,3]dioxolyl, benzofuranyl and isoxazolyl, which is unsubstituted or substituted by lower alkyl,

—(CH 2 ) m —NH—C(O)R′,

—(CH 2 ) m —NH—S(O) 2 —R′,

—S(O) 2 -lower alkyl,

—S(O) 2 -heterocyclyl, or

—S(O) 2 NH-cycloalkyl,

or is cycloalkyl;

R′ is hydrogen,

lower alkyl,

lower alkinyloxy,

hydroxy,

cycloalkyl,

COOH,

—C(O)O-lower alkyl,

—CH 2 C(O)O-lower alkyl,

halogen and

lower alkyl,

or is phenyl,

benzyl,

—(CH 2 ) m -lower alkoxy or

—(CHR) m —C(O)O-lower alkyl;

R″ is hydrogen,

cycloalkyl, which is unsubstituted or substituted by one or more halogen atoms,

lower alkyl,

lower alkyl substituted by halogen,

lower alkyl substituted by hydroxy,

—NR 2 ,

benzyl or

—(CHR) m —C(O)O-lower alkyl;

R is hydrogen or lower alkyl;

R 6 is hydrogen or lower alkyl;

X is —CHR—; and

m is 0, 1, 2 or 3;

or a pharmaceutically acceptable acid addition salt, optically pure enantiomer, racemate or diastereomeric mixture thereof,

wherein said process is selected from one of the following two processes which comprise

a) reacting a compound of formula

with a compound of formula

R 5 Xhal in the presence of a base, or

with a compound of formula

R 5 XOH in the presence of diethylazodicarboxylate and tripenylphosphine

to produce a compound of formula

wherein R 1 -R 5 and X have the meaning as described in claim 1 , and

b) reacting a compound of formula

with a compound of formula

R 1 —S(O) 2 —Cl in the presence of a base

to produce a compound of formula

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 18, 2005

From: GALLEY, GUIDO; ARGIRIOS KITAS, ERIC; JAKOB-ROETNE, ROLAND

To: F. HOFFMANN-LA ROCHE AG

Reel/Frame 016897/0643 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 18, 2005

From: F. HOFFMANN-LA ROCHE AG

To: HOFFMANN-LA ROCHE INC.

Reel/Frame 016897/0671 →

Priority Claims (1)

EP 04103339 · Jul 13, 2004 · regional

Continuity (1)

Related Publication 20060014945A1 · Jan 19, 2006