JP2006504766A5

JP2006504766A5 -

Info

Publication number: JP2006504766A5
Application number: JP2004547637A
Authority: JP
Filing date: 2003-10-30
Publication date: 2006-11-02

Claims

Formula (I):

[Where:
m is an integer from 2 to 8;
n is an integer from 3 to 11, preferably from 3 to 7;
Where m + n is 5-19, preferably 5-12;
R ¹ is -XNR ⁶ C (O) NR ⁷ R ⁸ ; where:
X is - (CH ₂₎ _p - and C _2-6 is selected from alkenylene;
R ⁶ and R ⁸ are independently selected from hydrogen, C _1-6 alkyl and C _3-7 cycloalkyl; wherein the C _1-6 alkyl and C _3-7 cycloalkyl moieties are optionally —CO ₂ Optionally substituted with H or -CO ₂ (C _1-4 ) alkyl;
R ⁷ is selected from hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, —C (O) R ⁹ , phenyl, naphthyl, hetaryl, and phenyl (C _1-4 alkyl)-, and R ⁷ is Optionally independently halo, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, —NHC (O) (C _1-6 alkyl), —SO ₂ (C _1-6 alkyl) Substituted with 1 or 2 groups selected from: —SO ₂ (phenyl), —CO ₂ H, —CO ₂ (C _1-4 alkyl) and CONR ¹⁰ R ¹¹ ;
R ⁹ is selected from C _1-6 alkyl, C _3-7 cycloalkyl, —CO ₂ H, CO ₂ (C _1-4 alkyl), phenyl, naphthyl, hetaryl, and phenyl (C _1-4 alkyl)-. , And R ⁹ is optionally independently halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, —NHC (O) (C _1-6 alkyl), —SO ₂ (C _{1- 6} alkyl), - SO ₂ (phenyl), - CO ₂ H, and substituted with one or two groups selected from -CO ₂ (C _1-4 alkyl);
R ¹⁰ and R ¹¹ are each independently hydrogen, C _1-4 alkyl or C _3-7 cycloalkyl, and
p is an integer from 0 to 6, preferably 0 to 4; or
Or
Via the ring carbon atom adjacent to R ^1, by the phenyl ring and R ⁸ wherein R ¹ is bonded to form a bond, R ¹ is cyclized to form the following moiety:

R ² is selected from hydrogen, C _1-6 alkyl, C _1-6 alkoxy, phenyl, halo, and C _1-6 haloalkyl;
R ³ is selected from hydrogen, hydroxy, C _1-6 alkyl, halo, C _1-6 alkoxy, phenyl, C _1-6 haloalkyl, and —SO ₂ NR ¹² R ¹³ ;
Wherein R ¹² and R ¹³ are independently selected from hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, phenyl, and phenyl (C _1-4 alkyl), or R ¹² and R ¹³ ¹³ together with the nitrogen to which they are attached form a nitrogen-containing 5-, 6-, or 7-membered ring;
And R ¹² and R ¹³ are each optionally substituted with 1 or 2 groups selected from halo, C _1-6 alkyl, and C _1-6 haloalkyl;
R ⁴ and R ⁵ are independently selected from hydrogen and C _1-4 alkyl, provided that the total number of carbon atoms in R ⁴ and R ⁵ is 4 or less;
And Ar ¹ is selected from the following groups:

as well as

Four
Here, R ¹⁴ is hydrogen, halogen,-(CH ₂ ) _q OR ¹⁸ , -NR ¹⁸ C (O) R ¹⁹ , -NR ¹⁸ SO ₂ R ¹⁹ , -SO ₂ NR ¹⁸ R ¹⁹ , -NR ¹⁸ R ¹⁹ -OC (O) R ²⁰ or OC (O) NR ¹⁸ R ¹⁹
And R ¹⁵ is hydrogen, halogen or C _1-4 alkyl; or
Or R ¹⁴ is -NHR ²¹ and R ¹⁵ and -NHR ²¹ together form a 5- or 6-membered heterocycle;
R ¹⁶ is hydrogen, halogen, -OR ¹⁸ or -NR ¹⁸ R ¹⁹ ;
R ¹⁷ is hydrogen, halogen, haloC _1-4 alkyl, —OR ¹⁸ , —NR ¹⁸ R ¹⁹ , —OC (O) R ²⁰ or OC (O) NR ¹⁸ R ¹⁹ ;
R ¹⁸ and R ¹⁹ are each independently hydrogen or C _1-4 alkyl, or in the groups —NR ¹⁸ R ¹⁹ , —SO ₂ NR ¹⁸ R ¹⁹ and —OC (O) NR ¹⁸ R ¹⁹ , R ¹⁸ and R ¹⁹ are independently hydrogen or C _1-4 alkyl, or together with the nitrogen atom to which they are attached, form a nitrogen-containing 5-, 6-, or 7-membered ring;
R ²⁰ is an aryl (eg phenyl or naphthyl) group, which is unsubstituted or substituted by one or more selected from halogen, C _1-4 alkyl, hydroxy, C _1-4 alkoxy or haloC _1-4 alkyl Optionally substituted with a group; and
q is 0 or an integer from 1 to 4;
However, in the group (a), when R ¹⁴ is — (CH ₂ ) _q OR ¹⁸ and q is 1, R ¹⁶ is not OH. ]
Or a salt, solvate or physiologically functional derivative thereof.

R ⁶ and R ⁸ are independently selected from hydrogen, C _1-6 alkyl and C _3-7 cycloalkyl;
R ⁷ is selected from hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, —C (O) R ⁹ , phenyl, naphthyl, hetaryl, and phenyl (C _1-4 alkyl)-, and R ⁷ is Optionally independently halo, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, —NHC (O) (C _1-6 alkyl), —SO ₂ (C _1-6 alkyl) ), -SO ₂ (phenyl), -CO ₂ H, and -CO ₂ (C _1-4 alkyl);
R ¹⁴ is as defined above except that R ¹⁴ is not hydrogen; and all other substituents are as defined in formula (I);
A compound of formula (I) according to claim 1 or a salt, solvate or physiologically functional derivative thereof.

R ¹⁴ is hydrogen, halogen, -NR ¹⁸ C (O) R ¹⁹ , -NR ¹⁸ SO ₂ R ¹⁹ , -SO ₂ NR ¹⁸ R ¹⁹ , -NR ¹⁸ R ¹⁹ , -OC (O) R ²⁰ or OC (O ) NR ¹⁸ R ¹⁹ ; and
R ¹⁶ is hydrogen, halogen, —OR ¹⁸ or —NR ¹⁸ R ¹⁹ ;
The compound according to claim 1 or 2.

R ¹⁴ is hydrogen, halogen,-(CH ₂ ) _q OR ¹⁸ , -NR ¹⁸ C (O) R ¹⁹ , -NR ¹⁸ SO ₂ R ¹⁹ , -SO ₂ NR ¹⁸ R ¹⁹ , -NR ¹⁸ R ¹⁹ , -OC (O) R ²⁰ or OC (O) NR ¹⁸ R ¹⁹ ; and
R ¹⁶ is hydrogen, halogen, or —NR ¹⁸ R ¹⁹ ;
The compound according to claim 1 or 2.

R ¹ is _{_{- (CH 2) p NHC (}} O) compounds of formula (I) according to claim 1 is NHR ^7.

p is 0, 1 or 2, compound of according to any one of claims 1 to 5.

Compounds of formula (I) and salts, solvates and physiologically functional derivatives thereof selected from the following group:
N- [3- (4-{[6-({(2R) -2- [3- (formylamino) -4-hydroxyphenyl] -2-hydroxyethyl} amino) hexyl] oxy} butyl) phenyl] urea ;
N- [3- (4-{[6-({(2R) -2- [3- (formylamino) -4-hydroxyphenyl] -2-hydroxyethyl} amino) hexyl] oxy} butyl) phenyl]- N'-phenylurea;
N- [3- (4-{[6-({(2R) -2- [3- (formylamino) -4-hydroxyphenyl] -2-hydroxyethyl} amino) hexyl] oxy} butyl) phenyl]- N'-pyridin-3-ylurea;
N- [3- (4-{[6-({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) hexyl] oxy} butyl) -5- Methylphenyl] urea.

8. A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, for use in medicine. .

8. A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, a pharmaceutically acceptable carrier. Or a pharmaceutical formulation comprising an excipient and optionally one or more other therapeutic ingredients.

A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof and one or more other treatments. A combination comprising ingredients for use.

11. A combination according to claim 10, wherein the other therapeutic ingredient is a corticosteroid, an anticholinergic or a PDE4 inhibitor.

8. The compound of formula (I) according to any one of claims 1 to 7, or its pharmacy in the manufacture of a medicament for the prevention or treatment of clinical conditions to which a selective β ₂ -adrenergic receptor agonist is indicated. Use of physiologically acceptable salts, solvates, or physiologically functional derivatives.

A process for the preparation of a compound of formula (I) according to any one of claims 1 to 7, or a salt, solvate or physiologically functional derivative thereof:
(a) For example formula (II):

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , m, and n are as defined for the compound of formula (I), Ar ^1a is an optionally protected form of Ar ¹ And P ¹ and P ² are each independently hydrogen or a protecting group (provided that the compound of formula (II) contains at least one protecting group). ]
Deprotection of the protected intermediate represented by: or a salt or solvate thereof;
(b) Formula (IX):

Wherein, Ar ¹ form protected optionally Ar ^1a and P ^2, is either hydrogen or a protecting group. ]
Of the amine of formula (X):

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , m and n are as defined for compounds of formula (I) or formula (Ia) and L ¹ is a leaving group . ]
Alkylation with a compound of
(c) Formula (XII):

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , m, and n are as defined for formula (I), Ar ^1a is optionally protected form of Ar ¹ , and P ¹ And P ² are independently hydrogen or a protecting group as defined above. ]
Reduction of a compound of
(d) Formula (XVI):

[Wherein Ar ^1a is an optionally protected form of Ar ¹ , P ¹ is hydrogen or a protecting group, and L ⁴ is a leaving group as defined for the group LL ³ . ]
Or a compound of formula (XVII):

[Wherein Ar ^1a is as defined above. ]
A compound of formula (XVIII):

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , P ² , m, and n are as defined for formula (II). ]
Reaction with amines; or
(e) Formula (IIa):

[Wherein R ¹ -R ⁵ , m and n are as defined for formula (I), Ar ^1a and P ¹ are as defined for formula (II), each independently hydrogen or protected And R ²⁸ is a chiral auxiliary. ]
Removal of the chiral auxiliary from the compound of
Then the following in any order:
(i) optionally removing the protecting group if present;
(ii) optionally separation of one enantiomer from the enantiomeric mixture;
(iii) optionally conversion of the product into the corresponding salt, solvate or physiologically functional derivative.
The process of;
Including said method.