Aryl aniline beta2 adrenergic receptor agonists

• US 20030229058A1
• Filed: 05/08/2003
• Published: 12/11/2003
• Est. Priority Date: 11/13/2001
• Status: Abandoned Application

• Current Assignee: Theravance Biopharma R&D IP, LLC (Theravance Biopharma, Inc.)
• Original Assignee: Theravance Biopharma R&D IP, LLC (Theravance Biopharma, Inc.)
• Inventors: Nodwell, Matthew B., Moran, Edmund J., Leadbetter, Michael R., Church, Timothy J., Jacobsen, John R., Trapp, Sean G., Aggen, James
• Application Number:
  US10/431,762
• Publication Number:
  US 20030229058A1
• Time in Patent Office: Days
• US Class Current: 514/171
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/136 having the amino group directly attached to the aromatic ring, e.g. benzeneamine
• CPC Class Codes: A61K 31/277 having a ring, e.g. verapamil
• CPC Class Codes: A61K 31/325 Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof thiurams A61K31/145
• CPC Class Codes: A61K 31/33 Heterocyclic compounds
• CPC Class Codes: A61K 31/343 condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• CPC Class Codes: A61K 31/35 having six-membered rings with one oxygen as the only ring hetero atom
• CPC Class Codes: A61K 31/36 Compounds containing methylenedioxyphenyl groups, e.g. sesamin
• CPC Class Codes: A61K 31/381 having five-membered rings
• CPC Class Codes: A61K 31/385 having two or more sulfur atoms in the same ring
• CPC Class Codes: A61K 31/405 Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/423 condensed with carbocyclic rings
• CPC Class Codes: A61K 31/428 condensed with carbocyclic rings
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/4704 2-Quinolinones, e.g. carbostyril
• CPC Class Codes: A61K 31/4706 4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 : Antiasthmatics
• CPC Class Codes: C07C 213/04 : by reaction of ammonia or amines with olefin oxides or halohydrins
• CPC Class Codes: C07C 215/34 : containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton and at least one hydroxy group bound to another carbon atom of the carbon skeleton
• CPC Class Codes: C07C 215/60 : the chain having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
• CPC Class Codes: C07C 217/84 : the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
• CPC Class Codes: C07C 229/38 : having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
• CPC Class Codes: C07C 233/43 : having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
• CPC Class Codes: C07C 317/36 : with the nitrogen atoms of the amino groups bound to hydrogen atoms or to carbon atoms
• CPC Class Codes: C07D 213/75 : Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 215/227 : only one oxygen atom which is attached in position 2
• CPC Class Codes: C07D 215/26 : Alcohols; Ethers thereof
• CPC Class Codes: C07D 231/22 : with aryl radicals attached to ring nitrogen atoms
• CPC Class Codes: C07D 239/38 : One sulfur atom
• CPC Class Codes: C07D 239/42 : One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 239/47 : One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
• CPC Class Codes: C07D 239/69 : Benzenesulfonamido-pyrimidines
• CPC Class Codes: C07D 277/46 : by carboxylic acids, or sulfur or nitrogen analogues thereof
• CPC Class Codes: C07D 311/80 : Dibenzopyrans; Hydrogenated dibenzopyrans
• CPC Class Codes: C07D 321/10 : condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links

Abstract

The invention provides novel β₂ adrenergic receptor agonist compounds of formula (I):

wherein R₁-R¹³ and w have any of the values described in the specification. The invention also provides combinations of such compounds and other therapeutic agents, pharmaceutical compositions comprising such compounds and combinations, methods of using such compounds to treat diseases associated with β₂ adrenergic receptor activity, and processes and intermediates useful for preparing such compounds.

Claims

1. A combination comprising a compound of formula (I):

2. The combination of claim 1 wherein

R⁶, R⁸, and R¹⁰ are each hydrogen;

and

w is 0, 1, or 2.

3. The combination of claim 1 wherein

each of R¹-R⁴ is independently selected from the group consisting of hydrogen, fluoro, chloro, amino, hydroxy, N,N-dimethylaminocarbonyloxy, —

CH₂OH, and —

NHCHO, and R⁵ is hydrogen;

or

R¹ is hydrogen, R² is hydrogen, R³ is hydroxy, and R⁴ and R⁵ together are —

NHC(═

O)CH═

CH—

or —

SC(═

O)NH—

.

4. The combination of claim 1 wherein each of R¹-R⁵ is independently selected from the group consisting of hydrogen, alkyl, and R^a;

wherein each R^a is independently —

OR^d, halo, —

NR^dR^e, —

NR^dC(═

O)RC, or —

OC(═

O)NR^dR^e;

or R¹ and R², or R⁴ and R⁵, are joined together to form a group selected from the group consisting of —

C(R^d)═

C(R^d)C(═

O)NR^d—

, —

CR^dR^d—

CR^dR^d—

C(═

O)NR^d—

, —

NR^dC(═

O)C(R^d)═

C(R^d)—

, —

NR^dC(═

O)CR^dR^d—

CR^dR^d—

, —

NR^dC(═

O)S—

, and —

SC(═

O)NR^d—

;

R⁶, R⁸, and R¹⁰ are each hydrogen;

each of R¹¹ and R¹² is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —

NO₂, halo, —

NR^dR^e, —

CO₂R^d, —

OC(═

O)R^d, —

CN, —

C(═

O)NR^dR^e, —

NR^dC(═

O)R^e, —

OR^d, —

S(O)_mR^d, —

NR^d—

NR^d—

C(═

O)R^d, —

NR^d—

N═

CR^dR^d, N(NR^dR^e)R^d, and —

S(O)₂NR^dR^e;

wherein for R¹-R⁵, R¹¹, and R¹², each alkyl is optionally substituted with R^m, or with 1, 2, 3, or 4 substituents independently selected from R^b;

for R¹¹ and R¹², each aryl and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^c, and for R¹¹ and R¹², each cycloalkyl and heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^b and R^c;

R¹³ is hydrogen;

the group comprising —

NR¹⁰ is meta or para to the group comprising R⁷; and

w is 0, 1, or 2.

5. The combination of claim 4 wherein each of R¹¹ and R¹² is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, —

OR^d, —

S(O)_mR^d, and —

S(O)₂NR^dR^e;

wherein each alkyl is optionally substituted with 1 or 2 substituents independently selected from R^b, each aryl is optionally substituted with 1 or 2 substituents independently selected from R^c, and each heterocyclyl is optionally substituted with 1 or 2 substituents independently selected from R^b and R^c; and

m is 0 or 2.

16. A pharmaceutical composition comprising a therapeutically effective amount of a combination of claim 1 and a pharmaceutically-acceptable carrier.

17. The pharmaceutical composition of claim 16, wherein the composition is formulated for administration by inhalation.

20. A method of treating a disease or condition in a mammal associated with β

₂ adrenergic receptor activity, the method comprising administering to the mammal, a therapeutically effective amount of a pharmaceutical composition comprising a combination of claim 1 and a pharmaceutically-acceptable carrier.

21. The method of claim 20 wherein the disease or condition is a pulmonary disease.

22. The method of claim 21 wherein the pulmonary disease is asthma or chronic obstructive pulmonary disease.

6. A combination of a compound of formula (IIa):

7. The combination of claim 6 wherein R¹¹ is phenyl, optionally substituted with 1 substituent selected from halo, —

OR^d, —

CN, —

NO₂, —

SO₂R^d, C(═

O)R^d, and C_1-3alkyl, wherein C_1-3alkyl is optionally substituted with 1 or 2 substituents selected from carboxy, hydroxy, and amino, and R^d is hydrogen or C_1-3alkyl.

8. The combination of claim 6 wherein R¹¹ is pyridyl, thiophenyl, furanyl, pyrrolyl, isoxazolyl, or indolyl, each of which is optionally substituted with 1 or 2 C_1-3alkyl substituents.

9. The combination of claim 6 wherein R¹¹ is phenyl, pyridyl, or thiophenyl, wherein each phenyl is optionally substituted with 1 substituent selected from the group consisting of chloro, —

OCH₃, —

CN, and —

CH₂NH₂; and

R¹² is hydrogen, —

OCH₃, or —

OC₂H₅.

10. The combination of claim 9 wherein R⁴ and R⁵ taken together are —

NHC(═

O)CH═

CH—

;

R¹¹ is phenyl or pyridyl, wherein each phenyl is optionally substituted with 1 substituent selected from the group consisting of chloro, —

OCH₃, —

CN, and —

CH₂NH₂; and

R¹² is —

OCH₃.

11. The combination of claim 6 wherein the compound of formula (IIa) is a mixture of stereosiomers wherein the amount of the stereoisomer having the (R) orientation at the chiral center to which the hydroxy group is attached is greater than the amount of the stereoisomer having the (S) orientation at the chiral center to which the hydroxy group is attached.

12. The combination of claim 6 wherein the compound of formula (IIa) is the stereoisomer having the (R) orientation at the chiral center to which the hydroxy group is attached.

13. The combination of claim 6 wherein the compound of formula (IIa) is selected from the group consisting of:

N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;

N-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;

N-{2-[4-(3-phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;

N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

N-{2-[4-(4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;

N-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;

N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;

N-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;

N-{2-[4-(3-phenylphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;

N-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;

N-{2-[4-(4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;

N-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

N-{2-[4-(3-phenylphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

N-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

N-{2-[4-(4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

N-{2-[4-(3-(2-chlorophenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

N-{2-[4-(3-(2-methoxyphenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

N-{2-[4-(3-(3-cyanophenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

N-{2-[4-(3-(4-aminomethylphenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

N-{2-[4-(3-(3-chlorophenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

N-{2-[4-(3-(4-aminomethylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

N-{2-[4-(3-(3-cyanophenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

N-{2-[4-(3-(4-hydroxyphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

N-{2-[4-(3-(3-pyridyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

N-{2-[4-(3-(3-pyridyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

N-{2-[4-(3-(4-pyridyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

N-{2-[4-(3-(thiophen-3-yl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine; and

N-{2-[4-(3-(3-chlorophenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

N-{2-[4-(3-(3-aminomethylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

and pharmaceutically-acceptable salts or solvates thereof.

14. The combination of claim 6 wherein the compound of formula (1Ha) is selected from the group consisting of:

N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

N-{2-[4-(3-(4-aminomethylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

N-{2-[4-(3-(3-cyanophenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

N-{2-[4-(3-(3-chlorophenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

N-{2-[4-(3-(3-aminomethylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;

and pharmaceutically-acceptable salts or solvates thereof.

15. The combination of claim 14 wherein the corticosteroid is 6(x,9α

-difluoro-17α

-[(2-furanylcarbonyl)oxy]-11β

-hydroxy-16α

-methyl-3-oxo-androsta-1,4-diene-17β

-carbothioic acid S-fluoromethyl ester.

18. A pharmaceutical composition comprising a therapeutically effective amount of a combination of claim 6 and a pharmaceutically-acceptable carrier.

19. The pharmaceutical composition of claim 18, wherein the composition is formulated for administration by inhalation.

23. A method of treating a disease or condition in a mammal associated with β

₂ adrenergic receptor activity, the method comprising administering to the mammal, a therapeutically effective amount of a pharmaceutical composition comprising a combination of claim 6 and a pharmaceutically-acceptable carrier.

24. The method of claim 23 wherein the disease or condition is a pulmonary disease.

25. The method of claim 24 wherein the pulmonary disease is asthma or chronic obstructive pulmonary disease.