Compounds having β2 adrenergic receptor agonist and muscarinic receptor antagonist activity

• US 7,345,060 B2
• Filed: 11/19/2004
• Issued: 03/18/2008
• Est. Priority Date: 11/21/2003
• Status: Expired due to Fees

• Current Assignee: Theravance Biopharma R&D IP, LLC (Theravance Biopharma, Inc.)
• Original Assignee: Theravance, Inc
• Inventors: Mammen, Mathai, Dunham, Sarah
• Primary Examiner(s): SHIAO, REI TSANG
• Application Number:
  US10/992,927
• Publication Number:
  US 20050113417A1
• Time in Patent Office: 1,215 Days
• Field of Search: 546/202, 546/200, 546/201, 514/323, 514/324, 514/320
• US Class Current: 514/323
• CPC Class Codes: A61K 31/439 the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 277/68 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

The invention is directed to compounds of formula I:

• • wherein R¹, R², R³, R⁴, R⁵, R⁶, R^7a, R^7b, W, G¹, G², a, b, c, d and m are as defined in the specification, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. The invention is also directed to pharmaceutical compositions comprising such compounds; methods of using such compounds; and process and intermediates for preparing such compounds.

Claims

1. A compound of formula I:

2. The compound of claim 1, wherein W represents O.

3. The compound of claim 1, wherein a, b, and c are each 0, and R⁵ is hydrogen.

4. The compound of claim 1, wherein d is 0.

5. The compound of claim 1, wherein d is 1;

and R^7a and R^7b are both hydrogen.

6. The compound of any one of claims 1 to 5, wherein R⁶ is hydrogen.

7. The compound of any one of claims 1 to 5, wherein R⁶ hydroxy.

8. The compound of claim 1, wherein R⁴ is a divalent group of the formula:

—

(R^4a)<sub>d—

where R</sub>^4a is (4-10C)alkylene.

9. The compound of claim 8, wherein R⁴ is —

(CH₂)₄—

, —

(CH₂)₅—

, —

(CH₂)₆—

, —

(CH₂)₇—

, —

(CH₂)₉, or —

(CH₂)₁₀—

.

10. The compound of claim 1, wherein R⁴ is a divalent group of the formula:

—

(R^4a)_d-(A²)_h-(R^4d)_i—

where R^4a is (1-10C)alkylene;

A² is (6-10C)arylene or (2-9C)heteroarylene; and

R^4d is (1-10C)alkylene.

11. The compound of claim 1, wherein R⁴ is a divalent group of the formula:

—

(R^4a)_d-Q-(A²)_h-(R^4d)_i—

where Q is —

O—

or —

N(Q^k)—

;

Q^k is hydrogen or (1-3C)alkyl;

R^4a is (1-10C)alkylene;

A² is (6-10C)arylene or (2-9C)heteroarylene; and

R^4d is (1-10C)alkylene.

12. The compound of claim 1, wherein Q is —

N(Q^a)C(O)—

or —

C(O)N(Q^b)—

.

13. The compound of claim 1, wherein the compound has formula Ia:

14. The compound of claim 13, wherein

a is 0 or an integer of from 1 to 3;

each R¹ is independently selected from the group consisting of (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —

OR^1a, —

C(O)OR^1b, SR^1c, —

S(O)R^1d, —

S(O)₂R^1e, and —

NR^1fR^1g;

each of R^1a, R^1b, R^1c, R^1d, R^1e, R^1f and R^1g is independently hydrogen or (1-4C)alkyl;

b is 0 or an integer of from 1 to 3;

each R² is independently selected from the group consisting of (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —

OR^2a, —

C(O)OR^2b, SR^2c, —

S(O)R^2d, —

S(O)₂R^2e, and —

NR^2fR^2g;

each of R^2a, R^2b, R^2c, R^2d, R^2e, R^2f and R^g is independently hydrogen or (1-4C)alkyl;

W is attached to the 3- or 4-position with respect to the nitrogen atom in the piperidine ring, and represents O or NW^a;

W^a is hydrogen or (1-4C)alkyl;

c is 0 or an integer of from 1 to 4;

each R³ is a substituent on carbon independently selected from the group consisting of (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —

OR^3a, —

C(O)OR^3b, SR^3c, —

S(O)R^3d, —

S(O)₂R^3e, and —

NR^3fR^3g;

each of R^3a, R^3b, R^3c, R^3d, R^3e, R^3f and R^3g is independently hydrogen or (1-4C)alkyl;

R⁴ is a divalent group of the formula;

—

(R^4a)_d-(A¹)_e-(R^4b)_f-Q-(R^4c)_g-(A²)_h-(R^4d)_i—

wherein

d, e, f, g, h and i are each independently selected from 0 and 1;

R^4a, R^b, R^4c and R^4d are each independently selected from the group consisting of (1-10C)alkylene, (2-10C)alkenylene and (2-10C)alkynylene wherein each alkylene, alkenylene or alkynylene group is unsubstituted or substituted with from 1 to 5 substituents independently selected from the group consisting of (1-4C)alkyl, fluoro, hydroxy, phenyl and phenyl(1-4C)-alkyl;

A¹ and A² are each independently selected from (3-7C)cycloalkylene, (6-10C)arylene, (2-9C)heteroarylene and (3-6C)heterocyclene;

wherein each heteroarylene or heterocyclene is selected from piperidinylene, pyridylene, pyrrolidinylene, benzimidazolylene, thienylene, furanylene, and tetrahydrofuranylene;

wherein each cycloalkylene is unsubstituted or substituted with from 1 to 4 substituents selected independently from (1-4C)alkyl and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted with from 1 to 4 substituents independently selected from the group consisting of halogen, (1-4C)alkyl and (1-4C)alkoxy;

Q is selected from a bond, —

O—

, —

C(O)O—

, —

OC(O)—

, —

S—

, —

S(O)—

, —

S(O)₂—

, —

N(Q^a)C(O)—

, —

C(O)N(Q^b)-, —

N(Q^c)S(O)₂—

, —

S(O)₂N(Q^d)-, —

N(Q^e)C(O)N(Q^f)-, —

N(Q^g)S(O)₂N(Q^h)-, —

OC(O)N(Qⁱ)-, —

N(Q^j)C(O)O— and

—

N(Q^k);

Q^a, Q^b, Q^c, Q^d, Q^e, Q^f, Q^g, Q^h, Qⁱ, Q^j and Q^k are each independently selected from the group consisting of hydrogen, (1-6C)alkyl, A³ and (1-4C)alkylene-A⁴;

wherein the alkyl group is unsubstituted or substituted with from 1 to 3 substituents independently selected from fluoro, hydroxy and (1-4C)alkoxy;

A³ and A⁴ are each independently selected from (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroaryl and (3-6C)heterocyclyl;

wherein each heteroaryl or heterocyclyl is selected from piperidinyl, pyridyl, pyrrolidinyl, benzimidazolyl, thienyl, furanyl, and tetrahydrofuranyl;

wherein each cycloalkyl is unsubstituted or substituted with from 1 to 4 substituents selected independently from (1-4C)alkyl and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted with from 1 to 4 substituents independently selected from the group consisting of halogen, (1-4C)alkyl and (1-4C)alkoxy;

provided that the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R⁴ is attached is in the range of from 4 to 14;

R⁵ represents hydrogen or (1-4C)alkyl;

R⁶ represents hydrogen or hydroxyl; and

G¹ represents S;

G¹ represents NH;

or a pharmaceutically-acceptable salt or solvate or stereoisomer thereof.

15. The compound of claim 1, wherein the compound has formula Ib:

16. The compound of claim 1, wherein the compound has formula Ic:

17. The compound of claim 13, 15 or 16, wherein W represents O.

18. The compound of claim 13, 15 or 16, wherein a, b and c are 0.

19. The compound of claim 1, wherein the compound has formula Id:

20. The compound of claim 13, 15, 16 or 19, wherein R⁴ is selected from:

—

(CH₂)₇—

;

—

(CH₂)₈—

;

—

(CH₂)₉—

;

—

(CH₂)₁₀—

;

—

(CH₂)₁₁—

;

—

(CH₂)₂C(O)NH(CH₂)₅—

;

—

(CH₂)₂N(CH₃)C(O)(CH₂)₅—

;

—

(CH₂)₂C(O)NH(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂NHC(O)(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂NHC(O)NH(CH₂)₅—

;

—

(CH₂)₃NHC(O)NH(CH₂)₅—

;

—

(CH₂)₂C(O)NHCH₂(cyclohex-1,3-ylene)CH₂—

;

—

(CH₂)₂NHC(O)(cyclopent-1,3-ylene)-;

—

(CH₂)₂NHC(O)NH(phen-1,4-ylene)(CH₂)₂—

;

1-[—

(CH₂)₂C(O)](piperidin-4-yl)(CH₂)₂—

;

—

(CH₂)₂NHC(O)(trans-cyclohex-1,4-ylene)CH₂—

;

—

(CH₂)₂NHC(O)(cis-cyclopent-1,3-ylene)-;

—

(CH₂)₂NH(phen-1,4-ylene)(CH₂)₂—

;

1-[—

(CH₂)₂NHC(O)](piperidin-4-yl)(CH₂)₂—

;

—

CH₂(phen-1,4-ylene)NH(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂C(O)NHCH₂(phen-1,3-ylene)CH₂—

;

—

(CH₂)₂C(O)NHCH₂(pyrid-2,6-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(cis-cyclohex-1,4-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(trans-cyclohex-1,4-ylene)CH₂—

;

—

(CH₂)₂NHC(O)(cis-cyclopent-1,3-ylene)CH₂—

;

—

(CH₂)₂N(CH₃)C(O)(phen-1,3-ylene)CH₂—

;

—

(CH₂)₂N(CH₃)C(O)(trans-cyclohex-1,4-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(phen-1,4-ylene)C*H(CH₃)—

((S)-isomer);

—

(CH₂)₂C(O)NH(phen-1,4-ylene)C*H(CH₃)—

((R)-isomer);

2-[(S)-(—

CH₂—

](pyrrolidin-1-yl)C(O)(CH₂)₄—

;

2-[(S)-(—

CH₂—

](pyrrolidin-1-yl)C(O)(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(4-chlorophen-1,3-ylene)CH₂—

;

—

CH₂(2-fluorophen-1,3-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(4-methylphen-1,3-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(6-chlorophen-1,3-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(2-chlorophen-1,4-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(2,6-dichlorophen-1,4-ylene)CH₂—

;

—

(CH₂)₂NHC(O)NHCH₂(phen-1,3-ylene)CH₂—

;

4-[—

CH₂—

](piperidin-1-yl)C(O)(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂C(O)N(CH₂CH₃)(phen-1,4-ylene)CH₂—

;

1-[—

(CH₂)₂NHC(O)](piperidin-4-yl)-;

—

(CH₂)₂C(O)NH(phen-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₂NHC(O)(thien-2,5-ylene)CH₂—

;

—

(CH₂)₂N(CH₃)C(O)(3-nitrophen-1,4-ylene)CH₂—

;

—

(CH₂)₂N(CH₃)C(O)(trans-cyclohex-1,4-ylene)-;

1-[—

CH₂(2-fluorophen-1,3-ylene)CH₂](piperidin-4-yl)-;

5-[—

(CH₂)₂NHC(O)](pyrid-2-yl)CH₂—

;

—

(CH₂)₂(phen-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₃(thien-2,5-ylene)(CH₂)₃—

;

—

(CH₂)₂(phen-1,4-ylene)NH(phen-1,4-ylene)(CH₂)₂—

;

—

CH₂(phen-1,2-ylene)NH(phen-1,4-ylene)(CH₂)₂—

;

1-[—

CH₂(2-fluorophen-1,3-ylene)CH₂](piperidin-4-yl)(CH₂)₂—

;

1-[—

CH₂(2-fluorophen-1,3-ylene)CH₂](piperidin-4-yl)CH₂—

;

—

(CH₂)₂C(O)NH(3-chlorophen-1,4-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(2-(CF₃O—

)phen-1,4-ylene)CH₂—

;

—

(CH₂)₃(phen-1,3-ylene)NH(phen-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₂S(O)₂NH(CH₂)₅—

;

—

CH₂(phen-1,3-ylene)NH(phen-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₂C(O)NH(2-iodophen-1,4-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(2-chloro-5-methoxyphen-1,4-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(2-chloro-6-methylphen-1,4-ylene)CH₂—

;

—

(CH₂)₂N(CH₃)S(O)₂(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(2-bromophen-1,4-ylene)CH₂—

;

—

(CH₂)₃(phen-1,4-ylene)NH(phen-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₃(phen-1,2-ylene)NH(phen-1,4-ylene)(CH₂)₂—

;

1-[—

CH₂(2-fluorophen-1,3-ylene)CH₂](piperidin-4-yl)(CH₂)₃—

;

—

(CH₂)₂C(O)NH(2-methoxyphen-1,4-ylene)CH₂—

;

—

(CH₂)₅NH(phen-1,4-ylene)(CH₂)₂—

;

4-[—

(CH₂)₂—

](piperidin-1-yl)(phen-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₂C(O)NH(phen-1,4-ylene)CH(CH₃)CH₂—

;

—

(CH₂)₂-(trans-cyclohex-1,4-ylene)NH(phen-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₂C(O)NH(2-fluorophen-1,4-ylene)CH₂—

;

—

(CH₂)₂(phen-1,3-ylene)NH(phen-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₂C(O)NH(2,5-difluorophen-1,4-ylene)CH₂—

;

—

(CH₂)₂NHC(O)(phen-1,4-ylene)(CH₂)₂—

;

1-[—

CH₂(pyrid-2,6-ylene)CH₂](piperidin-4-yl)CH₂—

;

—

(CH₂)₃NH(phen-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₂NH(naphth-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₃O(phen-1,4-ylene)CH₂—

;

1-[—

(CH₂)₃](piperidin-4-yl)CH₂—

;

4-[—

(CH₂)₂](piperidin-1-yl)C(O)(phen-1,4-ylene)CH₂—

;

—

(CH₂)₃(phen-1,4-ylene)NHC(O)(CH₂)₂—

;

—

(CH₂)₃O(phen-1,4-ylene)(CH₂)₂—

;

2-[—

(CH₂)₂](benzimidazol-5-yl)CH₂—

;

—

(CH₂)₂-(trans-cyclohex-1,4-ylene)NHC(O)(CH₂)₂—

;

—

(CH₂)₂-(trans-cyclohex-1,4-ylene)NHC(O)(CH₂)₄—

;

—

(CH₂)₂-(trans-cyclohex-1,4-ylene)NHC(O)(CH₂)₅—

;

4-[—

(CH₂)₂](piperidin-1-yl)C(O)(CH₂)₂—

;

—

(CH₂)₂NHC(O)NH(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂N(CH₃)(CH₂)₂(cis-cyclohex-1,4-ylene)-;

—

(CH₂)₂C(O)NH(2,3,5,6-tetrafluorophen-1,4-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(2,6-diiodophen-1,4-ylene)CH₂—

;

4-[—

(CH₂)₂](piperidin-1-yl)C(O)(CH₂)₃—

;

4-[—

(CH₂)₂](piperidin-1-yl)C(O)(CH₂)₄—

;

4-[—

(CH₂)₂](piperidin-1-yl)C(O)(CH₂)₅—

;

—

(CH₂)₂C(O)NHCH₂(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂NHC(O)NHCH₂(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(2-methylphen-1,4-ylene)CH₂—

;

1-[—

(CH₂)₃O(phen-1,4-ylene)(CH₂)₂](piperidin-4-yl)CH₂—

;

—

(CH₂)₂C(O)NHCH₂(phen-1,3-ylene)(CH₂)₂—

;

—

(CH₂)₂O(phen-1,3-ylene)CH₂—

;

—

(CH₂)₂N(CH₃)C(O)CH₂O(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂N(CH₃)C(O)CH₂O(phen-1,3-ylene)CH₂—

;

—

(CH₂)₂N(CH₃)C(O)(fur-2,5-ylene)CH₂—

;

—

(CH₂)₂N(CH₃)C(O)(thien-2,5-ylene)CH₂—

;

—

(CH₂)₂O(phen-1,4-ylene)O(CH₂)₂—

;

—

(CH₂)₂(trans-cyclohex-1,4-ylene)NHC(O)(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂(trans-cyclohex-1,4-ylene)NHC(O)CH₂O(phen-1,2-ylene)CH₂—

;

—

(CH₂)₂(trans-cyclohex-1,4-ylene)NHC(O)CH₂O(phen-1,3-ylene)CH₂—

;

—

(CH₂)₂(trans-cyclohex-1,4-ylene)NHC(O)CH₂O(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂(trans-cyclohex-1,4-ylene)NHC(O)(fur-2,5-ylene)CH₂—

;

—

(CH₂)₂(trans-cyclohex-1,4-ylene)NHC(O)(thien-2,5-ylene)CH₂—

;

4-[—

(CH₂)₂](piperidin-1-yl)C(O)CH₂O(phen-1,2-ylene)CH₂—

;

4-[—

(CH₂)₂](piperidin-1-yl)C(O)CH₂O(phen-1,3-ylene)CH₂—

;

4-[—

(CH₂)₂](piperidin-1-yl)C(O)CH₂O(phen-1,4-ylene)CH₂—

;

4-[—

(CH₂)₂](piperidin-1-yl)C(O)(fur-2,5-ylene)CH₂—

;

4-[—

(CH₂)₂](piperidin-1-yl)C(O)(thien-2,5-ylene)CH₂—

;

—

(CH₂)₂(phen-1,4-ylene)NHC(O)(phen-1,3-ylene)CH₂—

;

—

(CH₂)₂(phen-1,4-ylene)NHC(O)(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂(phen-1,4-ylene)NHC(O)CH₂O(phen-1,2-ylene)CH₂—

;

—

(CH₂)₂(phen-1,4-ylene)NHC(O)CH₂O(phen-1,3-ylene)CH₂—

;

—

(CH₂)₂(phen-1,4-ylene)NHC(O)CH₂O(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂(phen-1,4-ylene)NHC(O)(fur-2,5-ylene)CH₂—

;

—

(CH₂)₂(phen-1,4-ylene)NHC(O)(thien-2,5-ylene)CH₂—

;

—

(CH₂)₂(trans-cyclohex-1,4-ylene)NHC(O)(phen-1,3-ylene)CH₂—

;

—

(CH₂)₃O(phen-1,3-ylene)CH₂—

;

—

CH₂CH(OH)CH₂NH(phen-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₄NH(phen-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₂C(O)NH(phen-1,4-ylene)CH₂NHC(O)CH₂—

;

—

(CH₂)₂C(O)NH(phen-1,4-ylene)(CH₂)₂NHC(O)CH₂—

;

—

(CH₂)₂C(O)NHCH₂(trans-cyclohex-1,4-ylene)CH₂—

;

—

(CH₂)₂NHC(O)(CH₂)₅—

;

—

(CH₂)₂O(phen-1,3-ylene)O(CH₂)₂—

;

—

(CH₂)₂O(phen-1,2-ylene)O(CH₂)₂—

;

—

CH₂(phen-1,2-ylene)O(phen-1,2-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(CH₂)₆—

;

—

(CH₂)₃(phen-1,4-ylene)(CH₂)₃—

;

—

(CH₂)₃(phen-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₄(phen-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₃(furan-2,5-ylene)(CH₂)₃—

;

—

(CH₂)₂N(CH₃)C(O)NH(phen-1,4-ylene)(CH₂)₂—

;

4-[—

(CH₂)₂](piperidin-1-yl)C(O)NH(phen-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₃(phen-1,3-ylene)(CH₂)₃—

;

—

(CH₂)₃(tetrahydrofuran-2,5-ylene)(CH₂)₃—

; and

—

(CH₂)₂O(phen-1,4-ylene)C(O)(CH₂)₂—

.

22. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any one of claims 1, 13, 14, 15, 16, 19, or 21.

21. A compound selected from:

biphenyl-2-ylcarbamic acid 1-{9-[2-(4-hydroxy-2-oxo-2,3-dihydrobenzothiazol-7-yl)-ethylamino]nonyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-(4-{[2-(4-hydroxy-2-oxo-2,3-dihydrobenzothiazol-7-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]-piperidin-4-yl ester;

3-[4-(3-biphenyl-2-ylureido)piperidin-1-yl]-N-(4-{[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)ethylamino]methyl}-phenyl)propionamide; and

biphenyl-2-ylcarbamic acid 1-[2-(4-{2-[2-(4-hydroxy-2-oxo-2,3-dihydrobenzothiazol-7-yl)-ethylamino]ethyl}phenylcarbamoyl)ethyl]-piperidin-4-yl ester;

or a pharmaceutically acceptable salt or solvate thereof.