Cyanoguanidine compounds

• US 6,255,323 B1
• Filed: 04/07/2000
• Issued: 07/03/2001
• Est. Priority Date: 04/09/1999
• Status: Expired due to Fees

• Current Assignee: Synta Pharmaceuticals Corp. (Madrigal Pharmaceuticals, Inc.)
• Original Assignee: Shionogi Bioresearch Corp. (Shionogi & Co., Ltd.)
• Inventors: Zhang, Shijie, Przewloka, Teresa, Liang, Guiqing, Liu, Weimin, Huang, Tai-Nang, Shen, Ming
• Primary Examiner(s): NORTHINGTON DAVIS, ZINNA
• Application Number:
  US09/545,430
• Time in Patent Office: 452 Days
• Field of Search: 546/163, 546/306, 514/313, 514/353
• US Class Current: 514/313
• 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 213/81 Amides; Imides
• CPC Class Codes: C07D 215/38 Nitrogen atoms nitro radicals C07D215/18
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 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

Abstract

A cyanoguanidine compound of the following formula:

is disclosed. A cyanoguanidine compound of the present invention possess a high specificity for tumor cells. Also disclosed are methods for preparing a cyanoguanidine compound.

Claims

1. A compound of the following formula:

wherein

R¹ is 3-pyridyl, 4-pyridyl, or quinolinyl, optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminocarbonyl, alkylsulfonylamino, aminosulfonyl, sulfonic acid, or alkylsulfonyl;

each of R² and R³, independently, is hydrogen, alkyl, alkoxy, hydroxylalkyl, thioalkyl, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylcarbonylamino, or aminocarbonyl;

L¹ is —

X¹—

Y¹—

X²—

in which each of X₁ and X², independently, is a bond, or a C_1-6 alkylene chain optionally containing a double bond or a triple bond and further optionally substituted with alkoxy, hydroxyl, halo, carboxyl, amino, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonylamino, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, formyl, alkylcarbonylamino, or aminocarbonyl; and

Y¹ is —

O—

, —

S—

, —

SO—

, —

SO₂—

, —

N(R^a)—

, —

CO—

, —

N(R^a)—

CO—

, —

CO—

N(R^a)—

, —

N(R^a)—

CO—

CO—

, —

N(R^a)—

SO₂—

, —

SO₂—

N(R^a)—

, —

N(R^a)—

CO—

O—

, —

O—

CO—

N(R^a)—

, —

N(R^a)—

CO—

N(R^b)—

, —

N(R^a)—

CS—

N(R^b)—

CO—

, —

CO—

N(R^a)—

CS—

N(R^b)—

, —

O—

CO—

, —

CO—

O—

, —

O—

SO₂—

, —

SO₂—

O—

, —

O—

S—

CO—

N(R^a)—

, —

N(R^a)—

CO—

S—

O—

, —

O—

CO—

O—

, —

CO—

N(R^a)—

S—

CO—

N(R^b)—

, —

N(R^a)—

CO—

S—

N(R^b)—

CO—

, or a bond;

each of R^a and R^b, independently, being hydrogen, alkyl, alkoxy, hydroxylalkyl, hydroxyl, amino, nitro, cyano, halo, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;

R⁴ is aryl, optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminioalkyl, nitro, cyano, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, formyl, oxo, alkylcarbonylamino, aminocarbonyl, alkylsulfonylamino, aminosulfonyl, sulfonic acid, or alkylsulfonyl;

L² is —

X³—

Y²—

X⁴—

in which each of X³ and X⁴, independently, is a bond, or a C_1-6 alkylene chain optionally containing a double bond or a triple bond and further optionally substituted with alkoxy, hydroxyl, halo, carboxyl, amino, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonylamino, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, formyl, alkylcarbonylamino, or aminocarbonyl; and

Y² is —

O—

, —

S—

, —

SO—

, —

SO₂—

, —

N(R^c), —

CO—

, —

N(R^c)—

CO—

, —

CO—

N(R^c)—

, —

N(R^c)—

CO—

CO—

, —

N(R^c)—

SO₂—

, —

SO₂—

N(R^c)—

, —

N(R^c)—

CO—

O—

, —

O—

CO—

N(R^c)—

, —

N(R^c)—

CO—

N(R^d)—

, —

N(R^c)—

CS—

N(R^d)—

CO—

, —

CO—

N(R^c)—

CS—

N(R^d)—

, —

O—

CO—

, —

CO—

O—

, —

O—

, SO₂—

, —

SO₂—

O—

, —

O—

S—

CO—

N(R^c)—

, —

N(R^c)—

CO—

S—

O—

, —

O—

CO—

O—

, —

CO—

N(R^c)—

S—

CO—

N(R^d)—

, —

N(R^c)—

CO—

S—

N(R^d)—

CO—

or a bond;

each of R^c and R^d, independently, being hydrogen, alkyl, alkoxy, hydroxylalkyl, hydroxyl, amino, nitro, cyano, halo, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; and

R⁵ is cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl, optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, nitro, cyano, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxyalkyl, aryloxycarbonylalkyl, alkylcarbonyl, formyl, oxo, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl, aminocarbonyloxy, or alkyloxycarbonylamino;

provided that each of Y¹ and Y² is not a bond simultaneously; and

that when neither Y¹ nor Y² is a bond, at least one of X², R⁴, and X³ is not a bond;

or an N-oxide derivative or a salt thereof.

2. The compound of claim 1, wherein R¹ is unsubstituted 4-pyridyl.

3. The compound of claim 1, wherein each of R² and R³, independently, is hydrogen.

4. The compound of claim 1, wherein Y¹ is —

SO—

, —

SO₂—

, —

N(R^a)—

CO—

CO—

, —

N(R^a)—

SO₂—

, —

SO₂—

N(R^a)—

, —

N(R^a)—

CO—

N(R^b)—

—

N(R^a)—

CS—

N(R^b)—

CO—

, —

CO—

N(R^a)—

CS—

N(R^b)—

, —

O—

SO₂—

, —

SO₂—

O—

, —

CO—

N(R^a)—

S—

CO—

N(R^b)—

, —

N(R^a)—

CO—

S—

N(R^b)—

CO—

, or a bond.

5. The compound of claim 1, wherein Y² is —

SO—

, —

SO₂—

, —

N(R^a)—

CO—

CO—

, —

N(R^a)—

SO₂—

, —

SO₂—

N(R^a)—

, —

N(R^a)—

CO—

N(R^b)—

, —

N(R^a)—

CS—

N(R^b)—

CO—

, —

CO—

N(R^a)—

CS—

N(R^b)—

, —

O—

SO₂—

, —

SO₂—

O—

, —

CO—

N(R^a)—

S—

CO—

N(R^b)—

, —

N(R^a)—

CO—

S—

N(R^b)—

CO—

, or a bond.

6. The compound of claim 1, wherein neither one of Y¹ and Y² is a bond.

7. The compound of claim 6, wherein R⁵ is phenyl or naphthyl, optionally substituted with alkyl, alkoxy, amino, or halo.

8. The compound of claim 7, wherein R¹ is unsubstituted 4-pyridyl, and each of R² and R³, independently, is hydrogen.

9. The compound of claim 8, wherein X¹ is a C_1-4 alkylene chain, Y¹ is —

O—

, —

S—

, —

O—

CO—

, —

N(R^a)—

, —

N(R^a)—

CO—

, or —

N(R^a)—

CO—

N(R^b)—

, in which each of R^a and R^b, independently, is alkyl, alkylcarbonyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, and X² is a bond.

10. The compound of claim 9, wherein X³ is a C_1-4 alkylene chain, Y² is —

O—

, —

S—

, —

O—

CO—

, —

N(R^c)—

, —

N(R^c)—

CO—

, or —

N(R^c)—

CO—

N(R^d)—

, in which each of R^c and R^d, independently, is alkyl, alkylcarbonyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, and X⁴ is a bond or a C_1-2 alkylene chain optionally substituted with aryl, heteroaryl, aralkyl, or heteroaralkyl.

11. The compound of claim 1, wherein Y¹ is a bond.

12. The compound of claim 11, wherein X¹ is a C_1-2 alkylene chain, and X² is a bond or a C_1-2 alkylene chain.

13. The compound of claim 11, wherein X³ is a bond or a C_1-4 alkylene chain optionally containing a double bond, Y² is —

O—

, —

S—

, —

SO₂—

, —

N(R^c)—

, —

N(R^c)—

CO—

, —

N(R^c)—

CO—

CO—

, —

N(R^c)—

CO—

O—

, —

N(R^c)—

SO₂—

, —

N(R^c)—

CS—

N(R^d)—

CO—

, —

N(R^c)—

CO—

S—

N(R^d)—

CO—

, —

N(R^c)—

CO—

S—

O—

, or —

N(R^c)—

CO—

N(R^d)—

, in which each of R^c and R^d, independently, is alkyl, alkylcarbonyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, and X⁴ is a bond or a C_1-4 alkylene chain optionally substituted with aryl, heteroaryl, aralkyl, or heteroaralkyl.

14. The compound of claim 11, wherein R⁴ is phenyl.

15. The compound of claim 11, wherein R⁵ is aryl or heteroaryl.

16. The compound of claim 15, wherein R⁵ is phenyl, naphthyl, indolyl, or chromanyl, optionally substituted with alkyl, aralkyl, alkylcarbonyloxy, alkyloxycarbonyl, alkoxy, amino, halo, or haloalkyl.

17. The compound of claim 16, wherein R¹ is unsubstituted 4-pyridyl, and each of R² and R³, independently, is hydrogen.

18. The compound of claim 17, wherein X¹ is a C_1-2 alkylene chain, Y¹ is a bond, and X² is a bond or a C_1-2 alkylene chain.

19. The compound of claim 18, wherein X³ is a bond or a C_1-2 alkylene chain optionally containing a double bond, Y² is —

O—

, —

SO₂—

, —

N(R^c)—

SO₂—

, —

N(R^c)—

CO—

, —

N(R^c)—

CO—

N(R^d)—

, or a bond, and X⁴ is a bond or a C_1-2 alkylene chain optionally substituted with aryl, heteroaryl, aralkyl, or heteroaralkyl.

20. The compound of claim 19, wherein R⁵ is phenyl or naphthyl, optionally substituted with alkyl, aralkyl, alkoxy, amino, halo, or haloalkyl.

21. The compound of claim 20, wherein R⁴ is phenyl, X³ is a bond, and Y² is —

N(R^c)—

CO—

or —

N(R^c)—

SO₂—

.

22. The compound of claim 21, where the compound is 5-dimethylamino-naphthalene-1-sulfonic acid (4-(N′

-cyano-″

-pyridin-4-yl-guanidinomethyl)-phenyl)-amide, naphthalene-1-sulfonic acid (4-(N′

-cyano-N″

-pyridin-4-yl-guanidinomethyl)-phenyl)-amide, N-(4-(N′

-cyano-N″

-pyridin-4-yl-guanidino-methyl)-phenyl)-3-trifluoromethyl-benzenesulfonamide, 2,4,6-trimethyl-N-(4-(N′

-cyano-N″

-pyridin-4-yl-guani-dinomethyl)-phenyl)-benzenesulfonamide, or 4-chloro-N-(4-(N′

-cyano-N″

-pyridin-4-yl-guanidinomethyl)-phenyl)-benzenesulfonamide.

23. A compound of the following formula:

wherein

R¹ is 3-pyridyl, 4-pyridyl, or quinolinyl, optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminocarbonyl, alkylsulfonylamino, aminosulfonyl, sulfonic acid, or alkylsulfonyl;

each of R² and R³, independently, is H, alkyl, alkoxy, hydroxylalkyl, thioalkyl, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylcarbonylamino, or aminocarbonyl;

L¹ is —

X¹—

Y¹—

X²—

in which each of X¹ and X², independently, is a bond, or a C_1-6 alkylene chain optionally containing a double bond or a triple bond and further optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, halo, carboxyl, amino, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonylamino, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, formyl, alkylcarbonylamino, or aminocarbonyl; and

Y¹ is —

O—

, —

S—

, —

SO—

, —

SO₂—

, —

N(R^a)—

, —

CO—

, —

N(R^a)—

CO—

, —

CO—

N(R^a)—

, —

N(R^a)—

CO—

CO—

, —

N(R^a)—

SO₂—

, —

SO₂—

N(R_a)—

,—

N(R^a)—

CO—

O—

, —

O—

CO—

N(R^a)—

, —

N(R^a)—

CO—

N(R^b)—

, —

N(R^a)—

CS—

N(R^b)—

CO—

, —

CO—

N(R^a)—

CS—

N(R^b)—

, —

O—

CO—

, —

CO—

O—

, —

O—

SO₂—

, —

SO₂—

O—

, —

O—

S—

CO—

N(R^a)—

, —

N(R^a)—

CO—

S—

O—

, —

O—

CO—

O—

, —

CO—

N(R^a)—

S—

CO—

N(R^b)—

, —

N(R^a)—

CO—

S—

N(R^b)—

CO—

, or a bond;

each of R^a and R^b, independently, being H, alkyl, alkoxy, hydroxylalkyl, hydroxyl, amino, nitro, cyano, halo, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;

R⁴ is a bond, or cycloalkyl, cycloalkenyl, or aryl, optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminioalkyl, nitro, cyano, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, formyl, oxo, alkylcarbonylamino, aminocarbonyl, alkylsulfonylamino, aminosulfonyl, sulfonic acid, or alkylsulfonyl;

L² is —

X³—

Y²—

X⁴—

in which each of X³ and X⁴, independently, is a bond, or a C_1-6 alkylene chain optionally containing a double bond or a triple bond and further optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, halo, carboxyl, amino, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonylamino, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, formyl, alkylcarbonylamino, or aminocarbonyl; and

Y² is —

O—

, —

S—

, —

SO—

, -SO₂—

, —

N(R^c)—

, —

CO—

, —

N(R^c)—

CO—

, —

CO—

N(R^c)—

, —

N(R^c)—

CO—

CO—

, —

N(R^c)—

SO₂—

, —

SO₂—

N(R^c)—

, —

N(R^c)—

CO—

O—

, —

O—

CO—

N(R^c)—

, —

N(R^c)—

CO—

N(R^d)—

, —

N(R^c)—

CS—

N(R^d)—

CO—

, —

CO—

N(R^c)—

CS—

N(R^d)—

, —

O—

CO—

, —

CO—

O—

, —

O—

SO₂—

, —

SO₂—

—

, —

O—

S—

CO—

N(R^c)—

, —

N(R^c)—

CO—

S—

O—

, —

O—

CO—

O—

, —

CO—

N(R^c)—

S—

CO—

N(R^d)—

, —

N(R^c)—

CO—

S—

N(R^d)—

CO—

, or a bond;

each of R^c and R^d, independently, being H, alkyl, alkoxy, hydroxylalkyl, hydroxyl, amino, nitro, cyano, halo, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; and

R⁵ is a cyclic moiety having 12-20 ring atoms, optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, nitro, cyano, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxyalkyl, aryloxycarbonylalkyl, alkylcarbonyl, formyl, oxo, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, aminosulfonyl, aminocarbonyloxy, or alkyloxycarbonylamino;

provided that when neither one of Y¹ and Y² is a bond, at least one of X², R⁴, and X³ is not a bond;

or an N-oxide derivative or a salt thereof.

24. The compound of claim 23, wherein R¹ is unsubstituted 4-pyridyl, and each of R² and R³, independently, is hydrogen.

25. The compound of claim 23, wherein Y¹ is —

SO—

, —

SO₂—

, —

N(R^a)—

CO—

CO—

, —

N(R^a)—

SO₂—

, —

SO₂—

N(R^a)—

, —

N(R^a)—

CO—

N(R^b)—

, —

N(R^a)—

CS—

N(R^b)—

CO—

, —

CO—

N(R^a)—

CS—

N(R^b)—

, —

O—

SO₂—

, —

SO₂—

O—

, —

CO—

N(R^a)—

S—

CO—

N(R^b)—

, —

N(R^a)—

CO—

S—

N(R^b)—

CO—

, or a bond.

26. The compound of claim 23, wherein Y² is —

SO—

, —

SO²—

, —

N(R^a)—

CO—

CO—

, —

N(R^a)—

SO₂—

, —

SO₂—

N(R^a)—

, —

N(R^a)—

CO—

N(R^b)—

, —

N(R^a)—

CS—

N(R^b)—

CO—

, —

CO—

N(R^a)—

CS—

N(R^b)—

, —

O—

SO₂—

, —

SO₂—

O—

, —

CO—

N(R^a)—

S—

CO—

N(R^b)—

, —

N(R^a)—

CO—

S—

N(R^b)—

CO—

, or a bond.

27. The compound of claim 23, wherein R⁵ is optionally substituted with alkyl, aralkyl, alkylcarbonyloxy, alkyloxycarbonyl, alkoxy, amino, halo, or haloalkyl.

28. The compound of claim 27, wherein R¹ is unsubstituted 4-pyridyl, each of R² and R³, independently, is hydrogen.

29. The compound of claim 28, wherein each of X¹ and X², independently, is a bond or a C_1-2 alkylene chain, and Y¹ is a bond.

30. The compound of claim 29, wherein each of X³ and X⁴, independently, is a bond or a C_1-4 alkylene chain, and Y² is —

O—

, —

N(R^c)—

CO—

, —

N(R^c)—

SO₂—

, —

N(R^c)—

CO—

N(R^d)—

, or a bond.

31. The compound of claim 30, wherein R⁵ is fluorenyl, dihydrodibenzoazepine, or dibenzocycloheptenyl.

32. The compound of claim 31, wherein R⁴ is a bond.

33. The compound of claim 32, where the compound is N-(5-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)pentyl)-N′

-cyano-N″

-pyridin-4-yl-guanidine.

34. The compound of claim 28, wherein neither one of Y¹ and Y² is a bond.

35. The compound of claim 34, wherein X¹ is a C_1-4 alkylene chain, Y¹ is —

O—

, —

S—

, —

O—

CO—

, —

N(R^a)—

, —

N(R^a)—

CO—

, or —

N(R^a)—

CO—

N(R^b)—

, in which each of R^a and R^b, independently, is alkyl, alkylcarbonyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, and X² is a bond.

36. The compound of claim 35, wherein X³ is a C_1-4 alkylene chain, Y² is —

O—

, —

S—

, —

O—

CO—

, —

N(R^c)—

, —

N(R^c)—

CO—

, or —

N(R^c)—

CO—

N(R^d)—

, in which each of R^c and R^d, independently, is alkyl, alkylcarbonyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, and X⁴ is a bond or a C_1-2 alkylene chain optionally substituted with aryl, heteroaryl, aralkyl, or heteroaralkyl.

37. The compound of claim 36, wherein R⁴ is a bond.

38. The compound of claim 37, wherein R⁵ is fluorenyl, dihydrodibenzoazepine, or dibenzocycloheptenyl.

39. The compound of claim 38, where the compound is N-{2-[2-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)-ethoxy]-ethyl}-N′

-cyano-N″

-pyridin-4-yl-guanidine or N-[2-(10,11-dihydro-5H-dibenzo[ad]cyclohepten-5-yloxy)-ethyl]-N-[2-(N′

-cyano-N″

-pyridin-4yl-guanidino)-ethyl]-acetamide.