CN1028755C - Azole derivate, manufacturing method and application thereof - Google Patents

Abstract

The pyrrole derivative in formula (I) is a receptor antagonist of an effective hypertension, wherein, the meanings of A, L, O, R1, X, Y, Z and q could be seen in the description, which contains explanations about the preparation method, pharmaceutical preparation and the application of the compounds.

Description

Azole derivate, manufacturing method and application thereof

Develop new Angiotensin and be subjected to increasing attention.As the imdazole derivatives that in EP-A-28834, replaces for the 1-benzene toluene, EP-A-253310 and EP-A-0401030 are the imdazole derivatives with a diaryl-carboxylic functional group, EP-A-323841 is pyrazoles and triazole derivative, EP-A-0409332 also is a triazole derivative, all have the diaryl-carboxylic functional group, EP-A-324377 is the imdazole derivatives that has the diaryl tetrazol group.They all are known because of using as the Hangzhoupro short of money agent of angiotensin-ii-receptor.

In addition, (corresponding US application number 07/679,233) is loaded with substituted azole in DE-A4010797.Wherein contain the sulfonylurea group.

As new a new alkylsulfonyl urea groups, sulphonyl mephenesin Carbamate base are arranged, or the azole derivative of alkylsulfonyl sulfahydantoin structure invented, it all has the antagonistic action of very high angiotensin-ii-receptor in external and body.

The present invention relates to formula I compound and pharmaceutical salts thereof,

The following meaning of symbol tool wherein:

A) X, Y and Z are identical or different, are N or CR ²,

B) R ¹Be 1.(2-10 carbon) alkyl,

2.(3-10 thiazolinyl carbon).

3.(3-10 alkynyl carbon),

4.-OR ³，

5.(3-8 cycloalkyl carbon),

6.(4-10 cycloalkylalkyl carbon),

7.(5-10 cycloalkyl thiazolinyl carbon),

8.(5-10 cycloalkyl alkynyl carbon),

9.-（CH ₂）m-B-（CH ₂）n-R ⁴，

10. phenmethyl,

11.b) 1,2,3 or the group of 9 one of them definition; It is by CO ₂R ³The single replacement,

12.b) 1,2,3 or the group of 9 one of them definition, wherein 1 is replaced by fluorine to whole hydrogen atoms, or

13. at b) 10 indication groups, on its phenyl ring, replace: halogen, 1-4 carbon alkoxyl group and nitro by 1 or 2 identical or different following group.

C) R ²Be 1. hydrogen,

2. halogen,

3. nitro,

4.CvF ₂v+1，

5. pentafluorophenyl group,

6. cyano group,

7.-O-R ⁶，

8. phenyl,

9. phenyl-(1-3 carbon) alkyl,

10.(1-10 alkyl carbon),

11.(3-10 thiazolinyl carbon),

12. phenyl-(2-6 carbon) thiazolinyl,

13.1-imidazolyl-(CH ₂) m-,

14.1,2,3-triazolyl-(CH ₂) n-,

15. tetrazyl-(CH ₂) m-,

16.-（CH ₂） _0-1-CHR ⁷-OR ⁵，

17.-（CH ₂） ₀-O-CO-R ³，

18.-（CH ₂） _o-S-R ⁶，

19.-S（O） _r-R ¹⁹，

20.-CH＝CH-（CH ₂） _m-CHR ³-OR ⁶，

21.-CH ₂＝CH-（CH ₂） _m-CO-R ⁸，

22.-CO-R ⁸，

23.-CH＝CH-（CH ₂） _m-O-CO-R ⁷，

24.-（CH ₂） _m-CH（CH ₃）-CO-R ⁸，

25.-（CH ₂） _o-CO-R ⁸，

28.-（CH ₂） _o-NR ⁷-CO-NHR ⁹，

29.-（CH ₂） _o-NR ⁷-SO ₂R ⁹，

31.-（CH ₂） _nF，

32.-（CH ₂） _n-O-NO ₂，

33.-CH ₂-N ₃，

34.-（CH ₂） _n-NO ₂，

35.-CH＝N-NR ⁵R ⁷，

36. Phthalimide base-(CH ₂) _n-,

37.-（CH ₂） _n

，

41. phenyl-SO ₂-NH-N=CH-,

43.-（CH ₂） _n-SO ₂-NR ⁷-CS-NR ⁶R ⁹，

44.-（CH ₂） _n-SO ₂-NR ⁷-CO-NR ⁶R ⁹，

45.-（CH ₂） _o-SO ₂R ⁹，

46.c) 8 or 9 defined groups, phenyl is wherein replaced by 1 or 2 identical or different following group: halogen, hydroxyl, methoxyl group, trifluoromethyl, CO ₂R ³And phenyl,

47.c) definition group in 10,11 or 19, wherein 1 is replaced by fluorine to all hydrogen atoms,

48.c) 14 groups that define, it is replaced by 1 to 2 identical or different following groups: methoxycarbonyl and (1-4 carbon) alkyl,

49.-（CH ₂） _n-SO ₂-NR ⁷-CO-R ⁶，

50.-（CH ₂） _n-SO ₂-NR ⁷-CS-R ⁶，

D) R ³Be 1. hydrogen,

2.(1-8 alkyl carbon),

3.(3-8 cycloalkyl carbon),

4. phenyl,

5. phenmethyl, or

6.d) the 2. group of definition, wherein 1 is replaced by fluorine to whole hydrogen atoms,

E) R ⁴Be 1. hydrogen,

2.(1-6 alkyl carbon),

3.(3-8 cycloalkyl carbon),

4.(2-4 thiazolinyl carbon), or

5.(2-4 alkynyl carbon),

F) R ⁵Be 1. hydrogen,

2.(1-6 alkyl carbon),

3.(3-8 cycloalkyl carbon),

4. phenyl, or

5. phenmethyl;

G) R ⁶, R ⁹Identical or different, for

1. hydrogen,

2.(1-6 alkyl carbon), it can be replaced by 1-3 group in (1-6 carbon) alkoxyl group series, and alkoxyl group itself again can be by hydroxyl, (1-6 carbon) alkoxyl group, and amino, single (1-6 carbon) alkylamino radical, 1-3 group in two-(1-6 carbon) alkylamino radicals replaces; It also can be by (2-10 carbon) thiazolinyl, hydroxyl, amido, list-(1-6 carbon) alkylamino radical, two-(1-6 carbon) alkylamino radicals, (1-6 carbon) alcoxyl carbonyl amido, (6-12 carbon)-aryl-(1-4 carbon) alcoxyl carbonyl amido, (6-10 carbon)-aryl, (6-10 carbon) aryl-(1-3 carbon) alkyl, (1-9 carbon) heteroaryl, carboxyl and (1-4 carbon) carbalkoxy replace;

3.(3-8 carbon)-and cycloalkyl, cycloalkyl moiety also can be replaced by 1-3 group in (1-4 carbon) alkyl and (2-4 the carbon)-thiazolinyl series;

4.(3-8 carbon)-cycloalkyl-(1-3 carbon) alkyl,

5.(6-12 carbon)-aryl, benzene preferably,

6.(6-10 carbon)-aryl-(1-4 carbon) alkyl,

7.(1-9 carbon)-heteroaryl,, it can be by partially or completely hydrogenation,

8.g) 5,6,7,9,15,16,17,19,20 or 21 groups that define, it can be by halogen family, hydroxyl, (1-4 carbon) alkyl, methoxyl group, nitro, cyano group, CO ₂R ³, trifluoromethyl ,-NR ¹¹R ¹²With In the identical or different group of 1-2 replace,

9.(1-9 heteroaryl-(1-3 carbon) alkyl carbon), wherein heteroaryl moieties can be by partially or completely hydrogenation,

10.(1-6 alkyl carbon), wherein 1 extremely whole hydrogen atom is replaced by fluorine,

11.(2-10 carbon)-and thiazolinyl, (2-10 carbon)-alkenoyl or (2-10 carbon) alkadienyl,

12.(3-8 cycloalkenyl group carbon),

13.(3-8 cycloalkenyl group-(1-3 carbon) alkyl carbon),

14. two or trinucleated (4-10 carbon) cycloalkenyl group-(1-4 carbon) alkyl, it also can be replaced by 1-3 (1-4 carbon) alkyl,

15.(6-10 aryl-(1-4 carbon) alkyl carbon),

16.(6-10 aryl-(3-6 carbon) thiazolinyl carbon),

17.(1-9 carbon)-heteroaryl-(3-6 carbon) thiazolinyl,

18.(3-6 alkynyl carbon),

19.(6-10 carbon)-aryl-(3-6 carbon) alkynyl,

20.(1-9 carbon)-heteroaryl-(3-6 carbon)-alkynyl,

21.R ⁶, R ⁹Heteroaryl of the common formation of the N-atom that links to each other with them also can partly or entirely be hydrogenated;

H) R ⁷Be 1. hydrogen,

2.(1-6 alkyl carbon),

3.(3-8 cycloalkyl carbon),

4.(6-12 carbon)-aryl-(1-6 carbon) alkyl, phenmethyl preferably,

5. phenyl, or

6.(1-9 heteroaryl carbon);

I) R ⁸Be 1. hydrogen,

2.(1-6 alkyl carbon),

3.(3-8 cycloalkyl carbon),

4. phenyl-(CH ₂) q-,

5.OR ⁶，

6.NR ¹¹R ¹², or

J) R ¹⁰Be cyano group, nitro or CO ₂R ⁷,

K) R ¹¹And R ¹²Identical or different, can be

1. hydrogen,

2.(1-4 alkyl carbon),

3. phenyl,

4. phenmethyl, or

5. Alpha-Methyl phenmethyl,

L) D is NR ¹³, O or CH ₂,

M) R ¹³Be hydrogen, (1-4 carbon) alkyl or benzene

N) A is an xenyl, can be by as many as 4,2 following R preferably ¹⁵Group or by R ¹⁴And R ¹⁵The common group that forms replaces, wherein, and R ¹⁵For-SO ₂-NR ⁷-CO-NR ⁶R ⁹,-SO ₂-NH-COO-R ⁶,-SO ₂-NH-SO ₂-NR ⁶R ⁹,-SO ₂-NH-CO-R ⁶Or-SO ₂-NH-SO ₂-R ⁶, and R ¹⁴And R ¹⁵The common group that forms is-CO-NH-SO ₂-;

O) R ¹⁴Be 1. halogens,

2. nitroso-group,

3. nitro,

4. amino,

5. cyano group,

6. hydroxyl,

7.(1-6 alkyl carbon),

8.(1-4 carbon)-chain acyl,

9.(1-4 carbon)-the chain acyloxy,

10.CO ₂R ³，

11. the methylsulfonyl amido,

12. the fluoroform sulfoamido,

13.-CO-NH-OR ⁹，

14.-SO ₂-NR ⁶R ⁷，

15.-CH ₂-OR ⁷，

16.(1-9 heteroaryl-(CH carbon) ₂) q-, be preferably the 1-tetrazyl,

17.(7-13 aroyl carbon),

20.(6-12 aryl carbon);

P) R ¹⁵Be 1. hydrogen,

2.(1-6 alkyl carbon),

3.(3-8 cycloalkyl carbon),

4.(6-12 aryl carbon),

5.(7-13 aroyl carbon),

6.(1-4 alkoxyl group carbon),

7.(1-4 chain acyloxy carbon),

8.(1-9 heteroaryl carbon),

9.CO ₂R ³，

10. halogen,

11. cyano group,

12. nitro,

13.NR ⁶R ⁷，

14. hydroxyl,

15.-CO-NH-CHR ⁵-CO ₂R ³，

16. alkylsulfonyl,

17.-SO ₃R ³，

18.-SO ₂-NR ⁷-CO-NR ⁶R ⁹Or

-SO ₂-NR ⁷-CS-NR ⁶R ⁹

19.-NR ⁷-CO-NR ⁶-SO ₂-CH ₂-R ⁵，

20.-C（CF ₃） ₂OH，

21. phosphonato,

22.-PO ₃H ₂，

23.-NH-PO（OH） ₂，

24.-S（O） _rR ⁶，

25.-CO-R ⁸，

26.-CO-NR ⁶R ⁹，

27.-CR ²⁰（OH）-PO（OH） ₂，

28. at o) group of definition in 20.,

32.5-tetrazyl-NH-CO-,

33.-CO-NH-NH-SO ₂CF ₃，

40.-CO-NH-SO ₂-R ¹⁹

41.-SO ₂-NH-CO-R ⁶, or

42.p) 4 defined groups, it is by halogen, cyano group, nitro, NR ⁶R ⁷And 1 or 2 identical or different group replaces in the hydroxyl,

43.R ¹⁵With R ¹⁴Be jointly-CO-NH-SO ₂-,

44.-SO ₂-NH-CO-O-R ⁶，

45.-SO ₂-NH-SO ₂-NR ⁶R ⁹，

46.-SO ₂-NH-SO ₂-R ⁶;

Q) B is O, NR ⁷Or S;

R) W is O or S;

S) L is (1-3 carbon)-alkylidene group;

T) R ¹⁶Be CO ₂R ³Or CH ₂CO ₂R ³;

U) R ¹⁷Be hydrogen, halogen, (1-4 carbon) alkyl or (1-4 carbon) alkoxyl group;

V) R ¹⁸Be hydrogen, (1-4 carbon) alkyl or phenyl;

W) R ¹⁹Be 1.(1-6 carbon) alkyl,

2.(3-8 cycloalkyl carbon),

3. phenyl,

4. phenmethyl, or

5.w) 1. defined group, wherein 1 extremely whole H atom is replaced by fluorine,

X) T is 1. singly-bounds,

2.-CO-，

3.-CH ₂-

4.-O-

5.-S-

6.-NR ²¹-

7.-CO-NR ²¹-

8.-NR ²¹-CO-

9.-O-CH ₂-

10.-CH ₂-O-

11.-S-CH ₂-

12.-CH ₂-S-

13.-NH-CR ²⁰R ²²-

14.-NR ²¹-SO ₂-

15.SO ₂-NR ²¹-

16.-CR ²⁰R ²²-NH-

17.-CH＝CH-

18.-CF＝CF-，

19.-CH＝CF-，

20.-CF＝CH-，

21.-CH ₂-CH ₂-，

22.-CF ₂-CF ₂-，

23.-CH（OR ³）-

24.-CH（OCOR ⁵）-

Y) R ²⁰And R ²²Identical or different, for

Hydrogen, (1-5 carbon) alkyl, phenyl, allyl group or phenmethyl;

Z) R ²¹Be hydrogen, (1-6 carbon) alkyl, phenmethyl or allyl group;

A ') R ²³Be 1.NR ²⁰R ²¹,

2. urea groups,

3. thioureido,

4. toluene-4-alkylsulfonyl, or

5. benzene sulfonamido,

B ') R ²⁴And R ²⁵Identical or different, for (1-4 carbon) alkyl or be-(CH jointly ₂) q-,

C ') Q is CH ₂, NH, O or S;

D ') m is from 0 to 5 integer,

E ') integer of n from 1 to 5,

F ') o is from 1 to 10 integer;

G ') q is 0 or 1,

H ') r is 0,1 or 2, or

I ') v is from 1 to 6 integer;

Except the formula α compound

Alkyl, thiazolinyl and alkynyl can be straight or brancheds, and this also is applicable to the group that derives from corresponding to thus, as chain acyl or alkoxyl group.

Cycloalkyl also can be considered to the ring that alkyl replaces.

(6-12 carbon) aryl is as phenyl, naphthyl or xenyl, phenyl especially, and this also is applicable to the group that derives from thus, as aroyl or aralkyl.

(1-9 carbon) heteroaryl is considered to the specific groups that derives from from benzene or naphthalene, and one of them or more CH-base are substituted by N, or at least two adjacent CH-bases are by S, and NH or O substitute, and form the 5-membered aromatic ring.Also may bicyclic radicals and close the position 1 or 2 atom is arranged be nitrogen-atoms (as the indolizine base).

Heteroaryl mainly refers to: furyl, thienyl, pyrryl, imidazolyl, pyrazolyl, triazolyl, tetrazyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, indyl, indazolyl, quinolyl, isoquinolyl, 2 base, quinoxalinyl, quinazolyl and cinnolines base.

Sometimes the three-dimensional center of Chu Xianing may be that (R)-also may be (S) configuration.

A combines with alkylidene group-bridge L, mainly connects by methylene radical.

This methylene radical refers to directly especially and xenyl links.

The pharmaceutical salts of formula I compound can be organically, and is also inorganic.Narrated in Remington ' s pharmacology (the 17th edition 1418 pages, 1985) as it.Based on physical and chemical stability and solubleness, concerning acidic-group, preferably form sodium, potassium, calcium and ammonium salt, concerning basic group, preferably form the salt of hydrochloric acid, sulfuric acid, phosphoric acid or carboxylic acid, sulfonic acid such as the salt of acetic acid, citric acid, phenylformic acid, toxilic acid, fumaric acid, tartrate and p-toluenesulphonic acids.

Formula I compound is preferably:

A) X is N, and Y is CR ²With Z be CR ²;

B) X is CR ², Y is that N and Z are CR ²,

C) X is CR ², Y is CR ²With Z be N, or

D) X, Y and Z are N.

Formula I compound also can be preferably those compounds that wherein symbol has following implication:

X is N, and Y is CR ², Z is CR ²;

X is CR ², Y is N, Z is CR ²;

X is CR ², Y is CR ², Z is N, or

X, Y and Z are N;

A) R ¹Be 1.(2-10 carbon)-alkyl,

2.(3-10 thiazolinyl carbon),

3.(3-10 alkynyl carbon),

4.(3-8 cycloalkyl carbon),

5. phenmethyl, or

6. phenmethyl, it can (b.13) as mentioned above mode be substituted,

B) R ²Be 1. hydrogen,

2. halogen,

3. nitro,

4.Cv F _2v+1

5. pentafluorophenyl group,

6. cyano group,

7.-O-R ⁶，

8. phenyl,

9. phenyl-(C ₁-C ₃)-alkyl,

10.(C ₁-C ₁₀)-alkyl,

11.(C ₃-C ₁₀)-alkenyl,

12. phenyl-(C ₂-C ₆)-alkenyl,

13.1-imidazolyl-(CH ₂) m-,

14.1,2,3-triazolyl-(CH ₂) _o-,

15. tetrazyl-(CH ₂) m-,

16.-（CH ₂） _o-1-CHR ⁷-OR ⁵

17.-（CH ₂） _o-O-COR ³，

18.-COR ⁸，

19.-（CH ₂） _o-CO-R ⁸，

20.-S（O） _rR ¹⁹，

21.-CH＝CH-（CH ₂） _m-CHR ³-OR ⁶，

22.-CH ₂＝CH-（CH ₂） _m-CO-R ⁸，

23.-（CH ₂） _o-NH-CO-OR ⁹，

24.-（CH ₂） _o-NH-SO ₂-R ⁹，

25.-（CH ₂） _nF，

26.-（CH ₂） _o-SO ₃R ⁹，

27.-（CH ₂） _n-SO ₂-NH-CO-NR ⁶R ⁹，

28.-(CH ₂) _n-SO ₂-NH-CS-NR ⁶R ⁹, or

29.b) group of definition in 8,9,10,11,14, to each this group, it all presses aforesaid c) be substituted like that described in 46,47 or 48,

30.-（CH ₂） _n-SO ₂-NR ⁷-CO-R ⁶

31.-（CH ₂） _n-SO ₂-NR ⁷-CS-R ⁶

C) R ⁸Be hydrogen, (1-5 carbon) alkyl, OR ⁶, NR ¹¹R ¹²Or morpholino base;

D) T is 1. 1 singly-bounds

2.-CO-

3.-CONR ²¹-

4.-CH ₂-CH ₂-

5.-NR ²¹-CO-

6.-O-CH ₂-

7.-CH ₂-O-

8.-S-CH ₂-

9.-CH ₂-S-

10.-NH-CH ₂-

11.-CH ₂-NH-or

12.-CH＝CH-

Remaining group and variation with illustrate previously consistent.

Particularly preferably be some formula I compounds like this, wherein

X is N, and Y is CR ², Z is CR ²;

X is CR ², Y is N, Z is CR ²,

X is CR ², Y is CR ², Z be N or

X, Y and Z are N,

A) R ¹Be (2-7 carbon) alkyl, (3-7 carbon) thiazolinyl or (3-7 carbon) alkynyl;

B) R ²Be 1. chlorine,

2. bromine,

3.Cv F _2v+1, v=1 wherein, 2, or 3,

4. pentafluorophenyl group,

5.O-R ⁶，

6.-S（O） _rR ¹⁹，

7.（CH ₂） _o-1-CHR ⁷-OR ⁵，

8.（CH ₂） _o-O-CO-R ³，

9.-COR ⁸，

10.-（CH ₂） _o-CO-R ⁸，

11.-CH ₂-NH-CO-R ⁸，

12.-（CH ₂） _o-NH-SO ₂-R ⁹，

13.-CH＝CH-CHR ³-OR ⁶，

14.Tetrazolyl-（CH ₂） _m-

15.-（CH ₂） _nSO ₂-NH-CO-NR ⁶R ⁹，

16.-(CH ₂) _o-SO ₃R ⁹Or

Be (1-6 carbon)-alkyl that hydroxyl replaces in case of necessity, methylol preferably,

C) R ³Be hydrogen, (1-4 carbon) alkyl or phenmethyl,

D) R ⁶, R ⁹Identical or different, for

1. hydrogen,

2.(1-6 alkyl carbon), it can be replaced by 1-3 group in (1-6 carbon) alkoxyl group series, and alkoxyl group itself again can be by hydroxyl, (1-6 carbon) alkoxyl group, and amino, single (1-6 carbon) alkylamino radical, 1-3 group in two-(1-6 carbon) alkylamino radicals replaces; It also can be by (2-10 carbon) thiazolinyl, hydroxyl, amido, list-(1-6 carbon) alkylamino radical, two-(1-6 carbon) alkylamino radicals, (1-6 carbon) alcoxyl carbonyl amido, (6-12 carbon)-aryl-(1-4 carbon) alcoxyl carbonyl amido, (6-10 carbon)-aryl, (6-10 carbon) aryl-(1-3 carbon) alkyl, (1-9 carbon) heteroaryl, carboxyl and (1-4 carbon) carbalkoxy replace;

3.(3-6 cycloalkyl carbon),

4.(3-6 cycloalkyl-(1-3 carbon) alkyl carbon),

5. phenyl,

6. phenyl-(1-3 carbon) alkyl,

7.(1-7 carbon) heteroaryl, its partly or entirely hydrogenation,

8. top g) 5,6,7 or 9, group of definition among 14-16 and the 18-20, it is selected from halogen, hydroxyl, (1-4 carbon) alkyl, methoxyl group, nitro, cyano group, CO ₂R ³, trifluoromethyl ,-NR ¹¹R ¹²With-

In the identical or different group of 1-2 replace,

9.(1-9 heteroaryl-(1-3 carbon) alkyl carbon), wherein heteroaryl moieties can be by partially or completely hydrogenation,

10.(1-6 alkyl carbon), wherein 1 extremely whole hydrogen atom is replaced by fluorine,

11.(2-4 carbon)-thiazolinyl or 3 carbochain enoyl-s,

12.(3-6 cycloalkenyl group carbon),

13.(3-6 cycloalkenyl group-(1-3 carbon) alkyl carbon),

14. two or trinucleated (4-10 carbon) cycloalkenyl group-(1-4 carbon) alkyl, it also can be replaced by 1-3 (1-4 carbon) alkyl,

15.6 carbon aryl-(1-3 carbon) alkyl,

16.6 carbon aryl-3 carbene base,

17.(1-6 carbon)-heteroaryl-3 carbene base,

18.3 the carbyne base,

19.6 carbon aryl-3 carbyne base,

20.(1-6 heteroaryl-3 carbyne base carbon),

21.R ⁶, R ⁹Heteroaryl of the common formation of the N-atom that links to each other with them also can partly or entirely be hydrogenated;

E) R ⁷Be hydrogen, (1-4 carbon) alkyl, (1-9 carbon) heteroaryl, or (6-12 carbon)-aryl-(1-4 carbon)-alkyl;

F) R ⁸Be hydrogen, (1-4 carbon) alkyl, OR ⁶Or morpholino base;

G) R ¹⁴Be 1.(1-4 carbon) alkyl, OR ⁶Or morpholino base;

2.(1-4 alkoxyl group carbon),

3. cyano group,

4. amino,

5. nitroso-group,

6. nitro,

7. fluorine,

8. chlorine,

9. bromine,

10.(1-9 heteroaryl-CH carbon) ₂-

11.(1-4 alkanoyloxy carbon),

12.(1-4 alkanoyl carbon),

13. benzoyl,

14.-NH-COR ⁷, or

15. tetrazyl;

(h) R ¹⁵Be 1.(1-4 carbon) alkyl,

2.(6-12 carbon)-aryl,

3.(1-3 alkanoyloxy carbon),

4.(1-4 alkoxyl group carbon),

5.(1-9 heteroaryl carbon) is preferably the 5-tetrazyl,

6. cyano group,

7. nitro,

8. hydroxyl,

9.-S（O） _rR ⁶，

10.-SO ₃R ³，

11. chlorine,

12. bromine,

13. benzoyl,

14.-CO ₂R ³，

15.-CO-NH-R ⁶，

16.-CO-R ⁸，

17.-SO ₂-NR ⁶R ⁷，

18.-SO ₂-NH-CO-NR ⁶R ⁹，

19.-PO ₃H

20.-CO-CHR ⁵-CO ₂H，

21.-NH-CO-NH-SO ₂-CH ₂-R ⁵，

22.5-tetrazyl-NH-CO-,

28.h) group of definition in 2, it replaces and aforementioned p) 42 defined identical,

29.R ¹⁵With R ¹⁴Be jointly-CO-NH-SO ₂-,

30.-SO ₂-NH-COO-R ⁶，

31.-SO ₂-NH-SO ₂-NR ⁶R ⁹，

32.-SO ₂-NH-SO ₂-R ⁶;

I) R ¹⁸Be hydrogen, methyl or ethyl;

J) T is-singly-bound ,-O-,-CO-,-NHCO-or-OCH ₂-;

K) q=O, the L=methylene radical,

Remaining group and variation thereof are as hereinbefore.

In addition, the azole derivative of formula I particularly preferably is, and wherein Z represents a nitrogen-atoms, and Y and X represent CR mutually solely ², all the other symbols are with aforesaid identical.

In the azole derivative of formula I, the salt of those of each symbol has following meaning that suitable especially is and physiologic adaptation thereof:

Z. be nitrogen,

X., Y. is separate CR ²,

R ¹Be (2-7 carbon) alkyl, (3-7 carbon) thiazolinyl or (3-7 carbon) alkynyl,

R ²For hydrogen, halogen, nitro, (1-3 carbon) perfluoroalkyl, cyano group, (1-10 carbon)-alkyl, (3-10 carbon)-thiazolinyl ,-CH ₂OR ⁵,-S(O) _r-R ¹⁹,-CO-R ⁸Or-O-R ⁶, R ⁵Be hydrogen; Or (1-6 carbon)-alkyl,

R ⁶, R ⁹Be 1. hydrogen

2.(1-6 alkyl carbon), it can be replaced by 1-3 group in (1-6 carbon) alkoxyl group series, alkoxyl group itself again can be by hydroxyl, and 1-3 group in (1-6 carbon) alkoxyl group, amino, list (1-6 carbon) alkylamino radical, two-(1-6 carbon) alkylamino radical replaces; It also can be by (2-10 carbon) thiazolinyl, hydroxyl, amido, list-(1-6 carbon)-alkylamino radical, two-(1-6 carbon) alkylamino radical, (1-6 carbon) alcoxyl carbonyl amido, (6-12 carbon)-aryl-(1-4 carbon) alcoxyl carbonyl amido, (6-10 carbon)-aryl, (6-10 carbon) aryl-(1-3 carbon) alkyl, (1-9 carbon) heteroaryl, carboxyl and (1-4 carbon) carbalkoxy replace;

3.(3-8 cycloalkyl carbon),

4.(3-6 cycloalkyl-(1-3 carbon) alkyl carbon),

5.(6-12 carbon)-aryl, benzene preferably,

6.(6-10 carbon)-aryl-(1-4 carbon) alkyl,

7.(1-9 carbon)-heteroaryl,, it can be by partially or completely hydrogenation,

8.(1-9 carbon)-and heteroaryl-(1-3 carbon)-alkyl, wherein partly or entirely hydrogenation of heteroaryl,

9.5, one of 6,7,8 groups that wherein define, its is selected from halogen, hydroxyl, (1-4 carbon)-alkyl, methoxyl group, nitro, cyano group, CO ₂R ³, trifluoromethyl ,-NR ¹¹R ¹²With In 1 or 2 identical or different groups replace,

10.(1-6 carbon)-alkyl,, wherein 1 is replaced by fluorine to whole hydrogen atoms,

11.(2-6 carbon)-thiazolinyl or (3-6 carbon)-alkenoyl,

12.(3-8 cycloalkenyl group carbon),

13.(3-8 cycloalkenyl group-(1-3 carbon) alkyl carbon),

14.(6-10 aryl-(1-4 carbon) alkyl carbon),

15.(6-10 aryl-(3-6 carbon) thiazolinyl carbon),

16.(1-9 carbon)-heteroaryl-(3-6 carbon) thiazolinyl,

17.(3-6 alkynyl carbon),

18.(6-10 carbon)-aryl-(3-6 carbon) alkynyl,

19.(1-9 carbon)-heteroaryl-(3-6 carbon) alkynyl,

20.R ⁶, R ⁹The N atom that links to each other with them constitutes heteroaryl jointly, and it also can partly or entirely be hydrogenated,

R ⁷Be hydrogen,

R ⁸For hydrogen or-OR ⁶,

R ¹¹, R ¹²Be hydrogen or (1-4 carbon) alkyl independently of each other,

D is-NR ¹³,-O or-CH ₂,

R ¹³Be hydrogen or (1-4 carbon) alkyl,

A is an xenyl, and it is by R ¹⁵Or R ¹⁴And R ¹⁵The common replacement,

R ¹⁵For-SO ₂-NR ⁷-CO-NR ⁶R ⁹,-SO ₂-NH-COO-R ⁶,-SO ₂-NH-SO ₂-NR ⁶R ⁹,-SO ₂-NH-CO-R ⁶Or-SO ₂-NH-SO ₂-R ⁶Or

R ¹⁴And R ¹⁵Can be jointly-CO-NH-SO ₂-,

L is-CH ₂-

Q is a zero-sum

R is zero, 1 or 2.

The invention still further relates to the preparation method of formula I compound and pharmaceutical salts thereof, it is characterized in that, make formula II compound and formula 9 III) compound carries out alkylated reaction:

R wherein ¹, X, Y, Z as mentioned above,

U-L-（O） _q-A （Ⅲ）

Wherein L, A and q are as indicated above; U is a leavings group; the temporary transient in case of necessity blocking group of introducing cracking again falls; the sulphonamide of formula I is converted into the carbamate of formula I in case of necessity; the sulphonamide of the formula I that generates or the sulfonylurea that carbamate can be converted into the formula I in case of necessity, the formula I compound with gained is converted into its pharmaceutical salts in case of necessity.

Suitable leavings group U preferably Electron Affinities group (referring to Angew.Chem.72 (1960) 71) as halogen, neighbour-tosylate, methylsulfonyl root or trifluoromethayl sulfonic acid root.

The method of preparation formula II raw material is known, sees US4355044, EP-A-324377 and EP-A-328841.

Other methods are G.L ' abbe(Chem.Rev.69,345(1969)), T.Srodsky(" The Chemistry of the Arido Group ", Wiley, New York, 1971, S.331), H.Wamhoff(" Comprehensive Heterocyclic Chemistry) and S.Katritzky Ed.(Pergamon Press, New York(1984)) etc. people's narration.

The further preparation method of formula II compound is from 1-cyanoacetaldehyde acyl acid-2-9 oxime derivate, with behind the known reductive agent of the document reduction oxime and under the situation of using the due care group, sulfhydryl compound added on the itrile group and has obtained this raw material.It is cyclized into imidazoles under the condition of dehydration.This cyclisation step can be used Pcl ₅Mixture, POcl with Dimethylamino pyridine (DMAP) ₃And SOcl ₂And the mixture of they and DMAP.

R in the formula I ²For-S(O) _rR ¹⁹, r=0 or 1 corresponding sulfone of the oxidable one-tenth of sulfocompound and sulfoxide, the most handy peracid of this reaction carries out in The suitable solvent such as methylene dichloride.

The alkanisation of formula II azole for example should be used corresponding benzyl halide, toluenesulphonic acids benzyl ester, methylsulfonyl benzyl ester or trifluoromethayl sulfonic acid benzyl ester or corresponding haloalkane, toluenesulphonic acids alkane ester methylsulfonic acid alkane ester or trifluoromethayl sulfonic acid alkane ester.

Alkanisation is that currently known methods carries out with similar process on principle.

Formula II azole derivative is for example in the presence of alkali and metallize, preferred alkali is the metal hydride of formula MH, hydride as lithium, sodium or potassium, make solvent with for example DMF or DMSO, or as the metal alkyl oxide of formula MOR, wherein R is methyl, ethyl, t-butyl, is reflected among corresponding alcohol, DMF or the DMSO and carries out, the azole salt of Xing Chenging is dissolved in the solvent of protic as among DMF and the DMSO like this, and reacts with an amount of alkylating agent.

Another can be for example to react in DMF or DMSO with salt of wormwood the method for azole derivative deprotonation.

Be reflected at room temperature and carry out in the reaction mixture boiling spread, preferred temperature is to its boiling point at+20 ℃.Reaction times is 1 to 10 hour.

Biphenyl derivatives can by the aryl boric acid derivative by with the aromatic hydrocarbons halide reaction that replaces and with transition metal particularly palladium carry out the coupling synthetic as catalyzer.Relevant reaction is referring to (Synthetic Commun.11(7) such as (Organometallics 1984,3,1261) such as R.B.Miller and A.Zuzuki, 513(1981)) narration.

The sulphonyl mephenesin Carbamate of formula I can by corresponding sulphonamide in the formula I in inert high boiling solvent such as toluene, under the boiling point of about 100 ℃ or corresponding solvent through with carbonochloridic acid ester (Chlorkohlensaureestern) reaction and obtain.

Equally, the alkylsulfonyl sulphonamide can and obtain from corresponding sulphonamide and SULPHURYL CHLORIDE or the reaction of sulphonamide chlorine.

In case of necessity, this sulfamoyl group can be obtained by the Meerwein reaction by amino.For this reason, the hydrochloride of amine reacts in acetic acid with sulfurous gas in the presence of copper catalyst then at first by diazotization, and ammonia changes sulfamyl gradually into.

In addition, corresponding thiophenol can be changed ammonia into sulphonamide then by oxychlorination.

Formula I compound of the present invention has the antagonistic action of angiotensin-ii-receptor, therefore can be used for the dependent hypertension therapeutic of angiotensin-ii-receptor.Also can be further used for treating cardiac insufficiency, Cardioprotective, myocardial infarction, cardiac hypertrophy, arteriosclerosis, ephrosis, the depletion of kidney function and cerebrovascular disease such as momentary local asphyxia and Intracerebral hemorrhage.

Feritin is the proteolytic ferment of an aspartyl protease class, can be descended by volume, and sodium deficiency or beta receptor stimulate generation.Be secreted into the circulation of blood from juxtaglomerular cell, be converted into the vasotonia primitive element at liver, and be cracked into angiotensin (+peptide), change angiotensin into by Zinc metallopeptidase Zace1 (ACE) again, angiotensin plays an important role in blood pressure regulation, and its blood pressure that directly raises by vasoconstriction also stimulates aldosterone to secrete from suprarenal gland in addition, and pass through to hinder row's sodium and the molten amount of rising extracellular fluid, hypertensive effect hoists.

Effect behind the acceptor is meant phosphoinositide metabolism (Ca ⁺⁺Discharge), the hormone receptor effect that activated protein kinase C and promotion cAMP rely on.

Formula I compound can be used the avidity of angiotensin-ii-receptor ¹²⁵I-angiotensin or ³The H-angiotensin combines with the competition of bovine adrenal medullary substance membrane receptor and measures.This for this reason membrane product is suspended in the damping fluid of pH7.4.

For fear of the degraded of radioligand during temperature is incubated, also to add a kind of peptidase inhibitors (Aprotinin), add about 14000cpm radioligand in addition, specific activity is a 74TBq/mmol(Amersham Buchler company, Braunschweig, German), and add a certain amount of receptor protein.About 50% radiation is combined.At first 50 μ l film suspensions are added in 100 μ l damping fluids and the Aprotinin solution, add 50 μ l damping fluids again, it contains or does not contain angiotensin or receptor antagonist and 50 μ l radioligands, the reaction beginning.After incubating, 25 ℃ of 60 minutes temperature incite somebody to action combination and free radioligand Whatmann

The GF/C filter membrane separates on the Skatron cell harvestor.

Handle filter membrane with 0.3% polymine (pH 10) (Sigma, Nr3143), can reduce non-specific combination.On Gamma liquid flashing counting device, measure radioactivity, to determine the intensity of radioligand and receptor competition.IC ₅₀Value promptly suppresses the mensuration of 50% aglucon bonded inhibitor concentration and sees J.Theor.Biol.59, and 253(1970), this value scope of formula I compound is 10 ^-4-10 ^-9M.

In addition, the avidity of formula I compound and angiotensin-ii-receptor can be passed through ¹²⁵I-angiotensin or ³The H-angiotensin is measured with the combining of body preparation (liver, lung, kidney, brain etc.) that be subjected to of Different Organs.

Film preparation is suspended in temperature and incubates that (20mM Tris, pH7.4 contain 135mM Nacl, 10mM kcl, 10mM Mgcl in the liquid ₂, 5mM glucose, 0.2% bovine serum albumin and proteinase inhibitor PMSF0.3mM and bacitracin 0.1mM) and wait that with radiolabeled angiotensin and different concns trying compound incubated 90 minutes 25 ℃ of following temperature.At last on cell harvestor (Skatron) through little glass fibre filter (GF51 Schleicher/schull) filters, separation and combination with the free radioligand.

By measuring on the filter membrane radioactivity with receptors bind, utilize β or alpha counter, determine to wait to try the competitive power of compound to radioligand and acceptor.Wait to try the intensity IC of compound competition radioligand to acceptor ₅₀Represent, promptly compete the inhibition concentration of 50% radiative aglycone combination, IC from acceptor ₅₀The calculating of value PC-software (LIGAND, G.A.Mepherson 1985, Elsevier-BIOSOFT.68Hills Road, Cambridge CB21LA UK) carries out.The I C of formula I compound ₅₀The value scope is 10 ^-5-10 ^-11The tabulation I has been listed the I C of each compound of the present invention under the M( ₅₀Value).

Table 1

Example I C ₅₀[nM]

1 5000

2 8000

3 1100

4 1100

5 16000

22 2000

24 800

25 1400

29 1，1

30 2030，0

31 153，0

32 3，5

33 34，0

34 1，0

35 50，0

36 16，0

37 1，1

55 8，8

56 4，6

57 1100

58 3，0

59 1，3

60 2，2

61 1，1

62 3，6

63 1，3

Table 1(is continuous)

Example I C ₅₀[nM]

64 0，5

65 1，8

66 6，9

67 0，91

68 12，0

69 3，2

70 4，4

71 2，2

73 2，5

76 9，5

79 5，8

80 0，69

81 0，79

83 0，96

84 4，3

85 3，9

89 1，1

90 0，69

92 280，0

93 3，3

95 1，8

98 1，4

99 26，6

100 68，5

101 2，4

102 2，3

Table 1(is continuous)

Example I C ₅₀[nM]

105 3，0

107 2，5

108 0，95

109 0，6

110 0，5

111 2，9

112 1，5

113 0，3

115 0，9

116 2，4

117 1，2

124 1，8

125 2，8

127 3，0

128 5，6

129 1，5

134 180，0

135 5，6

138 1，7

139 2，8

140 8，2

141 4，4

144 5，3

146 40，0

151 0，4

152 1，5

153 0，88

Table 1(is continuous)

Example I C ₅₀[nM]

154 1，8

155 6，0

156 4，7

157 1，4

159 8，7

160 0，73

161 57，0

162 3，9

163 3，7

164 0，86

165 2，3

166 1，2

167 4，0

168 7，0

169 2，9

170 2，7

171 0，7

172 0，48

174 5，1

179 2，6

181 1，0

183 1，7

185 5，9

186 6，5

187 1，2

190 22，0

191 21，4

194 21，7

195 3，0

Measure on the SD rat that acts on anesthesia of formula I compound antiangiotensin II rising blood pressure.Thiobarbital sodium (Byk Gulldn trade(brand)name: Trapanal, Germany) is the injection of 100mg/kg film chamber as narcotic, dosage.Intravenously administrable is measured blood pressure by jugular vein in carotid artery, animal gives pentolinium tartrate (10mg/kg i.m.) earlier then, makes blood pressure reduce to lower level (neuroganglion blocking-up).Angiotensin (Hypertensin CIBA) is intact with 0.1ml/100g volume quiet notes in 10 minutes, and dosage is 0.5 μ g/kg.Formula I compound dissolution is in distilled water, with the quiet notes of 0.1-1mg/kg or 10 and the 100mg/kg duodenal administration.

The effect dosage of formula I compound is 0.1-100mg/kg, but the best use of dosage is at 0.1-3mg/kg.

The present invention also relates to that (as the pharmaceutical preparation that diuretic(s) and non-steroidal anti-inflammatory pharmaceutically active ingredient are formed, formula I compound also can be used as the diagnostic reagent use of renin-angiotensin system by formula I compound and other effective ingredient.

Pharmaceutical preparation comprises the significant quantity of formula I compound and other possible effective constituent, and inorganic or organic medicinal excipient, can intranasal administration, vein, subcutaneous or oral administration, and its effective dose is relevant with animal species, body weight, age and administrated method.

Pharmacy preparation of the present invention can be made into known solution, mixture, granule and drageeing.

For oral dosage form, this active compound and typical additives, as vehicle, stablizer or inert diluent mix and make certain formulation with ordinary method, as, tablet, drageeing, capsule, water-based, ethanol, oiliness suspended matter or water, ethanol and oil solution.Non-activity is composed vehicle can use gum arabic, magnesium oxide, magnesiumcarbonate, potassiumphosphate, lactose, glucose, stearoyl-fumarate magnesium or starch, especially W-Gum.Preparation can be made with that do or wet particle, when with oiliness improver or solvent, can select plant or animal oil for use, as sunflower seed oil and Oils,glyceridic,cod-liver.

During subcutaneous or intravenously administrable, this active compound or its pharmaceutical salts form solution, suspension or emulsion with the material commonly used such as hydrotropy medium, emulsifying agent or other auxiliary agent of solution in case of necessity.As solvent used water, physiological saline or alcohols, as ethanol, propylene glycol or glycerine, and sugar soln, as glucose, the mixture that mannitol solution or these solvents constitute.

The abbreviation table:

DMF N, dinethylformamide

NBS N-bromine succinimide

AIBN α, α-azo is two-isopropyl cyanide

The EI electron-bombardment

The DCI DCI desorption chemical ionization

The RT room temperature

The EE ethyl acetate

The DIP isopropyl ether

The MTB methyl tertiary butyl ether

The mP fusing point

The HEP normal heptane

DME dimethoxy ethane

The bombardment of FAB high velocity electron

CH ₂Cl ₂Methylene dichloride

The present invention is illustrated with following embodiment:

Embodiment 1

1-((2 '-aniline carbonyl sulfamic-biphenyl-4-yl)-methyl-2-normal-butyl-4-chloro-imidazoles-5-formaldehyde synthetic

A) 4 '-preparation of methyl diphenyl-2-amine

23.9g(0.112Mol) 4 '-methyl-2 nitro biphenyl (R.B.Miller and S.Dugar, organo-metallic 1984,3,1261) adds in the 50ml methyl alcohol, adds in Ruan 3g-nickel, and hydrogenation under normal pressure, normal temperature is until the hydrogen that has absorbed theoretical amount.Filter then and tell catalyzer, filtrate is used SiO after concentrating ₂Chromatography, (500g), EE/HEP(1/6) wash-out obtains this title compound of 19g, is oily matter (92.5%).

Rf（EE/HEP 1/4）＝0.3，MS（EI）＝183（M ⁺）

B) 4 '-methyl diphenyl-2-ammonium salt hydrochlorate

10g compound 1a is dissolved in 50ml 6NHcl and the 100ml diox, and steaming promptly obtains described compound after falling solution, just need not be further purified and can use.

C) 4 '-methyl biphenyl-2-sulphonamide

31g(140mmol) compound 1b is suspended among the 200ml 6N Hcl, adds 7.9g(114mmol in the time of-10 ℃) Sodium Nitrite, solution becomes is clear, adds by using SO in the time of 0 ℃ ₂Saturated 200ml acetic acid, 17g Cucl ₂H ₂O and 25mlH ₂The solution of O stirred 2 hours under room temperature then, added 250mlEE then, and the dried over mgso organic phase is used in phase-splitting, obtains an oily matter, and it is dissolved in 300ml acetone, adds 150ml 25% ammoniacal liquor again, stirs 2 hours.After concentrating, add 500mlEE, EE uses H mutually ₂O washes once, adds MgSO ₄Dry concentrating.Use EE/HEP(1/1) carry out SiO ₂Chromatography obtains this title compound 4.6g.

Rf（EE/HEP 1/1）＝0.25，MS（DCI）＝248（M ⁺+H）

Fusing point: 122 ℃

D) 4 '-methyl biphenyl-2-N, N dimethylamine formyl sulphonamide

4.6g(18.6mmol) compound 1C) and 2.5g(19.3mmol) N, the dinethylformamide dimethyl-acetal stirred 2 hours under the room temperature in 30mlDMF, added 100mlH then ₂O, the throw out suction strainer of formation at air drying, obtains this title compound 4.2g.

Rf（EE/HEP 1/1）＝0.2，MS（DCI）＝303（M ⁺+H）

E) 4 '-bromomethylbiphenyl base-2-N, N dimethylamine base-formyl sulphonamide

3.76g(13.5mmol) compound 1d) and 2.4gNBS(13.5mmol) be dissolved in the 50ml chlorobenzene, add the 150mg benzoyl peroxide, refluxes after 4 hours, adding 50mlEE, EE uses 10%Na mutually ₂SO ₄Solution and water are respectively washed once, use Na ₂SO ₄After the drying, concentrate SiO ₂Chromatography (eluent: EE/HEP 2/1).Obtain this title compound of 1.2g.

Rf（EE/HEP 2/1）＝0.23，MS（DCI）＝381，383（M ⁺+H）

2-just-butyl-4-chloro-5-formylimidazoles

20g(0.106mol) 2-just-butyl-4-chloro-5-hydroxy methylimidazole (press EP-A-253310 synthetic) under 10-15 ℃, slowly adds 305ml 1M(NH in 350ml acetic acid ₄) ₂Ce(NO ₃) ₆The aqueous solution, room temperature is after following 2.5 hours, transfers pH value to 4 with 2N KOH, (20 ℃ time add alkali).Use CH then ₂Cl ₂Extract 4 times, each 500ml, organic extraction merges, and uses saturated NaHCO ₃The aqueous solution is washed 3 times, and each 300ml uses Na ₂SO ₄Drying concentrates, and gets this title compound (18g, 92%), is colorless solid.

Fusing point=90 ℃

Rf（DIP/MTB 1/1）＝0.5

G) 1-((2 '-N, N dimethylamine base formyl sulfonamido xenyl-4-yl)-methyl)-2-just-butyl-4-chloro-imidazoles-5-formaldehyde.

690mg(1.98mmol) compound 1e), 370mg(1.98mmol) compound 1f) and 270mg(1.98mmol) salt of wormwood at DMF(10ml) in stirred 2 hours under the room temperature, add 50mlEE then, wash organic phase Na 2 times ₂SO ₄Drying concentrates SiO ₂Chromatography EE/HEP(2/1) is eluent, gets this title compound (380mg, 40%).

Rf（EE/HEP 2/1）＝0.15，MS（DCI）＝487（M ⁺+H）

H) 1-((2 '-sulfonamido biphenyl-4-yl) methyl)-2-just-butyl-4-chloro-imidazoles-5-formaldehyde

280mg(0.58mmol) compound 1g) be dissolved in 7ml methyl alcohol and the 14ml water, add 110mg(2.88mmol again) sodium hydroxide, heated and boiled 4 hours at room temperature transfers to pH about 6 with 4NHcl after the cooling, extracts 3 times the dry mutually (Na of EE with 30mlEE ₂SO ₄), concentrate this title compound of 190mg.

Rf（EE/HEP 2/1）＝0.45，MS（DCI）＝432（M ⁺+H）

I) 1-((2 '-anilino carbonyl sulfamic biphenyl-4-yl)-methyl)-2-just-butyl-4-chloro-imidazoles-5-formaldehyde

730mg(1.69mmol) compound 1h) and have in the 10ml isonitrile acid phenenyl ester 80 ℃ down heating concentrate SiO after 4 hours ₂Chromatography (eluent is EE/HEP(2/1)), obtain this title compound of 400mg.

Rf（EE/HEP 2/1）＝0.15，MS（DCI）＝551（M ⁺+H）

Another method for making of compound 1d

(4 '-methyl-2-N, N dimethylamine base formyl sulphonamide)

11g(37.9mmol) 2-N, N dimethylamine base formyl sulfonamido bromobenzene (similar approach of pressing 1b-1d is from the preparation of 2-bromaniline), 1g triphen phosphorus, 8gNa ₂CO ₃Add in 150ml toluene and the 40ml water, under argon atmospher, at first add 420mgPd(OAc) ₂, add the 5.66g(41.9mmol that is dissolved in the 100ml ethanol then) and the 4-methyl-boron-dihydroxide, boiled 4 hours, concentrate, add 500ml ethanol ethyl ester and 500mlH ₂O, the throw out of generation filters, and is this title compound, separating acetic acid ethyl ester phase, dry (Na ₂SO ₄), SiO ₂The chromatography eluent ethyl acetate can obtain this title compound of another part.(7.6g=66% altogether)

Another synthetic method of 2-bromobenzene sulphonamide (the similar intermediate product of 1c)

4.7g2-bromo thiophenol is at 60mlH ₂Among the O, to its logical chlorine 30 minutes, 0 ℃ was stirred 30 minutes then, needn't cool off blowing air subsequently 30 minutes under 0-10 ℃, add 60ml acetone after, be cooled to 0 ℃ again, slowly splash into the saturated and NH of 10ml ₄OH solution after 30 minutes, is transferred PH to 3 with 4NHcl again, obtains product 4.5g(77% by filtration).

Fusing point=190-191 ℃, Rf(EE/H 1/1)=0.4

Embodiment 2

1-((2 '-just-propyl group amido carbonyl amido sulphonyl biphenyl-4-yl) methyl)-2-just-synthetic method of butyl-4-chlorine imidazoles-5-formaldehyde is similar to embodiment 1.

Rf（EE）＝0.6，MS（FAB）＝517（M ⁺+H）

Embodiment 3

1-((2 '-pyridine-2-amido carbonyl sulfamic biphenyl-4-yl) methyl)-2-just-butyl-4-chlorine imidazoles-5-formaldehyde synthetic

A) 1-((2 '-ethoxycarbonyl amido alkylsulfonyl biphenyl-4-yl) methyl)-2-just-butyl-4-chloro-imidazoles-5-formaldehyde

1.1g(2.5mmol) compound 1h) and 0.78g(5.6mmol) salt of wormwood in the anhydrous DME of 20ml, add 0.48ml(5.1mmol) Vinyl chloroformate, placed 1 hour under the room temperature, cooling also adds 50ml10%KH ₂PO ₄Solution is after the EE extraction, with Na ₂SO ₄Dry and concentrated, use EE/HEP(2/1) wash-out, make SiO ₂Chromatography gets (this title compound) 840mg

Rf（EE/HEP 2/1）＝0.32，MS（DCI）＝504（M ⁺+H）

B) 1-((2 '-pyridine-2-amido carbonyl sulfamic biphenyl-4-yl) methyl)-2-just-butyl-4-chlorine imidazoles-5-formaldehyde

150mg(0.3mmol) compound 3a) and 28.5mg(0.3mmol) 2-aminopyridine heated and boiled 2 hours in the 8ml dry toluene, concentrate SiO then ₂Chromatography, eluent EE gets this title compound of 34mg.

Rf(EE/ methyl alcohol 10/1)=0.4, MS(FAB)=552(M ⁺+ 1)

The synthetic method of the compound of embodiment 4-39 is similar to embodiment 3.

These compounds have following general formula (A) structure

Table 2

MS

Embodiment (FAB:M ⁺H) substituent position R

4（16） 553 3′（2′）

5（17） 543 3′（2′）

6（18） 558 3′（2′）

7（19） 559 3′（2′）

8（20） 597 3′（2′）

9（21） 541 3′（2′）

Table 2(is continuous)

Embodiment MS substituting group position R

FAB;M ⁺+H）

10（22） 596 3′（2′）

11（23） 596 3′（2′）

12（24） 569 3′（2′）

13（25） 569 3′（2′）

14（26） 631 3′（2′）

15（27） 631 3′（2′）

28 552 3′

29 580 2′

30 586 2′

31 584 2′

Table 2(is continuous)

Embodiment MS substituting group position R

FAB;M ⁺+H）

32 572 2′

33 581 2′

34 595 2′

35 565 2′

36 565 2′

37 579 2′

38 583 2′

39 589 2′

Embodiment 40

1-((2 '-anilino carbonyl amido alkylsulfonyl biphenyl-4-yl) methyl)-2-just-butyl-4-chloro-5-hydroxy methylimidazole synthetic.

100mg(0.18mmol) compound 1) be dissolved in the 5ml ethanol, at room temperature with 10mg(0.27mmol) sodium borohydride mixes.Add 10ml 5% sodium bisulfate after 20 hours, extract 3 times organic phase Na with EE ₂SO ₄Drying concentrates.SiO ₂Chromatography is used EE/HEP(3/1) wash-out, obtain this title compound of 55mg.

Rf（EE/HEP 3/1）＝0.25，MS（DCI）＝533（M ⁺+H）

Embodiment 41-54 compound (seeing formula B) synthesizes (table 3) with the method that is similar to example 40 by embodiment 2,3 and 16-27 compound

Table 3

Embodiment MS R

FAB;M ⁺+H）

41 519 n-propyls

42 554

43 555

44 545

45 560

46 561

Table 3(is continuous)

Embodiment MS R

FAB;M ⁺+H）

47 599

48 543

49 598

50 598

51 571

52 571

53 633

54 633

Embodiment 55

1-((2 '-allyl group amido carbonyl amido alkylsulfonyl biphenyl-4-yl) methyl)-2-just-preparation of butyl-4-chloro-imidazoles-5-formaldehyde

730mg(1.69mmol) compound 1h) in the 10ml allyl isocyanate, be heated to 80 ℃.After 4 hours, concentrate and carry out SiO ₂Chromatography (eluent: EE/HEP(2/1)) obtains this title compound of 400mg thus.

Rf（EE/HEP 2/1）＝0.15，MS（FAB）＝515（M ⁺+H）

Embodiment 56

1-((2 '-allyl group amido carbonyl amido alkylsulfonyl biphenyl-4-yl)-methyl)-2-just-preparation of butyl-4-methylthio group-imidazole-5-carboxylic acid

A) 2-amino-2-cyano group-ethyl acetate

35g(0.246mol) 2-cyanoacetaldehyde acetoacetic ester-2-oxime adding 350mlH ₂O and 280ml saturated sodium bicarbonate solution, gradation at room temperature adds (15 minutes) 119g dithionous acid sodium.Heated 1 hour for 35 ℃ then; Add Nacl then, make it saturated and with dichloromethane extraction 5 times.After organic phase is used the calcium chloride drying, concentrate, obtain this title compound of 11.8g oily.

Rf（CH ₂Cl ₂/CH ₃OH 9/1）＝0.6

B) 2-cyano group-2-normal-butyl-carbonyl glycine ethyl ester

3.6g(28.09mmol) compound 56a) in the anhydrous CH of 50ml ₂Cl ₂And 2.3ml(28.09mmol) in the pyridine, under 0 ℃, splash into 3.39ml(28.09mmol at-5 ℃) in 5mlCH ₂Cl ₂In valeryl chloride.At room temperature stirred then 1 hour.Organic phase H ₂O gives a baby a bath on the third day after its birth inferior, washes 1 time with saturated Nacl solution again, uses the calcium chloride drying, concentrates, and uses the DIP crystallization, gets this title compound of 1.7g.

Rf（CH ₂Cl ₂/CH ₃OH 9/1）＝0.35

Fusing point: 87 ℃

C) 3-amino-2-normal-butyl carbonyl amido-methyl sulfo-ethyl propenoate

2.9g(13.67mmol) compound 56b) and 0.19ml(1.36mmol) triethylamine in the 60ml dehydrated alcohol, at room temperature add 2ml(27.26mmol) spissated thiomethyl alcohol.Add the 0.5ml thiomethyl alcohol after 3 days again.Add 0.5ml thiomethyl alcohol and 0.19ml triethylamine after 24 hours under the room temperature once more, stirred 24 hours under the room temperature.Remove then and desolvate, residuum DIP crystallization gets this title compound 2.4g.

Rf（CH ₂Cl ₂/EE 4/1）＝0.3

Fusing point: 120 ℃

D) 2-just-butyl-4-first sulfo--imidazole-5-carboxylic acid ethyl ester

4.17g(20.0mmol) phosphorus pentachloride is in 20mlCH ₂Cl ₂In, under-78 ℃, will be dissolved in 12mlCH ₂Cl ₂2.44g(20.0mmol) the 4-dimethylamino pyridine splashes in this solution.Splash into after 5 minutes and be dissolved in 25mlCH ₂Cl ₂In 2.42g(10.0mmol) compound 56c.Be back to room temperature and with 30mlCH this moment ₂Cl ₂Dilute.At the ice-cooled 300ml 1N sodium hydrogen carbonate solution that adds down, stirred 1 hour after 2 hours.Separate two-phase then, water extracts 3 times with EE, and organic phase is merged, and uses the calcium chloride drying, concentrates SiO ₂Chromatography is used CH ₂Cl ₂/ EE(9/1) wash-out.

Rf（CH ₂Cl ₂/EE 9/1）＝0.6 MS（DCI）＝243（M ⁺+H）

E) 1-((2 '-sulfonamido biphenyl-4-yl) methyl)-2-just-butyl-4-methylthio group-imidazole-5-carboxylic acid ethyl ester

1.35g(2.5mmol) 1-((2 '-N, N dimethylamine base-formyl sulfonamido biphenyl-4-yl) methyl)-2-just-butyl-4-methylthio group-imidazole-5-carboxylic acid ethyl ester (from by embodiment 56d) and by embodiment 1e) by being similar to embodiment 1g) method make) be dissolved in the 30ml methyl alcohol, add the dense Hcl of 15ml.Reflux 90 minutes postcooling to room temperature, regulate pH value to 5-6 with 2N NaOH solution.Extract 3 times with EE100ml then at every turn.Organic extracting solution Na ₂SO ₄Dry and concentrated.Get this title compound, be foam-like material, needn't be further purified and enter next step reactions steps.

Rf（EE/HEP 1/1）＝0.2，MS（FAB）＝488（M ⁺+H）

F) method for making of title compound 56 is:

120mg1-((2 '-allyl group amido carbonyl sulfamic-biphenyl-4-yl)-methyl)-2-normal-butyl-4-methylthio group-imidazole-5-carboxylic acid ethyl ester (being similar to embodiment 55 obtains) stirred 4 days under the room temperature in 10ml ethanol and 1ml 2N sodium hydroxide solution.Concentrate then, add H ₂O also uses 1N Hcl to transfer pH value to 4.Filtering separation obtains this title compound.

Rf（EE/MeOH 10/1）＝0.1，MS（FAB）＝543（M+H）

Embodiment 57

1-((2 '-pyridine ethyl-2-amido carbonyl sulfamic biphenyl-4-yl) methyl)-2-just-butyl-4-thiamazole-4-carboxylic acid

A) 1-((2 '-ethoxy carbonyl alkylsulfonyl biphenyl-4-yl) methyl)-2-just-butyl-4-thiamazole-5-carboxylic acid, ethyl ester

1.21g(2.5mmol) compound 56e) and 0.78g(5.6mmol) salt of wormwood in the anhydrous DME of 20ml, be heated to boiling.Add 0.48ml(5.1mmol) Vinyl chloroformate.Cool off under the room temperature after 1 hour, sneak into 50ml 10%KH ₂PO ₄Solution.After the EE extraction, Na ₂SO ₄Dry and concentrated.Use EE/HEP(2/1) make SiO as eluent ₂Chromatography obtains this title compound of 840mg.

Rf（EE/HEP 2/1）＝0.5，MS（DCI）＝559（M ⁺+H）

B) 1-((2 '-pyridyl ethyl-2-amido carbonyl sulfamic biphenyl-4-base-methyl)-2-just-butyl-4-thiamazole-5-carboxylic acid, ethyl ester

168mg(0.3mmol) compound 57a) and 37mg(0.3mmol) 2-(2-aminoethyl)-pyridine adds in the 8ml dry toluene 2 hours ebuillition of heated.Concentrate SiO subsequently ₂Chromatography (moving phase EE) promptly obtains this title compound of 34mg.

Rf（EE）＝0.15，MS（FAB）＝636（M ⁺+H）

C) preparation method of title compound 57 is similar to 56f)

Rf（EE/MeOH 5/1）＝0.1，MS（FAB）＝608（M ⁺+H）

It is described that table 4 compound synthetic is similar to embodiment 57.

These compounds have molecular formula (c).

Table 4

MS R R′ R″

Embodiment F AB; M ⁺+ H

58 571 C ₂H ₅

H

59 585 H

H

60 599 H

H

61 583 H

62 611 H H

63 668 H

H

Table 4(is continuous)

Table 4(is continuous)

Table 4(is continuous)

Table 4(is continuous)

Table 4(is continuous)

Table 4(is continuous)

Table 4(is continuous)

Table 4(is continuous)

Below the compound of table 5 synthetic by the method that is similar to embodiment 57, the structure of these compounds is suc as formula (D)

Table 5

MS R R′

Embodiment F AB; M ⁺+ H

138 581 C ₂H ₅

139 553 H

140 601 C ₂H ₅

141 585 C ₂H ₅

142 557 H

143 573 H

Table 5(is continuous)

MS R R′

Embodiment F AB; M ⁺+ H

144 617 C ₂H ₅

145 603 C ₂H ₅

146 714 C ₂H ₅

147 589 H

148 686 H

149 575 H

Embodiment 150

1-{ ((2 '-benzyloxy carbonyl sulfamic)-biphenyl-4-yl)-methyl }-2-just-preparation of butyl-4-chloro-imidazoles-5-formaldehyde

The acquisition of title compound 150 is as follows: 215mg(0.5mmol) compound 1h, 71.3 μ l(0.5mmol) chloroformic acid benzyl ester and 70mg(0.5mmol) K ₂CO ₃Anhydrous at 10mlDMF() in, reflux 1.5 hours.Concentrate subsequently, add 100mlEE, use 40mlNaHSO respectively ₄With the Nacl solution washing once, organic phase Na ₂SO ₄Drying and rotary evaporation.Obtain 120mg(42% with the MTB chromatography) title compound 150, m.p.=56 ℃ of Rf(MTC)=0.20, MS(FAB)=566(M ⁺+ H)

The synthetic embodiment 150 and the 57a of being similar to of table 6 compound, these compounds have following molecular formula (E)

Table 6

Embodiment MS R R ' R "

FAB;M ⁺+H

151 674 -OC ₂H ₅-CH ₂-CH ₂-Ph -SMe

152 646 -OH -CH ₂-CH ₂-Ph -SMe

153 558 -OH -CH ₂-CH ₂-CH＝CH ₂-SMe

154 556 -OH -CH ₂-CH ₂-C≡CH -SMe

155 558 -OH -CH ₂

-SMe

156 618 -OC ₂H ₅-CH ₂-CH ₂-O-i-Pr -SMe

157 590 -OH -CH ₂-CH ₂-O-iPr -SMe

158 666 -OC ₂H ₅-CH ₂-CH ₂-O-CH ₂-Ph -SMe

159 628 -OC ₂H ₅

-SMe

Table 6(is continuous)

Table 6(is continuous)

Embodiment 178

1-((2 '-dimethylamino sulfoamido alkylsulfonyl biphenyl-4-base-methyl)-2-just-preparation of butyl-4-methylthio group-imidazole-5-carboxylic acid ethyl ester

Obtain the method for title compound 178: 244mg(0.5mmol) compound 56e), 108 μ l(1.0mmol) sulphonamide chlorine and 140mg(1.0mmol) K ₂CO ₃Anhydrous at 10mlDME() in reflux 5 days.With the 50mlEE dilution, use 50mlKHSO ₄/ H ₂SO ₄(PH=1.0) washing.Organic phase Na ₂SO ₄Dry rotary evaporation.Use the EE chromatography, obtain 69mg(23%) colorless oil.

Rf（EE）＝0.15，MS（FAB）＝617（M ⁺+Na）

Embodiment 179

1-(1-(2 '-dimethylamino alkylsulfonyl amido alkylsulfonyl biphenyl-4-base-methyl)-2-just-preparation of butyl-4-methylthio group-imidazole-5-carboxylic acid

50mg(84mmol) the title compound of embodiment 178,0.84ml 1NNaOH are dissolved in the 3ml ethanol, stirring at room 2 days.Steam and remove ethanol, add entry 5ml, regulate PH=2 with Hcl, precipitation is washed 2 times with 1ml, vacuum-drying.Obtain 33mg(70%) this title compound, be colourless powder.

Rf(EE/ methyl alcohol 5/1)=0.11, MS(FAB)=567(M ⁺+ H)

Embodiment 180

1-((2 '-allyloxycarbonyl sulfamyl-biphenyl-4-yl) methyl)-2-normal-butyl-4-methylthio group-imidazole-5-carboxylic acid ethyl ester

244mg(0.5mmol) compound 56e), 106 μ l(1.0mmol) allyl chlorocarbonate, and 140mg(1.0mmol) K ₂CO ₃Backflow was boiled 1 hour.Add 10%KHSO then ₄Solution 50ml extracts 3 times with 50mlEE at every turn.Organic phase Na ₂SO ₄Drying and evaporation.With 1: 1 chromatography of MTB/DIP, promptly obtain 115mg(40%) colorless oil,

Rf（MTB/DIP 1∶1）＝0.15，MS（FAB）＝572（M ⁺+H）

Embodiment 181

1-((2 '-allyloxy carbonyl ammonia alkylsulfonyl-biphenyl-4-yl) methyl)-2-normal-butyl-4-methylthio group-imidazole-5-carboxylic acid

95mg(0.17mmol) compound 180 presses embodiment 179 described method saponification.Promptly obtain 30mg(33%) colourless foam shape thing.

Rf(EE/ methyl alcohol 10/1)=0.1, MS(FAB)=544

Embodiment 182

1-((2 '-benzyloxycarbonyl sulfamyl-biphenyl-4-yl) methyl)-2-normal-butyl-4-methylthio group-imidazole-5-carboxylic acid ethyl ester

The synthetic embodiment 180 that is similar to of this compound

Rf（MTB/DIP 1/1）＝0.15，MS（FAB）＝622（M ⁺+H）

Embodiment 183

1-((2 '-benzyloxycarbonyl sulphonamide-biphenyl-4-yl) methyl)-2-normal-butyl-4-methylthio group-imidazole-5-carboxylic acid

The synthetic embodiment 181 that is similar to of this title compound.

Rf(EE/ methyl alcohol 10/1)=0.1, MS(FAB)=594(M ⁺+ H)

Embodiment 184

1-((2 '-allylamine carbonyl sulfamyl)-biphenyl-4-base-methyl)-2-normal-butyl-4-methoxyl group-imidazoles-5-formaldehyde

A) 1-(2 '-imido alkylsulfonyl biphenyl-4-yl)-methyl)-2-normal-butyl-4-methoxyl group-imidazoles-5-formaldehyde

215mg(0.5mmol) compound 1h) and 1.5mol1N NaOH in 10ml methyl alcohol, reflux and boiled 19 hours.Rotation is steamed and is removed methyl alcohol then, uses NaHSO ₄It is 2 that solution is transferred pH value.Extract 3 times each 50ml with EE.Organic phase Na ₂SO ₄Drying and rotary evaporation.Use MTB/DIP(1: 1) chromatography obtains 170mg(80%) title compound.Fusing point=189 ℃

Rf（MTB/DIP 1/1）＝0.19，MS（DCI）＝428（M ⁺+H）

150mg(0.35mmol) compound 184a) and 3ml allyl isocyanate reflux 5 hours b) acquisition of title compound 184:.Rotary evaporation is also used the EE chromatography then, promptly obtains 60mg(34%) colourless foam shape material.

Rf（EE）＝0.34，MS（FAB）＝511（M ⁺+H）

Embodiment 185

1-((2 '-the ethoxycarbonyl sulfamic)-biphenyl-4-yl)-methyl }-2-normal-butyl-4-methoxy-imidazoles-5-formaldehyde

1.0g(2.34mmol) compound 184a) be dissolved in the 50ml anhydrous propanone, add 650mgK ₂CO ₃Reflux slowly injecting the 0.45ml Vinyl chloroformate under the temperature like this, continued reflux 4 hours, and rotary evaporation is used NaHSO then ₄Solution transfers to 2 with PH, and each subsequently 100mlEE extracts 3 times.Na ₂SO ₄Drying, last rotary evaporation is also used MTB/DIP/HOAc(15: 83: 2) chromatography, the oil that obtains can obtain the 550mg colourless crystallization, fusing point in the ether crystallization: 134 ℃.

Rf（MTB）＝0.24，MS（FAB）＝500（M ⁺+H）

Embodiment 186

1-{ (2 '-carbobenzoxy-(Cbz) amido alkylsulfonyl-biphenyl-4-yl)-methyl }-2-just-butyl-4-methoxyl group-imidazoles-5-formaldehyde

The synthetic method of embodiment 186 is similar to embodiment 185.

Rf（MTB）＝0.16，MS（FAB）＝562（M ⁺+H）

Embodiment 187

1-{ ((2 '-benzylamine carbonyl sulfamic)-biphenyl-4-yl)-methyl }-2-just-butyl-2-imidazole-5-carboxylic acid ethyl ester

150mg(0.24mmol) embodiment 73 compounds are dissolved in 50ml methyl alcohol and 5mlHOAc, and adding catalytic amount pd/c, mixture at room temperature stirred 12 hours in the nitrogen atmosphere, carried out chromatography with the mixture rotary evaporation and with EE then, can get 30mg(22%) colourless foam shape product.

Rf（EE）＝0.42，MS（FAB）＝575（M ⁺+H）

Embodiment 188

1-{ ((2 '-ethoxy carbonyl sulfamic)-biphenyl-4-yl)-methyl }-2-just-butyl-imidazole-5-carboxylic acid ethyl ester

300mg(0.5mmol) compound 57a is dissolved in the 10ml ethanol, adds a nickel in about Ruan 200mg, reflux 10 hours.Add the 200mg Raney nickel again, reflux 5 hours filters catalyzer, and solvent rotary evaporation, residuum MTB chromatography gets 50mg(18%) colourless foam shape product.

Rf（EE）＝0.27，MS（FAB）＝514（M ⁺+H）

Embodiment 189

1-((2 '-{ 2-thienyl sulphonyl amido alkylsulfonyl }-biphenyl-4-yl)-methyl)-2-normal-butyl-4-methylthio group-imidazole-5-carboxylic acid ethyl ester

244mg(0.5mmol) sulphonamide of routine 56e is dissolved in the anhydrous diethylene glycol dimethyl ether of 10ml, and then adds 346mg(2.5mmol) K ₂CO ₃And 81mg(0.5mmol) 2-thiophene SULPHURYL CHLORIDE, reflux 2 hours is poured reaction mixture into 50ml5%NaHSO after the cooling ₄In the solution, extract 3 times Na with the EE of each 50ml ₂SO ₄Drying, rotary evaporation, and carry out chromatography with EE.Can get the faint yellow crystallization of 310mg.

m.p.＝120-122℃

Rf（EE）＝0.24，MS（FAB）＝634（M ⁺+H）

Embodiment 190

1-((2 '-{ 2-thiophenesulfonamide base alkylsulfonyl }-biphenyl-4-yl)-methyl)-2-normal-butyl-4-methylthio group-imidazole-5-carboxylic acid

The saponification of the ethyl ester of embodiment 189 and embodiment 56f are similar.

Rf(EE/ methyl alcohol 5: 1)=0.13, MS(FAB)=606(M ⁺+ H)

The synthetic embodiment of being similar to 189 or the 190(or the 56f of 7 compounds tabulate down).

These compounds have following structural formula F)

Table 7

MS（FAB）

Embodiment M ⁺+ H R R '

191 673 C ₂H ₅The 4-nitrophenyl

192 645 H ″

193 579 C ₂H ₅C ₂H ₅

194 634 C ₂H ₅The 2-thienyl

Embodiment 195

1-(2 '-methylamino carbonyl amido alkylsulfonyl biphenyl-4-yl)-methyl)-2-normal-butyl-4-methylthio group-imidazole-5-carboxylic acid ethyl ester

Sulphonamide manthanoate in autoclave among the 1g example 57a is dissolved in 50ml toluene, feed methylamine in 5 minutes in 80 ℃, 80 ℃ were heated 8 hours, concentrated in a vacuum then, residuum promptly obtains the amorphous powder of this title compound with silica gel column chromatography (EE/n-HEP 2/1).

Rf（EE/n-HEP 2/1）＝0.1，MS（FAB）＝545（M ⁺+H）

Be similar to embodiment 195 and embodiment 56f, can synthesize tabulation 8 compounds (embodiment 195 compounds are also listed in the table) down.

The structure of this compounds is formula c.

Table 8

MS（FAB）;

Embodiment M ⁺+ H R R '

195 545 -C ₂H ₅-CH ₃

196 517 H -CH ₃

197 559 -C ₂H ₅-C ₂H ₅

198 531 H -C ₂H ₅

199＊ 619 -C ₂H ₅-CH ₂-CH ₂-O-CH ₂-CH ₂-OH

200＊ 591 H -CH ₂-CH ₂-O-CH ₂-CH ₂-OH

^*It is synthetic that compound seems the method for embodiment 57 by class.

Claims (5)

1, a kind of preparation method of formula I compound or pharmaceutically acceptable salt thereof,

Wherein, each symbol has following meaning:

R ¹Be (C ₂-C ₁₀)-alkyl, (C ₃-C ₁₀)-alkenyl or (C ₃-C ₈)-cycloalkyl;

R ²For being selected from hydrogen, halogen, (C independently of one another ₁-C ₁₀)-alkyl ,-(CH ₂)-OR ⁵,-S (O) _r-R ¹⁹,-CO-R ⁸Or-O-R ⁶Group;

R ⁵Be hydrogen or (C independently of one another ₁-C ₆)-alkyl;

R ⁶Be independently of one another

(1) hydrogen;

(2) (C ₁-C ₆)-alkyl, it can be identical or different by 1-3, be selected from following group replaces: (C ₁-C ₆)-alkoxyl group, hydroxyl, carboxyl and (C ₁-C ₄)-carbalkoxy;

(C ₂-C ₄)-alkenyl, it can be replaced by phenyl; Or (C ₃-C ₆)-alkynyl;

(3) (C ₃-C ₈)-cycloalkyl, (C ₃-C ₈)-cycloalkyl-(C ₁-C ₃)-alkyl;

(4) (C ₆-C ₁₂)-aryl;

(5) (C ₆-C ₁₀)-aryl-(C ₁-C ₄)-alkyl, it can be replaced by 1 or 2 identical or different following group that are selected from: trifluoromethyl, methoxyl group, halogen and-NR ¹¹R ¹²

(6) (C ₁-C ₉)-heteroaryl, it can be by partially or completely hydrogenation;

(7) (C ₂-C ₁₀)-alkenoyl;

(8) (C ₆-C ₁₂)-aryl or (C ₁-C ₉)-heteroaryl, this heteroaryl by 1 or 2 identical or different, be selected from following group and replace: halogen, hydroxyl, methoxyl group, nitro, cyano group, trifluoromethyl and-NR ¹¹R ¹²

(9) (C ₁-C ₉)-heteroaryl-(C ₁-C ₃)-alkyl, assorted substrate wherein is disconnected can be by part or all of hydrogenation;

R ⁸Be independently of one another hydrogen ,-NR ¹¹R ¹²Or-OR ⁶

R ⁹Be hydrogen, (C ₁-C ₆)-alkyl, (C ₃-C ₈)-cycloalkyl or (C ₂-C ₄)-alkenyl;

R ¹¹And R ¹²Be hydrogen or (C independently of each other ₁-C ₄)-alkyl;

A be one by R ¹⁵The xenyl that replaces;

R ¹⁵For-SO ₂-NH-CO-NR ⁶R ⁹,-SO ₂-NH-COOR ⁶,

SO ₂-NH-COR ⁶Or-SO ₂-NH-SO ₂-NR ⁶R ⁹

R ¹⁹Each is (C independently ₁-C ₆)-alkyl, one of them extremely whole hydrogen atom can be replaced by fluorine; (C ₃-C ₈)-cycloalkyl; Phenyl or benzyl;

R is 0,1 or 2; And wherein

(C above-mentioned ₁-C ₉)-heteroaryl and (C ₁-C ₉)-heteroaryl-be independently selected from furyl, thienyl, pyrryl, imidazolyl, pyrazolyl, triazolyl, tetrazyl, oxazolyl.Isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, indyl, indazolyl, chinol base, different chinol base, 2 base, quinoxalinyl, quinazolyl and cinnolines base;

This method comprises, makes the formula II alkylation with the formula III compound

R wherein ¹And R ²As above definition,

U-CH ₂-A (Ⅲ)

Wherein

The same definition of A;

U is a leavings group,

As suitable, the interim protecting group of introducing of cancellation, and if suitable; the formula I sulphonamide that obtains is transformed accepted way of doing sth I urethane,, formula I sulphonamide or the formula I urethane that obtains transformed accepted way of doing sth I sulfonylurea if suitable; and, the formula I compound that obtains is changed into their pharmaceutical salts if suit.

2, according to the process of claim 1 wherein that prepare the formula I compound or pharmaceutically acceptable salt thereof according to claim 1, symbol wherein has following meaning:

R ¹Be (C ₂-C ₁₀)-alkyl, (C ₃-C ₁₀)-alkenyl or (C ₃-C ₈)-cycloalkyl;

R ²Be hydrogen, halogen, (C independently of one another ₁-C ₁₀)-alkyl ,-(CH ₂)-OR ⁵,-S(O) _r-R ¹⁹,-CO-R ⁸Or-O-R ⁶;

R ⁵Be hydrogen or (C independently of one another ₁-C ₆)-alkyl;

R ⁶Be independently of one another

(1) hydrogen;

(2) (C ₁-C ₆)-alkyl, it can be identical or different by 1-3, be selected from following group replaces: (C ₁-C ₆)-alkoxyl group, hydroxyl, carboxyl and (C ₁-C ₄)-carbalkoxy;

(C ₂-C ₄)-alkenyl, or

(C ₃-C ₆)-alkynyl;

(3) (C ₃-C ₈)-cycloalkyl, (C ₃-C ₈)-cycloalkyl-(C ₁-C ₃)-alkyl;

(4) (C ₆-C ₁₂)-aryl;

(5) (C ₆-C ₁₀)-aryl-(C ₁-C ₄)-alkyl, it can by 1 or 2 identical or different, be selected from following group and replace: trifluoromethyl, methoxyl group, halogen and-NR ¹¹R ¹²;

(6) (C ₂-C ₁₀)-alkenoyl;

(7) (C ₆-C ₁₂)-aryl, it by 1 or 2 identical or different, be selected from following group and replace: halogen, hydroxyl, methoxyl group, nitro, cyano group, trifluoromethyl and-NR ¹¹R ¹²;

(8) be independently of one another hydrogen or-OR ⁶;

(9) be hydrogen, (C ₁-C ₆)-alkyl, (C ₃-C ₈)-cycloalkyl or (C ₂-C ₄)-alkenyl;

R ¹¹And R ¹²Be hydrogen or (C independently of each other ₁-C ₄)-alkyl;

A is an xenyl, and it is by R ¹⁵Group replaces;

R ¹⁵For-SO ₂-NH-CO-NR ⁶R ⁹,-SO ₂-NH-COOR ⁶,-SO ₂-NH-COR ⁶Or-SO ₂-NH-SO ₂-NR ⁶R ⁹;

R ¹⁹Be (C independently ₁-C ₆)-alkyl, one of them extremely whole hydrogen atom can be replaced by fluorine; (C ₃-C ₈)-cycloalkyl; Phenyl; Or benzyl; And

R is 0,1 or 2.

3, according to the process of claim 1 wherein that prepare the formula I compound or pharmaceutically acceptable salt thereof according to claim 1, symbol wherein has following meaning:

R ¹Be (C ₂-C ₁₀)-alkyl;

R ²Be independently of one another-SCH ₃Or-CO-R ⁸;

R ⁶Be hydrogen or (C independently of one another ₁-C ₆)-alkyl;

R ⁸Be independently of one another hydrogen or-OR ⁶;

R ⁹Be hydrogen, (C ₁-C ₆)-alkyl or (C ₂-C ₄) alkenyl;

A be one by R ¹⁵The xenyl that replaces;

R ¹⁵For-SO ₂-NH-CO-NR ⁶R ⁹

4, comprise preparation 1-((2 '-n-propyl-amino carbonyl amino alkylsulfonyl biphenyl-4-yl) methyl according to the process of claim 1 wherein)-2-normal-butyl-4-methyl thiocarbamoyl imidazole-5-carboxylic acid, ethyl ester or its pharmaceutical salts.

5, comprise preparation 1-((2 '-n-propyl-amino carbonyl amino alkylsulfonyl biphenyl-4-yl) methyl according to the process of claim 1 wherein)-2-normal-butyl-4-methyl thiocarbamoyl imidazole-5-carboxylic acid or its pharmaceutical salts.