JP2004533457A5

JP2004533457A5 -

Info

Publication number: JP2004533457A5
Application number: JP2003500062A
Authority: JP
Filing date: 2002-05-30
Publication date: 2006-01-05
Anticipated expiration: 2022-05-30

Claims

A compound of formula I or a pharmaceutically acceptable salt thereof

[In the above formula,
One of X ₁ and X ₂ represents -N- and the other represents -C (R ¹ )-;
X ₃ represents -N- or -C (R ² )-;
X ₄ represents -N- or -C (R ³ )-;
R ¹ , R ² and R ³ independently represent H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl or halo;
However, when X ₁ represents -C (R ¹ )-, X ₃ represents -C (R ² )-, and X ₄ represents -C (R ³ )-, R ¹ represents H Represents;
Y ₁ , Y ₂ , Y ₃ and Y ₄ independently represent -CH- or -CF-;
Z ₁ represents -CH-, -O-, -S-, -N- or -CH = CH-;
Z ₂ represents -CH-, -O-, -S- or -N-;
However,
(a) Z ₁ and Z ₂ are not the same;
(b) when Z ₁ represents -CH = CH-, Z ₂ can represent only -CH- or -N-;
(c) Z ₁ represents -CH = CH-, with the exception of special cases that represent Z ₂ is -CH-, when one of Z ₁ and Z ₂ represents -CH-, other, -O- Or -S-;
R ⁴ is -S (O) ₂ N (H) C (O) R ⁶ , -S (O) ₂ N (H) S (O) ₂ R ⁶ , -C (O) N (H) S ( O) ₂ R ⁶ or when Z ₁ represents —CH═CH—, R ⁴ represents —N (H) S (O) ₂ N (H) C (O) R ⁷ or — N (H) C (O) N (H) S (O) ₂ R ⁷ may be represented;
R ⁵ is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy-C ₁ -C ₆ -alkyl or di-C ₁ -C ₃ -alkylamino-C ₁ -C ₄ alkyl Represents;
R ⁶ is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy-C ₁ -C ₆ -alkyl, C ₁ -C ₃ alkoxy-C ₁ -C ₆ -alkoxy, C ₁ -C ₆ alkyl amino or di -C ₁ -C ₆ alkylamino;
R ⁷ represents C ₁ -C ₆ alkyl].

The compound according to claim 1, wherein when X ₁ represents -C (R ¹ )-, X ₃ represents -C (R ² )-and X ₄ represents -N-.

3. A compound according to claim 2, wherein R < ¹ > represents H.

X ₁ is -C (R ¹⁾ - to represent a both X ₃ and X ₄ represents N, compounds of claim 1.

The compound according to claim 1, wherein when X ₁ represents -C (R ¹ )-, X ₃ represents -C (R ² )-and X ₄ represents -C (R ³ )-. .

When the X ₁ represents -N-, X ₃ is represents -N-, A compound according to claim 1.

X ₄ is -C (R ³⁾ - in the case of representing a, R ³ is represents H, compound of Claim 6.

The compound according to claim 1, wherein when X ₁ represents -N-, X ₃ represents -C (R ² ) and X ₄ represents -C (R ³ )-.

R ¹ is, H, represents a C ₁ -C ₃ alkyl or CF _3, A compound according to any one of claims 1, 2, 4 or 6 8.

10. A compound according to claim 9, wherein R < ¹ > represents H or ethyl.

R ² is, C ₁ -C ₃ alkyl, represents halo or H, A compound according to any one of 10 claims 1 to 3, 5 or 8.

R ² is H or methyl, A compound according to claim 11.

R ² is represents H, compound of claim 12.

R ³ is, C ₁ -C ₃ alkyl, represents halo or H, A compound according to any one of claims 1, 5, 6 or 8 13.

R ³ is represents H, compound of claim 14.

Y _1, Y _2, Y ₃ and Y ₄ are all represent -CH-, A compound according to any one of claims 1 to 15.

Z ₁ is, -S- or represents a -CH = CH-, A compound according to any one of claims 1 to 16.

Z ₁ is represents -S-, A compound according to claim 17.

Z ₂ is represents -CH-, A compound according to any one of claims 1 18.

R ⁴ is, -S (O) represents a _{2 N (H) C (O} ) R 6, A compound according to any one of claims 1 19.

R ⁵ is representative of the n- butyl or isobutyl, A compound according to any one of claims 1 20.

R ⁵ is represents isobutyl, compounds of claim 21.

R ⁴ is -S (O) ₂ N (H) C (O) R ⁶ , -S (O) ₂ N (H) S (O) ₂ R ⁶ or -C (O) N (H) S ( O) represents ₂ R ^6, R ⁶ is, n- butoxymethyl, iso - represents a butoxy or n- butoxy, compounds according to any one of claims 1 to 22.

R ⁶ is, represents a n- butoxy, compound of claim 23.

X ₁ , X ₃ and X ₄ all represent -CH-, Y ₁ , Y ₂ , Y ₃ and Y ₄ all represent -CH- and Z ₁ represents -S- or -CH = CH- When Z ₂ represents -CH- and R ⁵ represents n-butyl or isobutyl, R ⁴ represents -S (O) ₂ N (H) C (O) R ⁶ _2. The compound according to claim 1, wherein R ⁶ represents —On-butyl, —O-isopropyl, —O-isobutyl or —CH ₂ —On-butyl.

N-butyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide;
N-isobutyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide;
N-isopropyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide;
N- (butoxyacetyl) -3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide;
N-butyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-butylthiophene-2-sulfonamide;
N-butyloxycarbonyl-2- (4-imidazol-1-ylmethylphenyl) -4-isobutylbenzene-sulfonamide;
N-butyloxycarbonyl-5-isobutyl-3- (4-tetrazol-2-ylmethylphenyl) thiophene-2-sulfonamide;
N-butyloxycarbonyl-5-isobutyl-3- (4-tetrazol-1-ylmethylphenyl) thiophene-2-sulfonamide;
N-butyloxycarbonyl-3- (4- [1,2,4] triazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide;
N- (butylamino) carbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide;
N-butylsulfonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide;
N-butylsulfonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-carboxamide;
N-butyloxycarbonyl-4-butyl-2- (4-imidazol-1-ylmethylphenyl) benzene-sulfonamide;
N- (2-methoxyethyloxy) carbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide;
N-ethyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide;
Nt-butyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide;
N-butyloxycarbonyl-3- [4- (4-methylimidazol-1-ylmethyl) phenyl] -5-isobutylthiophene-2-sulfonamide;
N-butyloxycarbonyl-3- (4-pyrazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide;
N-butyloxycarbonyl-3- [4- (3-trifluoromethylpyrazol-1-ylmethyl) phenyl] -5-isobutylthiophene-2-sulfonamide;
N- (N-butyl-N-methylamino) carbonyl-3- (4-imidazol-1-ylmethylphenyl) -5-isobutylthiophene-2-sulfonamide; or
N-butyloxycarbonyl-3- (4-imidazol-1-ylmethylphenyl) -5- (2-methoxyethyl) -thiophene-2-sulfonamide.

A compound as defined in any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof, mixed with a pharmaceutically acceptable adjuvant, diluent or carrier, and containing AT2 receptor A pharmaceutical formulation for use in the treatment of conditions where selective agonism is desirable and / or required .

In vivo production of AngII containing a compound as defined in any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof , mixed with a pharmaceutically acceptable adjuvant, diluent or carrier A pharmaceutical formulation for use in the treatment of conditions that are deficient.

27. Increasing the Ang II effect comprising a compound as defined in any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof mixed with a pharmaceutically acceptable adjuvant, diluent or carrier A pharmaceutical formulation for use in the treatment of conditions that are desirable or needed.

A compound as defined in any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof , mixed with a pharmaceutically acceptable adjuvant, diluent or carrier , wherein the AT2 receptor is A pharmaceutical formulation for use in the treatment of a condition that is expressed and whose stimulation is desirable or required.

31. A formulation according to any one of claims 27 to 30, wherein the condition is of the gastrointestinal tract, cardiovascular system, respiratory organ, kidney, eye, female genital (ovulation) system or central nervous system.

The condition is esophagitis, Barrett's esophagus, gastric ulcer, duodenal ulcer, dyspepsia (including non-ulcer dyspepsia), gastro-esophageal reflux, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, liver damage (including hepatitis) Gallbladder disease, multiple organ failure, sepsis, xerostomia, gastritis, gastric insufficiency, hyperacidity, biliary duct disorders, coelicia, Crohn's disease, ulcerative colitis, diarrhea, constipation, colic, dysphagia, vomiting, Nausea, dyspepsia, Sjogren's syndrome, inflammatory disorder, asthma, obstructive pulmonary disease (including chronic obstructive pulmonary disease), pneumonia, pulmonary hypertension, adult respiratory distress syndrome, renal failure, nephritis, renal hypertension , Diabetic retinopathy, premature retinopathy, retinal microangiogenesis, ovulation disorder, hypertension, cardiac hypertrophy, heart failure, atherosclerosis, arterial thrombosis, venous thrombosis, endothelial disorder, endothelial damage, Stenosis after balloon dilatation, angiogenesis, diabetes Pathological complications, microvascular disorders, tonsillitis, cardiac arrhythmia, intermittent claudication, preeclampsia, myocardial infarction, reinfarction, ischemic disorder, erectile dysfunction, neointimal proliferation, cognitive impairment, eating disorder (hunger / fullness) ), Dry mouth, stroke, intracerebral hemorrhage, cerebral embolism, cerebral infarction, hypertrophic disorder, prostatic hypertrophy, autoimmune disorder, psoriasis, obesity, neuronal regeneration, ulcer, adipose tissue hyperplasia, stem cell differentiation and proliferation, cancer, apoptosis, 32. The formulation of claim 31, wherein the formulation is tumor, hypertrophic diabetes, neuronal damage or organ rejection.

The formulation of claim 32, wherein the condition is non-ulcer dyspepsia, irritable bowel syndrome, multiple organ failure, hypertension or heart failure.

27. A medicament comprising a compound as defined in any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof and an AT1 receptor antagonist mixed with a pharmaceutically acceptable adjuvant, diluent or carrier. Formulation.

In the kit, the ingredients:
(a) A pharmaceutical formulation comprising a compound as defined in any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof mixed with a pharmaceutically acceptable adjuvant, diluent or carrier. ;and
(b) comprising a pharmaceutical formulation containing an AT1 receptor antagonist mixed with a pharmaceutically acceptable adjuvant, diluent or carrier, wherein components (a) and (b) are each administered in combination with the other A kit consisting of parts that are provided in a suitable shape.

Comprising a compound as defined in any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof and an angiotensin converting enzyme inhibitor mixed with a pharmaceutically acceptable adjuvant, diluent or carrier, Pharmaceutical formulation.

In the kit, the ingredients:
(a) A pharmaceutical formulation comprising a compound as defined in any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof mixed with a pharmaceutically acceptable adjuvant, diluent or carrier. ;and
(b) comprising a pharmaceutical formulation containing an angiotensin converting enzyme inhibitor mixed with a pharmaceutically acceptable adjuvant, diluent or carrier, wherein components (a) and (b) are each administered in combination with the other A kit consisting of parts that are provided in a suitable shape.

A process for preparing the compound of claim 1
(i) R ⁴ in the formula represents -S (O) ₂ N (H) C (O) R ⁶ or -S (O) ₂ N (H) S (O) ₂ R ⁶ and R ⁶ claims For compounds of formula I defined as in paragraph 1, compounds of formula II:

[Wherein X ₁ , X ₂ , X ₃ , X ₄ , Y _1, Y ₂ , Y ₃ , Y ₄ , Z ₁ , Z ₂ and R ⁵ are defined as in claim 1] A compound of formula III:
R ⁶ GL ¹ III
[Wherein G represents C (O) or S (O) ₂ (suitably), L ¹ represents a suitable leaving group, and R ⁶ is defined as in claim 1. Or)];
R ⁴ in (ii) wherein represents _{-S (O) 2 N (H} ) C (O) R 6, compounds of formula I in which R ⁶ represents a C ₁ -C ₆ alkoxy -C ₁ -C ₆ alkyl Then, the compound of formula II as defined above is converted to the compound of formula IV
R ^6a CO ₂ H IV
[Wherein R ^6a represents C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl];
(iii) In the compounds of formula I, wherein R ⁴ represents -C (O) N (H) S (O) ₂ R ⁶ and R ⁶ is defined as in claim 1, the compound of formula V :

[Wherein X ₁ , X ₂ , X ₃ , X ₄ , Y _1, Y ₂ , Y ₃ , Y ₄ , Z ₁ , Z ₂ and R ⁵ are defined as in claim 1] A compound of formula VI:
R ⁶ S (O) ₂ NH ₂ VI
[Wherein R ⁶ is defined as in claim 1];
(iv) In the compounds of formula I, wherein R ⁴ represents -C (O) N (H) S (O) ₂ R ⁶ and R ⁶ is defined as in claim 1, the compound of formula VII :

[Wherein X ₁ , X ₂ , X ₃ , X ₄ , Y _1, Y ₂ , Y ₃ , Y ₄ , Z ₁ , Z ₂ and R ⁵ are defined as in claim 1] A compound of formula VIII:
R ⁶ S (O) ₂ Cl VIII
[Wherein R ⁶ is defined as in claim 1];
(v) in the compounds of formula I, wherein R ⁴ represents -N (H) S (O) ₂ N (H) C (O) R ⁷ and R ⁷ is defined as in claim 1, Compound of formula IX:

[Wherein X ₁ , X ₂ , X ₃ , X ₄ , Y _1, Y ₂ , Y ₃ , Y ₄ , Z ₁ , Z ₂ and R ⁵ are defined as in claim 1] A compound of formula X:
R ⁷ C (O) N (H) S (O) ₂ Cl X
[Wherein R ⁷ is defined as in claim 1];
(vi) in the compounds of formula I, wherein R ⁴ represents -N (H) C (O) N (H) S (O) ₂ R ⁷ and R ⁷ is defined as in claim 1, A compound of formula IX as defined above is converted to a compound of formula XI:
R ⁷ S (O) ₂ N (H) C (O) OR ^X XI
In which R ^x represents C ₁ -C ₂ alkyl and R ⁷ is defined as in claim 1 or
(vii) In the compounds of formula I, wherein R ⁴ represents -N (H) C (O) N (H) S (O) ₂ R ⁷ and R ⁷ is defined as in claim 1, A compound of formula IX as defined above is a compound of formula XII:
R ⁷ S (O) ₂ NCO XII
[Wherein R ⁷ is defined as in claim 1];
R ⁴ in (viii) wherein represents _{-S (O) 2 N (H} ) C (O) R 6, in the compound of formula I in which R ⁶ represents a C ₁ -C ₆ alkylamino, defined by the The compound of formula II is converted to the compound of formula XIII:
R ^6b NCO XIII
Reacting with wherein R ^6b represents C ₁ -C ₆ alkyl; or
(ix) in formula R ⁴ represents _{-S (O) 2 N (H} ) C (O) R 6, in the compounds of formula I wherein the R ⁶ is a di -C ₁ -C ₆ alkylamino, wherein the R ⁴ represents _{-S (O) 2 N (H} ) C (O) R 6, the corresponding compound of formula I in which R ⁶ represents a C ₁ -C ₆ alkoxy, wherein XIV:
R ^6c N (H) R ^6d XIV
Wherein R ^6c and R ^6d independently represent C ₁ -C ₆ alkyl].

A compound of formula II as defined in claim 38 or a protected derivative thereof.

X ₁ , X ₃ and X ₄ in the formula all represent -CH-, Y ₁ , Y ₂ , Y ₃ and Y ₄ all represent -CH-, and Z ₁ represents -S- or -CH = CH- the stands, represents Z ₂ is -CH-, R ⁵ represents n- butyl or isobutyl, compounds or protected derivatives thereof of the formula II according to claim 39.

39. A compound of formula V as defined in claim 38 or a protected derivative thereof.

39. A compound of formula VII as defined in claim 38 or a protected derivative thereof.

39. A compound of formula IX as defined in claim 38 or a protected derivative thereof.