RU2001103645A

RU2001103645A - SERO SUBSTITUTED N-ARILAMIDES OF SULFONILAMINO-CARBOXYLIC ACID, THEIR PRODUCTION, THEIR APPLICATION AND CONTAINING THEIR PHARMACEUTICAL DRUGS

Info

Publication number: RU2001103645A
Application number: RU2001103645/04A
Authority: RU
Inventors: Урзула ШИНДЛЕР; Карл ШЕНАФИНГЕР; Хартмут Штробель
Original assignee: Авентис Фарма Дойчланд Гмбх
Priority date: 1998-07-08
Filing date: 1999-06-25
Publication date: 2003-02-10

Claims

1. The compound of formula l

where A ¹ represents a divalent group from the series consisting of phenylene, naphthylene and heteroarylene, each of which may be substituted by one or more identical or different substituents from the series consisting of halogen, (C ₁ -C ₅ ) -alkyl, phenyl, tolyl , CF ₃ , NO ₂ , OH, -O- (C ₁ -C ₅ ) -alkyl, -O- (C ₂ -C ₄ ) -alkyl-O- (C ₁ -C ₃ ) -alkyl, (C ₁ -C ₂ ) -alkylenedioxy, NH ₂ , -NH (C ₁ -C ₃ ) -alkyl, -N ((C ₁ -C ₃ ) -alkyl) ₂ , -NH-CHO, -NH-CO- (C ₁ -C ₅ ) -alkyl, -CN, -CO-NH ₂ , -CO-NH- (C ₁ -C ₃ ) -alkyl, -CO-N ((C ₁ -C ₃ ) -alkyl) ₂ , -CO -OH, -CO-O- (C ₁ -C ₅ ) -alkyl, heterocyclyl, CHO, -CO- (C ₁ -C ₅ ) -alkyl, -S (O) _n - (C ₁ -C ₄ ) - alkyl, -S (O) _n -fe nyl and -S (O) _n- tolyl; the A ² ring, which contains carbon atoms bearing C (= X) -NH and NH-SO ₂ R ² groups, is a benzene ring, a naphthalene ring, a saturated or partially unsaturated 3-7 membered carbocycle, saturated or partially unsaturated, or aromatic monocyclic 5-7-membered heterocycle containing one or more ring heteroatoms from the series consisting of N, O and S, or saturated or partially unsaturated, or aromatic bicyclic 8-10-membered heterocycle containing one or more ring heteroatoms of row consisting of N, O and S;
R ¹ represents aryl, heterocyclyl or (C ₁ -C ₁₈ ) -alkyl, which may be substituted by one or more identical or different R ⁴ residues, or, if the number n in the group R ¹ -S (O) ₂ is 2, R ¹ may also represent NR ⁵ R ⁶ , or, if the number n in the group R ¹ —S (O) _n is O, R ¹ may also represent —CN;
R ² represents aryl, heterocyclyl, NR ⁵ R ⁶ or (C ₁ -C ₁₀ ) -alkyl, which may be substituted by one or more identical or different R ⁴ groups;
R ³ represents one or more identical or different groups from the series consisting of hydrogen, halogen, CF ₃ , OH, -O- (C ₁ -C ₇ ) -alkyl, -O- (C ₂ -C ₄ ) -alkyl- O- (C ₁ -C ₇ ) -alkyl, -O-aryl, (C ₁ -C ₂ ) -alkylenedioxy, NO ₂ , -CN, NR ⁷ R ⁸ , -CO-NR ⁷ R ⁸ , -CO-OH , -CO-O- (C ₁ -C ₅ ) -alkyl, heterocyclyl, -S (O) _n - (C ₁ -C ₅ ) -alkyl and (C ₁ -C ₅ ) -alkyl, which may be substituted with one or several identical or different groups of R ⁴ ;
R ⁴ is fluoro, OH, —O- (C ₁ -C ₁₀ ) -alkyl, -O- (C ₂ -C ₄ ) -alkyl-O- (C ₁ -C ₇ ) -alkyl, —O-aryl, -CN, NR ⁷ R ⁸ , -CO-NH ₂ , -CO-NH- (C ₁ -C ₃ ) -alkyl, -CO-N ((C ₁ -C ₃ ) -alkyl) ₂ , -CO-OH , -CO-O- (C ₁ -C ₅ ) -alkyl, heterocyclyl or oxo;
R ⁵ represents hydrogen, (C ₁ -C ₁₀ ) -alkyl, which may be substituted by one or more identical or different substituents R ⁴ and / or aryl, or represents aryl, heterocyclyl, -CO-NR ⁷ R ⁸ , -CO- aryl or -CO- (C ₁ -C ₁₀ ) -alkyl, in which the alkyl part may be substituted by one or more identical or different R ⁴ groups;
R ^6, irrespective of R ^5, has one of the meanings indicated for R ⁵ , or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a 5-8 membered saturated or partially unsaturated ring, which, in addition to the nitrogen atom, bearing groups R ⁵ and R ⁶ may contain one or more other ring heteroatoms from the series consisting of N, O and S, and which may be substituted by one or more identical or different substituents from the series consisting of fluorine, (C ₁ -C ₅ ) -alkyl, hydroxy- (C ₁ -C ₃ ) -alkyl-, - (C ₁ -C ₃ ) -alkyl-O- (C ₁ -C ₄ ) -alkyl, aryl, CF ₃ , OH, -O - (C ₁ -C ₇₎ -al sludge, -O-aryl, -O- _{_(C2-C4)} -alkyl-O- (C ₁ -C ₇₎ -alkyl, (C ₂ -C ₃₎ alkylenedioxy, NR ⁷ R ^8, -CN, -CO-NH ₂ , -CO-NH- (C ₁ -C ₃ ) -alkyl, -CO-N ((C ₁ -C ₃ ) -alkyl) ₂ , -CO-OH, -CO-O- (C ₁ -C ₅ ) -alkyl, CHO, -CO- (C ₁ -C ₅ ) -alkyl, -S (O) _n - (C ₁ -C ₄ ) -alkyl, -S (O) _n -NH ₂ , -S (O) _n -NH- (C ₁ -C ₃ ) -alkyl, -S (O) _n -N ((C ₁ -C ₃ ) -alkyl) ₂ , oxo,
- (CH ₂ ) _m -NH ₂ , - (CH ₂ ) _m -NH- (C ₁ -C ₄ ) -alkyl and - (CH ₂ ) _m -N ((C ₁ -C ₄ ) -alkyl) ₂ , where in the substituent - (CH ₂ ) _m -N ((C ₁ -C ₄ ) -alkyl) ₂ two alkyl groups can be connected by a simple bond, and then they, together with the nitrogen atom carrying them, form a 5-7 membered ring, which , in addition to the specified nitrogen atom and carbon atoms, may additionally contain as a member of the ring an oxygen atom, a sulfur atom or a group NR ⁵ ;
R ⁷ represents hydrogen or (C ₁ -C ₇ ) -alkyl, which may be substituted by one or more identical or different substituents from the series consisting of OH, -O- (C ₁ -C ₅ ) -alkyl, NH ₂ , - NH- (C ₁ -C ₄ ) -alkyl and -N ((C ₁ -C ₄ ) -alkyl) ₂ , where in the substituent -N ((C ₁ -C ₄ ) -alkyl) _2, two alkyl groups can be connected a single bond, and then they, together with the nitrogen atom carrying them, form a 5-7 membered ring, which, in addition to the specified nitrogen atom and carbon atoms, may additionally contain an oxygen atom, a sulfur atom or an NR ⁵ group as a ring member;
R ^8, independently of R ^7, has one of the meanings of R ⁷ or is —CO— (C ₁ –C ₄ ) -alkyl;
aryl is phenyl, naphthyl or heteroaryl which may be substituted by one or more, same or different substituents from the series consisting of halogen, (C ₁ -C ₅ ) -alkyl, phenyl, tolyl, CF ₃ , -O-CF ₃ , NO ₂ , OH, -O- (C ₁ -C ₅ ) -alkyl, -O- (C ₂ -C ₄ ) -alkyl-O- (C ₁ -C ₃ ) -alkyl, (C ₁ -C ₂ ) -alkylenedioxy, NH ₂ , -NH (C ₁ -C ₃ ) -alkyl, -N ((C ₁ -C ₃ ) -alkyl) ₂ , -NH-CHO, -NH-CO- (C ₁ -C ₅ ) -alkyl, -CN, -CO-NH ₂ , -CO-NH- (C ₁ -C ₃ ) -alkyl, -CO-N ((C ₁ -C ₃ ) -alkyl) ₂ , -CO-OH, - CO-O- (C ₁ -C ₅ ) -alkyl, heterocyclyl, CHO, -CO- (C ₁ -C ₅ ) -alkyl, -S (O) _n - (C ₁ -C ₄ ) -alkyl, -S (O) _n- phenyl and -S (O) _n- tolyl; heteroaryl and heteroarylene are the remainder of a monocyclic 5- or 6-membered aromatic heterocycle or a bicyclic 8-10-membered aromatic heterocycle, each of which contains one or more ring heteroatoms from the series consisting of N, O and S;
heterocyclyl is a residue of a monocyclic or polycyclic 5-11 membered saturated or partially unsaturated heterocycle that contains one or more ring heteroatoms from the series consisting of N, O and S, and which may be substituted by one or more identical or different substituents from the series consisting of fluorine, (C ₁ -C ₅ ) -alkyl, OH, -O- (C ₁ -C ₅ ) -alkyl, -O- (C ₂ -C ₄ ) -alkyl-O- (C ₁ -C ₃ ) -alkyl, NH ₂ , -NH- (C ₁ -C ₃ ) -alkyl, -N ((C ₁ -C ₃ ) -alkyl) ₂ , -CN, -CO-NH ₂ , -CO-NH- (C ₁ -C ₃ ) -alkyl,
-CO-N ((C ₁ -C ₃ ) -alkyl) ₂ , -CO-OH and -CO-O- (C ₁ -C ₅ ) -alkyl;
n is 0, 1 or 2;
m is 2, 3 or 4;
X represents O or NH or X represents a nitrogen atom which is attached via a single bond to a ring carbon atom in group A ¹ directly adjacent to the carbon atom in A ¹ carrying the group —NH — C (= X) -, whereby the group -NH-C (= X) - together with its carbon atoms in A ¹ forms an annelated imidazole ring;
in all its stereoisomeric forms and in the form of mixtures thereof in all ratios and its physiologically acceptable salts; moreover, however, the compound of the formula I is excluded, in which at the same time the ring A ² containing carbon atoms bearing the groups C (= X) -NH - and NH-S ₂ R ² is a benzene ring substituted in positions 3 and 5 with chlorine , R ² is methyl, X is oxygen, and R ¹ -S (O) _n -A ¹ is a 5-chloro-2- (4-chlorophenylmercapto) phenyl group.

2. The compound of formula I according to claim 1, in which A ¹ represents a phenylene group or a 5- or 6-membered heteroarylene group, all of which groups can be unsubstituted or substituted, in all its stereoisomeric forms and in the form of mixtures thereof in all ratios and its physiologically acceptable salts.

3. The compound of formula I according to claim 1 and / or 2, in which the ring A ² which contains two carbon atoms bearing the groups R ² —SO ₂ —NH and C (= X) —NH— is an aromatic ring, in all its stereoisomeric forms and in the form of mixtures thereof in all ratios and its physiologically acceptable salts.

4. The compound of formula I according to one or more of claims. 1-3, in which X represents oxygen, in all its stereoisomeric forms and in the form of mixtures thereof in all ratios and its physiologically acceptable salts.

5. The compound of formula I according to one or more of claims. 1-4, in which R ² represents unsubstituted or substituted aryl, in all its stereoisomeric forms and in the form of mixtures thereof in all ratios and its physiologically acceptable salts.

6. The compound of formula I according to one or more of claims. 1-5, in which R ¹ represents (C ₁ -C ₇ ) -alkyl, aryl or NR ⁵ R ⁶ , and all of these groups can be unsubstituted or substituted, in all its stereoisomeric forms and in the form of mixtures thereof in all ratios and its physiologically acceptable salts.

7. The compound of formula I according to one or more of claims. 1-6, in which R ¹ represents NR ⁵ R ⁶ and R ⁵ and R ⁶ independently represent hydrogen, (C ₁ -C ₉ ) -alkyl, (C ₁ -C ₄ ) -alkyl-O- (C ₁ -C ₃ ) -alkyl- or 5- or 6-membered aryl, or together with a nitrogen atom bearing R ³ and R ⁶ form a 5-7-membered heterocycle, which in addition to the nitrogen atom bearing the groups R ⁵ and R ⁶ , may contain one additional ring heteroatom from the series consisting of N, O and S, and which may be substituted by one or more identical or different groups from the series consisting of (C ₁ -C ₃ ) -alkyl, hydroxy- (C ₁ - C ₃₎ -alkila-, 5- or 6-membered aryl, carbamoyl, idroksi and oxo, in all its stereoisomeric forms and mixtures thereof in all ratios, and its physiologically acceptable salts.

8. The compound of formula I according to one or more of claims. 1-7, in which A ¹ represents phenylene or heteroarylene, and these groups can be unsubstituted or substituted by one or more identical or different substituents from the series consisting of halogen, (C ₁ -C ₄ ) -alkyl, CF ₃ , -O - (C ₁ -C ₄ ) -alkyl and -CN; the A ² ring, which contains two carbon atoms bearing the groups R ² —SO ₂ —NH and C (= X) —NH—, represents an aromatic ring; R ¹ represents (C ₁ -C ₇ ) -alkyl, which may be substituted by one or more identical or different R ⁴ groups, or aryl or, if the number n in the group R ¹ S (O) _n is 2, also represents a group NR ⁵ R ⁶ ; R ² represents aryl; R ³ represents one or more identical or different groups from the series consisting of hydrogen, halogen, CF ₃ , OH, -O- (C ₁ -C ₄ ) -alkyl, -O- (C ₂ -C ₄ ) -alkyl- O- (C ₁ -C ₄ ) -alkyl, -O-aryl, NO ₂ , -CN, NR ⁷ R ⁸ , -CO-NR ⁷ R ⁸ , -CO-OH, -CO-O- (C ₁ - C ₄ ) -alkyl, heterocyclyl, -S (O) _n - (C ₁ -C ₄ ) -alkyl and (C ₁ -C ₄ ) -alkyl, which may be substituted by one or more identical or different R ⁴ groups; R ⁴ is fluoro, OH, —O- (C ₁ -C ₁₀ ) -alkyl, -O- (C ₂ -C ₄ ) -alkyl-O- (C ₁ -C ₇ ) -alkyl, —O-aryl, -CN, NR ⁷ R ⁸ , -CO-NH ₂ , -CO-NH- (C ₁ -C ₃ ) -alkyl, -CO-N ((C ₁ -C ₃ ) -alkyl) ₂ , -CO-OH , -CO-O- (C ₁ -C ₄ ) -alkyl, heterocyclyl or oxo; R ⁵ and R ⁶ are independently hydrogen, (C ₁ -C ₉ ) -alkyl, (C ₁ -C ₄ ) -alkyl-O- (C ₁ -C ₃ ) -alkyl- or aryl, or together with an atom nitrogen bearing R ⁴ and R ⁶ form a 5-7 membered heterocycle, which, in addition to the nitrogen atom bearing the groups R ⁵ and R ⁶ , may contain one additional ring heteroatom from the series consisting of N, O and S, and which may be substituted by one or more identical or different groups from the series consisting of (C ₁ -C ₃ ) -alkyl, hydroxy- (C ₁ -C ₃ ) -alkyl-, aryl, carbamoyl, hydroxy and oxo; R ⁷ represents hydrogen, (C ₁ -C ₃ ) -alkyl, ((C ₁ -C ₄ ) -alkyl) ₂ N- (C ₁ -C ₃ ) -alkyl or (C ₁ -C ₄ ) -alkyl- O- (C ₁ -C ₃ ) -alkyl-; R ⁸ represents hydrogen, (C ₁ -C ₃ ) -alkyl or acetyl; aryl is phenyl or heteroaryl which may be substituted by one or more identical or different substituents from the series consisting of halogen, (C ₁ -C ₅ ) -alkyl, phenyl, CF ₃ , NO ₂ , -O- (C ₁ - C ₄ ) -alkyl, - (C ₁ -C ₂ ) -alkylenedioxy, NH ₂ , -NH-CO- (C ₁ -C ₄ ) -alkyl, -CN, -CO-NH ₂ , -CO-OH and - CO-O- (C ₁ -C ₄ ) -alkyl; heteroaryl and heteroarylene are the remainder of a monocyclic 5- or 6-membered aromatic heterocycle that contains one or more identical or different ring heteroatoms from the series consisting of N, O and S; heterocyclyl is a monocyclic 5- or 6-membered saturated heterocycle residue that contains one or more identical or different ring heteroatoms from the series consisting of N, O and S, and which can be substituted by one or more identical or different substituents from the series, consisting of fluorine, (C ₁ -C ₄ ) -alkyl, OH, -O- (C ₁ -C ₄ ) -alkyl, NH ₂ , -CN, -CO-NH ₂ , -CO-OH and -CO-O - (C ₁ -C ₄ ) -alkyl; n is 0, 1 or 2; X = oxygen; in all its stereoisomeric forms and in the form of mixtures thereof in all ratios and its physiologically acceptable salts.

9. The compound of formula I according to one or more of claims. 1-8, in which A ¹ represents phenylene, unsubstituted or substituted by one or more identical or different substituents from the series consisting of halogen, (C ₁ -C ₄ ) -alkyl, CF ₃ , -O- (C ₁ -C ₄ ) -alkyl and -CN; the A ² ring, which contains two carbon atoms bearing the groups R ² —SO ₂ —NH and C (= X) —NH—, represents a benzene ring; R ¹ represents a group NR ⁵ R ⁶ ; R ² represents aryl; R ³ represents one or more identical or different groups from the series consisting of hydrogen, halogen, CF ₃ , -O- (C ₁ -C ₄ ) -alkyl, -CN and (C ₁ -C ₄ ) -alkyl; R ⁵ and R ⁶ together with a nitrogen atom carrying R ⁵ and R ⁶ form a 5-7 membered saturated heterocycle, which, in addition to the nitrogen atom carrying R ⁵ and R ⁶ groups, may contain one additional ring heteroatom from the series consisting of from N, O and S, and which may be substituted by one or more identical or different groups from the series consisting of (C ₁ -C ₃ ) -alkyl, hydroxy- (C ₁ -C ₃ ) -alkyl-, aryl, carbamoyl hydroxy and oxo; aryl is phenyl or a 5- or 6-membered heteroaryl containing one or more identical or different ring heteroatoms from the series consisting of N, O and S, which (these groups) can be substituted by one or more identical or different substituents from the series consisting of halogen, (C ₁ -C ₄ ) -alkyl, CF ₃ , NO ₂ , -O- (C ₁ -C ₄ ) -alkyl, -NH-CO- (C ₁ -C ₄ ) -alkyl and - CN; n is 2; X = oxygen; in all its stereoisomeric forms and in the form of mixtures thereof in all ratios and its physiologically acceptable salts.

10. The compound of formula I according to one or more of claims. 1-9, in which A ¹ represents an unsaturated divalent phenylene group; the A ² ring, which contains two carbon atoms bearing the groups R ² —SO ₂ —NH and C (= X) —NH—, represents a benzene ring; R ¹ represents a group NR ⁵ R ⁶ ; R ² represents aryl; R ³ represents one or more identical or different groups from the series consisting of hydrogen, halogen, —O- (C ₁ -C ₄ ) -alkyl and (C ₁ -C ₄ ) -alkyl; R ⁵ and R ⁶ together with a nitrogen atom carrying R ⁵ and R ⁶ form a saturated 6-membered heterocycle, which, in addition to the nitrogen atom carrying R ⁵ and R ⁶ groups, may contain one additional ring heteroatom from the series consisting of N , O and S, and which may be substituted by one or more identical or different groups from the series consisting of (C ₁ -C ₃ ) -alkyl, aryl, oxo and carbamoyl; aryl is phenyl or a 5- or 6-membered heteroaryl containing one or more identical or different ring heteroatoms from the series consisting of N, O and S, which (these groups) can be substituted by one or more identical or different substituents from the series consisting of halogen, (C ₁ -C ₄ ) -alkyl, CF ₃ and -O- (C ₁ -C ₄ ) -alkyl; n is 2; X = oxygen; in all its stereoisomeric forms and in the form of mixtures thereof in all ratios and its physiologically acceptable salts.

11. The compound of formula I according to one or more of claims. 1-10, in which A ¹ represents an unsaturated divalent 1,4-phenylene group; the A ² ring, which contains two carbon atoms bearing the groups R ² —SO ₂ —NH and C (= X) —NH—, together with the R ³ groups, represents a benzene ring having one or two substituents from the series consisting of chlorine and methoxy; R ¹ represents a group NR ⁵ R ⁶ ; R ² represents phenyl or thienyl substituted with one or two chlorine atoms; R ⁵ and R ⁶ together with a nitrogen atom carrying R ⁵ and R ⁶ form a saturated 6-membered heterocycle, which, in addition to the nitrogen atom carrying R ⁵ and R ⁶ groups, may contain one additional ring heteroatom from the series consisting of O and S, and which is unsubstituted or substituted by one or two methyl groups; n is 2; X = oxygen; in all its stereoisomeric forms and in the form of mixtures thereof in all ratios and its physiologically acceptable salts.

12. The method of obtaining the compounds of formula I according to one or more of claims. 1-11, comprising the conversion of a cyclic aminocarboxylic acid of formula II to a sulfonylaminocarboxylic acid of formula III and converting a compound of formula III into a compound of formula I (see graphic part, Scheme 1),
or converting a cyclic nitrocarboxylic acid of formula IX to a nitrocarboxamide of formula XII and converting a compound of formula XII to a compound of formula I by reducing the nitro group to an amino group and sulfonylating the amino group (see graphic section, scheme 2),
moreover, in formulas I, II, III, IX and XII groups A ¹ , A ² , R ¹ , R ² , R ³ and X and n have the meanings indicated in paragraphs. 1-11, or functional groups may also be present in protected form or in the form of preceding groups.

13. The compound of formula I according to one or more of claims. 1-11 and / or its physiologically acceptable salts for use as a medicine.

14. A pharmaceutical preparation containing one or more compounds of formula I according to one or more of claims. 1-11 and / or their physiologically acceptable salts and a pharmaceutically acceptable carrier.

15. The compound of formula I according to one or more of claims. 1-11 and / or its physiologically acceptable salts for use as an activator of soluble guanylate cyclase.

16. The compound of formula I according to one or more of claims. 1-11 and / or its physiologically acceptable salts for use in the treatment or prevention of cardiovascular disease, endothelial dysfunction, diastolic dysfunction, atherosclerosis, hypertension, angina pectoris, thrombosis, restenosis, myocardial infarction, shock, heart failure, pulmonary hypertension, erectile dysfunction , bronchial asthma, chronic renal failure, diabetes or cirrhosis of the liver, or to increase a limited ability to memorize or learning ability.