RU98100770A

RU98100770A - AROMATIC COMPOUNDS AND CONTAINING THEIR PHARMACEUTICAL COMPOSITIONS

Info

Publication number: RU98100770A
Application number: RU98100770/04A
Authority: RU
Inventors: Энн Бро Глория
Original assignee: Зенека Лимитед
Priority date: 1995-06-20
Filing date: 1996-06-17
Publication date: 1999-11-10

Claims

1. The compound of formula I:

where A is optionally substituted: phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, thienyl, thiazolyl, oxazolyl, or thiadiazolyl, having at least two adjacent carbon atoms; provided that the —CH (R ³ ) N (R ² ) BR ¹ and -OR ⁴ groups are in the 1,2-position with respect to each other on the carbon atoms of the ring, and the atom of the ring that is in the ortho-position with respect to the OR ⁴ -adjoint group (and therefore in the 3-position relative to the -CHR ³ NR ² -binding group) is unsubstituted;
B is optionally substituted: phenyl, pyridyl, thiazolyl, oxazolyl, thienyl, thiadiazolyl, imidazolyl, pyrazinyl, pyridazinyl or pyrimidyl;
R ¹ is located on the ring B in the 1,3- or 1,4-position in relation to the -CH (R ³ ) N (R ² ) -binding group and represents carboxy, carboxy _1-3 alkyl, tetrazolyl, tetrazolyl _1-3 alkyl, tetronic acid, hydroxamic acid, sulfonic acid, or R ¹ represents a group of the formula —CONR ^a R ^a1 , where R ^a represents hydrogen or C _1-6 alkyl and R ^a1 represents hydrogen, C _1-6 alkyl (optionally substituted with halogen, amino, C _1-4 alkylamino, di-C _1-4 alkylamino, hydroxy, nitro, cyano, trifluoromethyl, C _1-4 alkoxy or C _1-4 alkoxycarbonyl), C _2-6 alkenyl (provided that the double the bond is not in the 1-position), C _2-6 alkynyl (provided that the triple bond is not in the 1-position), carboxyphenyl, 5- or 6-membered heterocyclylC _1-3 alkyl, 5- or 6-membered heteroarylC _1-3 alkyl, 5 or 6 membered heterocyclyl, or 5 or 6 membered heteroaryl; or R ^a and R ^a1 , taken together with the nitrogen atom of the amide group to which they are attached (NR ^a R ^a1 ), form an amino acid residue or its ester, or R ¹ represents a group of the formula -CONHSO ₂ R ^b , where R ^b is C _1-6 alkyl (optionally substituted with halogen, hydroxy, nitro, cyano, trifluoromethyl, C _1-4 alkoxy, amino, C _1-4 alkylamino, di C _1-4 alkylamino or C _1-4 alkoxycarbonyl), C _{2- 6} alkenyl (provided the double bond is not in the 1-position), _C2-6 alkynyl (provided the triple bond is not in the 1-position), 5- or 6-membered heterocyclyl, _1-3 alkyl, 5- or 6-membered geteroarilS _1-3 alkyl, phenylC _1-3 alkyl, 5- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl or phenyl;
wherein any heterocyclic or heteroaryl group in R ^{a1 is} optionally substituted with halogen, hydroxy, nitro, cyano, trifluoromethyl, C _1-4 alkoxy or C _1-4 alkoxycarbonyl, and any phenyl, heterocyclic or heteroaryl group in R ^{b is} optionally substituted with halogen, trifluoromethyl nitro, hydroxy, amino, cyano, C _1-6 alkoxy, C _1-6 alkylS (O) _p - (p = 0, 1 or 2), C _1-6 alkyl, carbamoyl, C _1-4 alkylcarbamoyl, di ( C _1-4 alkyl) carbamoyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 alkoxycarbonylamino, C _1-4 alkanoylamino, C _1-4 alkanoyl (N-C _1-4 alkyl) amino, C _{1 -4} al cansulfonamido, benzenesulfonamido, aminosulfonyl, C _1-4 alkylaminosulfonyl, di (C _1-4 alkyl) aminosulfonyl, C _1-4 alkoxycarbonyl, C _1-4 alkanoyloxy, C _1-6 alkanoyl, formylC _1-4 alkyl, hydroxyimoC _1-6 alkyl, C _1-4 alkoxyiminoC _1-6 alkyl or C _1-6 alkylcarbamoylamino; or R ¹ represents a group of the formula -SO ₂ N (R ^c ) R ^c1 , where R ^c represents hydrogen or C _1-4 alkyl, and R ^c1 represents hydrogen or C _1-4 alkyl; or R ¹ represents a group of formula (IA), (IB) or (IC):

where X represents CH or nitrogen; Y is oxygen or sulfur, Y 'is oxygen or NR ^d ; a Z is CH ₂ , NR ^d or oxygen, provided that no more than one oxygen atom is present in the ring, and there are at least two ring heteroatoms, and where R ^d is hydrogen or C _1-4 alkyl;
R ² is hydrogen; C _1-6 alkyl, optionally substituted with hydroxy, cyano or trifluoromethyl; C _2-6 alkenyl (provided that the double bond is not in the 1-position); C _2-6 alkynyl (provided that the triple bond is not in the 1-position); phenyl C _1-3 alkyl or pyridyl C _1-3 alkyl;
R ³ represents hydrogen, methyl or ethyl;
R ⁴ is optionally substituted: C _1-6 alkyl, C _3-7 cycloalkylC _1-3 alkyl or C _3-7 cycloalkyl; or N-oxide of the group —NR ² , where it is chemically possible; or S-oxide of sulfur-containing rings, where it is chemically possible; or a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable ester or amide;
with the exception of 2- [2-methoxybenzylamino] pyridine-5-carboxylic acid, 4- [2-methoxybenzylamino] benzoic acid, 3- [2-methoxybenzylamino] -4-chloro-5-sulfamoylbenzoic acid, 3- [2,3- dimethoxybenzylamino] -4-chloro-5-sulfamoylbenzoic acid and 5- [2,5-dimethoxybenzylamino] -2-hydroxybenzoic acid.

2. The compound according to claim 1, wherein A is optionally substituted with phenyl.

3. The compound according to any one of paragraphs. 1 or 2, where R ³ represents hydrogen.

4. The compound according to any one of paragraphs. 1-3, where R ² represents hydrogen, methyl, ethyl or propyl.

5. The compound according to any one of paragraphs. 1-4, in which B is optionally substituted with pyridyl, phenyl, thiazolyl, thienyl, pyridazinyl or oxazolyl.

6. The compound according to any one of paragraphs. 1-5, where R ¹ represents carboxy, carbamoyl or tetrazolyl; or R ¹ is a group of the formula —CONR ^a R ^a1 , where R ^a is hydrogen or C _1-6 alkyl, and R ^a1 is C _1-6 alkyl, optionally substituted with hydroxy; C _2-6 alkenyl; 1-morpholinyl; 1-piperidinyl; 1-pyrrolidinyl; pyridyl _1-3 alkyl; or R ¹ is a group of the formula —CONHSO ₂ R ^b , where R ^b is optionally substituted: C _1-6 alkyl, phenyl, or a 5- or 6-membered heteroaryl.

7. The compound according to any one of paragraphs. 1-5, where R ¹ is carboxy, tetrazole, or a group of the formula —CONHR ^a1 , where R ^a1 is pyridylmethyl or C _1-4 alkyl, optionally substituted with hydroxy; or a group of the formula —CONHSO ₂ R ^b , where R ^b is C _1-4 alkyl, 3,5-dimethylisoxazol-4-yl or 5-acetamido-1,3,4-thiadiazol-2-yl.

8. The compound according to any one of paragraphs. 1-7, where A is substituted with halogen, nitro, trifluoromethyl, cyano, C _1-6 alkoxy, carbamoyl, C _1-4 alkylcarbamoyl, di (C _1-4 alkyl) carbamoyl, C _1-4 alkanoylamino, C _1-6 alkylS (O) _p , C _1-4 alkanesulfonamido, benzenesulfonamido, C _1-6 alkanoyl, C _1-4 alkoxyiminoC _1-4 alkyl or hydroxyiminoC _1-4 alkyl.

9. The compound according to any one of paragraphs. 1-8, in which B is substituted with halogen, trifluoromethyl, C _1-4 alkyl, amino, C _1-4 alkylamino, di C _1-4 alkylamino, nitro, hydroxy, C _1-6 alkoxy or cyano; or B is unsubstituted (different from B shown in formula (I)).

10. The compound according to any one of paragraphs. 1-9, where R ⁴ represents an optionally substituted C _1-4 alkyl, C _3-6 cycloalkyl or C _3-6 cycloalkylmethyl.

11. The compound according to claim 1, selected from the group comprising 6- [N- (5-chloro-2-isobutoxybenzyl) -N-ethylamino] -N- (3,5-dimethylisoxazol-4-ylsulfonyl) pyridazin-3- carboxamide and N-propanesulfonyl-6- [N- (5-bromo-2- (cyclopropylmethoxy) benzyl) -N-ethylamino] pyridazine-3-carboxamide, or its pharmaceutically acceptable salt.

12. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims. 1-11 and a pharmaceutically acceptable carrier.

13. The way to eliminate pain by administering an effective amount of the compound of formula (1) to a patient in need thereof.

14. The method of producing the compound according to claim 1, which comprises removing protection from the compound of formula (III):

where R ⁶ denotes R ¹ specified in paragraph 1, or protected R ¹ ; R ⁷ denotes R ² specified in paragraph 1, or protected R ² ; and R ³ , R ⁴ , A and B are referred to in claim 1, and any optional substituents are optionally protected, and at least one protecting group is present; and then, if necessary: i) obtaining a pharmaceutically acceptable salt; ii) obtaining an in vivo hydrolyzable ester or amide; iii) converting one optional substituent to another optional substituent.

15. A method of obtaining a compound according to claim 1 or a compound of the formula (III) indicated in paragraph 14, which includes: a) the reduction of the compound of the formula (IV):

or b) if B is an activated heterocycle and R ⁷ is hydrogen or C _1-6 alkyl, the reaction of the compound of formula (V) with the compound of formula (VI):

or c) reacting a compound of formula (VII) with a compound of formula (VIII):
R ⁷ HN-BR ⁶ (VII)

or d) converting X ² to R ⁶ in the compound of formula (IX)

or e) if R ^{7 is} not hydrogen, reacting a compound of formula R ⁷ X ³ with a compound of formula (X):

or f) reacting a compound of formula (XI) with a compound of formula (XII):

X ⁴ NH-BR ⁶ (XII)
or g) the interaction of the compounds of formula (XIII) with the compound of the formula (XIV):

X ⁶ NH-BR ⁶ (XIV)
or h) the interaction of the compounds of formula (XV) with the compound of the formula X ⁷ R ⁴ :

where R ³ , R ⁴ , R ⁷ , R ⁹ , a and b are listed in paragraph 14; and X and X ¹ are leaving groups; X ² is the precursor of the group R ⁷ ; X ³ is a leaving group; X ⁴ is a removable activating group; X ⁵ is a leaving group; X ⁶ represents an activating group; and X ⁷ is a leaving group;
and then, if necessary: i) removing any protective groups; ii) obtaining a pharmaceutically acceptable salt; iii) obtaining an in vivo hydrolyzable ester or amide; iv) converting an optional substituent to another optional substituent.

16. The compound of formula (III):

where R ⁶ denotes R ¹ specified in paragraph 1, or protected R ¹ ; R ⁷ denotes R ² specified in paragraph 1, or protected R ² ; and R ³ , R ⁴ , A and B are indicated in clause 1, and any optional substituents are optionally protected, and at least one protective group is present.