RU2182574C2 - Aromatic compounds and pharmaceutical compositions comprising thereof - Google Patents

Abstract

FIELD: organic chemistry, pharmacy. SUBSTANCE: invention relates to compounds of the formula (I) R⁴-A-CH(R³)N(R²)B-R¹ where A means optionally substituted phenyl group under condition that groups -CH(R³)N(R²)B-R¹ and -OR⁴ are at 1,2-position in ring carbon atoms relative to one another and under condition that ring atom at orthoposition with respect to OR⁴-bound group (and, therefore, at 3-position with respect to -CHR³NR²-binding group) is not substituted; B means pyridyl or pyridazinyl; R¹ in ring B at 1,3- or 1,4-position with respect to -CH(R³)N(R²)-binding group and means carboxy-, carbamoyl- or tetrazolyl-group; or R¹ means the group of the formula -CONR^aR^a1 where R^a means hydrogen atom or C_1-6-alkyl; R^a1 means C_1-6-alkyl; or R¹ means the group of the formula -CONHSO₂R^b where R^b means C_1-6-alkyl, trifluoromethyl or 5-membered heteroaryl taken among isoxazolyl and thiadiazolyl optionally substituted with C_1-6-alkyl or C_1-4- alkanoylamino-group; R² means C_1-6-alkyl; R³ means hydrogen atom; R⁴ means C_1-4-alkyl, C_3-7-cycloalkyl-C_1-3-alkyl or C_3-7-cycloalkyl where indicated C_1-6-alkyl is optionally substituted with hydroxy-group or halogen atom, or their pharmaceutically acceptable salt or ester hydrolysable in vivo. Compounds are antagonists of the pain- enhancing effect of prostaglandins of type E. Invention discloses also method of synthesis of indicated compounds, intermediate compounds used for their synthesis, pharmaceutical composition for elimination of pain and method of analgesia. EFFECT: valuable medicinal properties of compounds and pharmaceutical composition. 11 cl, 1 tbl, 68 ex

Description

 The invention relates to new aromatic compounds and their pharmaceutically acceptable salts having valuable pharmacological properties. More specifically, the compounds of the invention are antagonists of the analgesic effect of E-type prostaglandins. The invention also relates to methods for producing aromatic compounds and their pharmaceutically acceptable salts; to new pharmaceutical compositions containing them and to the use of compounds for pain relief.

 The compounds of the invention can be used to relieve pain, such as pain associated with joint disease (e.g. rheumatoid arthritis and osteoarthritis), postoperative pain, postpartum pain, pain related to dental disease (e.g. tooth decay and gingivitis), pain, associated with burns (including sunburn); for the treatment of bone diseases (such as osteoporosis, malignant hypercalcemia and Paget's disease); for the relief of pain associated with sports injuries and sprain, as well as for the treatment of any other painful conditions in which E-type prostaglandins, in whole or in part, play a pathophysiological role.

 Nonsteroidal anti-inflammatory drugs (NSAIDs) and opiates are the main class of painkillers. However, both of these groups of compounds have an undesirable side effect. NSAIDs are known to cause irritation of the gastrointestinal tract, and opiates are known to be narcotic drugs.

 Applicants have discovered a class of compounds that are structurally different from NSAIDs and opiates and which can be used as painkillers.

The compounds of the invention may also have anti-inflammatory, antipyretic and antipyretic properties and be effective in treating other conditions in which prostaglandin E ₂ - (PGE ₂ ) plays a pathophysiological role in whole or in part.

 European patent application 0000816 (Example 28) describes 2- [2-methoxybenzylamino] pyridine-5-carboxylic acid, which, as indicated, can be used to treat diabetes. US Pat. No. 4,362,892 (Example 8) describes 4- [2-methoxybenzylamino] benzoic acid and indicates that this compound has lipid-lowering activity. 3- [2-Methoxybenzylamino] -4-chloro-5-sulfamoylbenzoic acid and 3- [2,3-dimethoxybenzylamino] -4-chloro-5-sulfamoylbenzoic acid are described by P. Feit et al. (J. Med. Chem., 1970, 13, 1071) as diuretic agents. 5- [2,5-Dimethoxybenzylamino] -2-hydroxybenzoic acid is described by P. Nussbaumer et al. (J. Med. Chem., 1994, 34, 4079) as an antiproliferative agent.

где А представляет необязательно замещенные:
фенил, нафтил, пиридил, пиразинил, пиридазинил, пиримидил, тиенил, тиазолил, оксазолил или тиадиазолил, имеющие, по крайней мере, два смежных кольцевых атома углерода;
при условии, что группы -CH(R³)N(R²)B-R¹ и -OR⁴ находятся в 1,2-положениях по отношению друг к другу на кольцевых атомах углерода и кольцевой атом углерода, находящийся в ортоположении по отношению к ОR⁴-присоединенной группе (и, следовательно, в 3-положении по отношению к -CHR³NR² - присоединенной группе), является незамещенным;
В представляет необязательно замещенные:
фенил, пиридил, тиазолил, оксазолил, тиенил, тиадиазолил, имидазолил, пиразинил, пиридазинил или пиримидил;
R¹ находится в кольце B в 1,3- или 1,4-положении по отношению к -CH(R³)N(R²)-присоединенной группе и представляет карбокси, карбоксиС_1-3алкил, тетразолил, тетразолилС_1-3алкил, тетроновую кислоту, гидроксамовую кислоту, сульфоновую кислоту, либо R¹ представляет группу формулы -CONR^aR^a1, где R^a представляет водород или C_1-6алкил и R^a1 представляет водород, C_1-6алкил (необязательно замещенный галогеном, амино, С_1-4алкиламино, ди-С_1-4алкиламино, гидрокси, нитро, циано, трифторметилом, С_1-4алкокси или C_1-4алкоксикарбонилом), С_2-6алкенил (при условии, что двойная связь не находится в 1-положении), С_2-6алкинил (при условии, что тройная связь не находится в 1-положении), карбоксифенил, 5- или 6-членный гетероциклилС_1-3алкил, 5- или 6-членный гетероарилС_1-3алкил, 5- или 6-членный гетероциклил или 5- или 6-членный гетероарил; либо R^a и R^a1, взятые вместе с атомом азота амидной группы, к которому они присоединены (NR^aR^a1), образуют аминокислотный остаток или его сложный эфир, либо R¹ представляет группу формулы -CONHSO₂R^b, где R^b представляет C_1-6алкил (необязательно замещенный галогеном, гидрокси, нитро, циано, трифторметилом, C_1-4алкокси, амино, С_1-4алкиламино, ди-С_1-4алкиламино или С_1-4алкоксикарбонилом), С_2-6алкенил (при условии, что двойная связь не находится в 1-положении), С_2-6алкинил (при условии, что тройная связь не находится в 1-положении), 5- или 6-членный гетероциклилС_1-3алкил, 5- или 6-членный гетероарилС_1-3алкил, фенилС_1-3алкил, 5- или 6-членный гетероциклил, 5- или 6-членный гетероарил или фенил;
где любая гетероциклическая или гетероарильная группа в R^a1 является необязательно замещенной галогеном, гидрокси, нитро, циано, трифторметилом, С_1-4алкокси или С_1-4алкоксикарбонилом и любая фенильная, гетероциклическая или гетероарильная группа в R^b является необязательно замещенной галогеном, трифторметилом, нитро, гидрокси, амино, циано, C_1-6алкокси, С_1-6алкилS(O)_р- (р=0, 1 или 2), C_1-6алкилом, карбамоилом, С_1-4алкилкарбамоилом, ди(С_1-4алкил) карбамоилом, С_2-6алкенилом, С_2-6алкинилом, С_1-4алкоксикарбониламино, С_1-4алканоиламино, С_1-4алканоил(N-С_1-4алкил) амино, С_1-4алкансульфонамидо, бензолсульфонамидо, аминосульфонилом, С_1-4алкиламиносульфонилом, ди(С_1-4алкил) аминосульфонилом, С_1-4алкоксикарбонилом, С_1-4алканоилокси, C_1-6алканоилом, формилС_1-4алкилом, гидроксииминоС_1-6алкилом, С_1-4алкоксииминоС_1-6алкилом или C_1-6алкилкарбамоиламино; или R¹ представляет группу формулы -SO₂N(R^c)R^c1, где R^c представляет водород или С_1-4алкил и R^c1 представляет водород или С_1-4алкил;
или R¹ представляет группу формулы (IA), (IB) или (IC):

где X представляет СН или азот, Y представляет кислород или серу, Y' представляет кислород или NR^d и Z представляет CH₂, NR^d или кислород, при условии, что в кольце имеется не более одного атома кислорода и, по крайней мере, имеется два гетероатома, и где R^d представляет водород или C_1-4алкил.The present invention relates to a compound of formula I:

where a represents optionally substituted:
phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, thienyl, thiazolyl, oxazolyl or thiadiazolyl having at least two adjacent ring carbon atoms;
with the proviso that the —CH (R ³ ) N (R ² ) BR ¹ and —OR ⁴ groups are in 1,2-positions relative to each other on the ring carbon atoms and the ring carbon atom is in the ortho position relative to OR ^{A 4-} attached group (and therefore at the 3-position with respect to the —CHR ³ NR ² - attached group) is unsubstituted;
B represents optionally substituted:
phenyl, pyridyl, thiazolyl, oxazolyl, thienyl, thiadiazolyl, imidazolyl, pyrazinyl, pyridazinyl or pyrimidyl;
R ¹ is in ring B at the 1,3- or 1,4-position with respect to the —CH (R ³ ) N (R ² ) attached group and is carboxy, carboxyC _1-3 alkyl, tetrazolyl, tetrazolyl C _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 the double I bond is not in the 1-position), _C2-6 alkynyl (provided the triple bond is not in the 1-position), carboxyphenyl, 5- or 6-membered heterocyclyl _1-3 alkyl, 5- or 6-membered heteroaryl C _1-3 alkyl, 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl; either 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 represents C _1-6 alkyl (optionally substituted with halogen, hydroxy, nitro, cyano, trifluoromethyl, C _1-4 alkoxy, amino, C _1-4 alkylamino, diC _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 heterocycle PM _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;
where 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 alkyl S (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 alkanesulfonamido, 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, hydroxyiminoC _1-6 alkyl, C _1-4 alkoxyimino C _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 represents oxygen or sulfur, Y 'represents oxygen or NR ^d and Z represents CH ₂ , NR ^d or oxygen, provided that there is no more than one oxygen atom in the ring and at least there is two heteroatoms, and where R ^d represents hydrogen or C _1-4 alkyl.

R ² represents 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 pyridylC _{1- 3} alkyl;
R ³ represents hydrogen, methyl or ethyl;
R ⁴ is optionally substituted: C _1-6 alkyl, C _3-7 cycloalkyl C _1-3 alkyl or C _3-7 cycloalkyl;
and N-oxides of the group —NR ² where chemically possible;
and S-oxides of sulfur-containing rings, where chemically possible;
and their pharmaceutically acceptable salts and in vivo hydrolyzable esters and amides, 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.

 A 5- or 6-membered heteroaryl ring system is a monocyclic aryl ring system having 5 or 6 ring atoms, where 1, 2 or 3 ring atoms are selected from nitrogen, oxygen and sulfur atoms.

 A 5- or 6-membered saturated or partially saturated heterocyclic ring is a ring system having 5 or 6 ring atoms, where 1, 2 or 3 ring atoms are selected from nitrogen, oxygen and sulfur atoms.

 Particular 5- or 6-membered monocyclic heteroaryl rings are pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiadiazolyl, thienyl, furyl and oxazolyl.

 Particular 5- or 6-membered saturated or partially saturated heterocyclic ring systems are pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl and morpholinyl.

Specific substituents on the ring carbon atoms in A (heterocyclic and heteroaryl rings) include halogen, trifluoromethyl, nitro, hydroxy, amino, C _1-4 alkylamino, di-C _1-4 alkylamino, cyano, C _1-6 alkoxy, C _{1- 6} alkyl S (O) _p - (p = 0, 1 or 2), C _1-6 alkyl (optionally substituted with hydroxy, amino, halogen, nitro or cyano), CF ₃ S (O) _p - (p = 0, 1 or 2), 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 alkanesulphonamido, benzenesulphonamido, aminosul onyl, C _1-4 alkylaminosulfonyl, C _1-4 alkanoilaminosulfonil, di (C _1-4 alkyl) aminosulphonyl, C _1-4 alkoxycarbonyl, C _1-4 alkanoyloxy, C _1-6 alkanoyl, formilS _1-4 alkyl triftorS _{1 -3} alkylsulfonyl, hydroxyiminoC _1-6 alkyl, C _1-4 alkoxyimino C _1-6 alkyl and C _1-6 alkylcarbamoylamino.

In the case where the ring nitrogen atom in A can be substituted but not quaternized, it is unsubstituted or substituted with C _1-4 alkyl.

Specific substituents on the ring carbon atoms in B include halogen, trifluoromethyl, nitro, hydroxy, C _1-6 alkoxy, C _1-6 alkyl, amino, C _1-4 alkylamino, di (C _1-4 alkyl) amino, cyano, C _1-6 alkylS (O) _p - (p = 0, 1 or 2), carbamoyl, C _1-4 alkylcarbamoyl and di (C _1-4 alkyl) carbamoyl.

In the case where the ring nitrogen atom in B can be substituted but not quaternized, it is unsubstituted or substituted with C _1-4 alkyl.

The term “alkyl”, as used herein, means straight or branched chain substituents, for example methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl; and functional groups on the alkyl chain may be present in any part of this chain, for example, hydroxyimino _{C 1-4} alkyl is 1- (hydroxyimino) propyl and 2- (hydroxyimino) propyl.

C _1-6 alkyl substituted with halogen is trifluoromethyl.

Amino acid residues formed from R ^a and R ^a1 taken together with the nitrogen atom to which they are attached are residues (—NHCH (R) COOH) derived from naturally occurring or non-naturally occurring amino acids. Examples of suitable amino acids include glycine, alanine, serine, threonine, phenyl alanine, glutamic acid, tyrosine, lysine and dimethyl glycine.

 Suitable ring systems of formulas (1A), (1B) or (1C) include 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, 3-oxo-2,3-dihydro-1, 2,4-oxadiazol-5-yl, 3-thioxo-2,3-dihydro-1,2,4-oxadiazol-5-yl, 5-oxo-4,5-dihydro-1,3,4-oxadiazole- 2-yl, 5-oxo-4,5-dihydro-1,2,4-triazol-3-yl, 5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl, 1, 3,4-oxadiazol-2-yl, 3-hydroxy-2-methylpyrazol-5-yl, 3-oxo-2,3-dihydroisoxazol-5-yl, 5-oxo-1,5-dihydroisoxazol-3-yl and 5-oxo-2,3-dihydropyrazol-3-yl.

Examples of C _1-6 alkoxycarbonyl are methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl; examples of carboxyC _1-3 alkyl are carboxymethyl, 2-carboxyethyl, 1-carboxyethyl and 3-carboxypropyl; examples of C _1-6 alkoxycarbonylC _1-3 alkyl are methoxycarbonylmethyl, ethoxycarbonylmethyl and methoxycarbonylethyl; examples of tetrazolylC _1-3 alkyl are tetrazolylmethyl and 2-tetrazolylethyl; examples of C _1-4 alkoxy are methoxy, ethoxy, propoxy and isopropoxy; examples of C _2-6 alkenyl are vinyl and allyl; examples of C _2-6 alkynyl are ethynyl and propynyl; examples of C _1-4 alkanoyl are formyl, acetyl, propionyl and butyryl; examples of halogen are fluorine, chlorine, bromine and iodine; examples of C _1-4 alkylamino are methylamino, ethylamino, propylamino and isopropylamino; examples of di (C _1-4 alkyl) amino are dimethylamino, diethylamino and ethylmethylamino; examples of C _1-6 alkyl S (O) _p - are methylthio, methylsulfinyl and methylsulfonyl; examples of C _1-4 alkylcarbamoyl are methylcarbamoyl and ethylcarbamoyl; examples of di (C _1-4 alkyl) carbamoyl are dimethylcarbamoyl, diethylcarbamoyl and ethylcarbamoyl; examples of C _1-6 alkyl are methyl, ethyl, propyl and isopropyl; examples of C _1-4 alkoxycarbonylamino are methoxycarbonylamino and ethoxycarbonylamino; examples of C _1-4 alkanoylamino are acetamido and propionamido; examples of C _1-4 alkanoyl (N — C _1-4 alkyl) amino are N-methylacetamido and N-methylpropionamido; examples of C _1-4 alkanesulfonamido are methanesulfonamido and ethanesulfonamido; examples of C _1-4 alkylamino-sulfonyl are methylaminosulfonyl and ethylaminosulfonyl; examples of di (C _1-4 alkyl) aminosulfonyl are dimethylaminosulfonyl, diethylaminosulfonyl and ethylmethylamino-sulfonyl; examples of C _1-4 alkanoyloxy are acetyloxy and propionyloxy; examples of formylC _1-4 alkyl are formylmethyl and 2-formylethyl; examples of hydroxyiminoC _1-6 alkyl are hydroxyiminomethyl and 2- (hydroxyimino) ethyl; and examples of C _1-4 alkoxyiminoC _1-6 alkyl are methoxyiminomethyl, ethoxyiminomethyl and 2- (methoxyimino) ethyl.

 It should be noted that, if the compounds of formula I have a chiral center, then the compounds of the invention can exist and can be isolated in optically active or racemic form. The invention includes any optically active or racemic form of a compound of formula I that has analgesic properties. The synthesis of optically active forms can be carried out using standard methods of organic chemistry, well known to specialists, for example, by separation of the racemic form, by synthesis from optically active starting compounds or by asymmetric synthesis. In addition, it should be noted that some compounds of formula I may exist in the form of geometric isomers. The present invention includes any geometric isomer of a compound of formula I that has analgesic properties.

 It should also be noted that some of the compounds of the present invention may exist in solvated, for example hydrated, and in unsolvated form. In addition, the present invention includes all of these solvated forms having analgesic properties.

 It should also be noted that tautomers of the compounds of formula (I) are included in the scope of the present invention.

 Preferably, A is optionally substituted: phenyl, naphthyl, thiadiazolyl, thienyl, pyridyl or pyrimidyl.

 Preferably B is optionally substituted: pyridyl, phenyl, thiazolyl, thienyl, pyridazinyl or oxazolyl.

 Most preferably, A is optionally substituted phenyl or thienyl.

 More preferably, B is optionally substituted: pyridyl, phenyl, thienyl, pyridazinyl or thiazolyl.

 In particular, A represents optionally substituted phenyl.

 In particular, B is optionally substituted: pyrid-2,5-diyl, pyridazin-3,6-diyl, phen-1,4-diyl or thien-2,5-diyl.

 Particularly preferably, B is an optionally substituted pyridazin-3,6-diyl or pyrid-2,5-diyl.

 Particularly preferably, B is pyridazinyl.

Preferred optional substituents for the ring carbon atoms in A are halogen, nitro, trifluoromethyl, cyano, amino, 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 alkoxyimino C _1-4 alkyl and hydroxyimino C _1-4 alkyl.

If A represents a 6-membered ring, then A is preferably unsubstituted or substituted at the 4-position with respect to the —OR ⁴ group.

Preferred optional substituents for the ring carbon atoms in B are halogen, trifluoromethyl, C _1-4 alkyl, amino, C _1-4 alkylamino, diC _1-4 alkylamino, nitro, hydroxy, C _1-6 alkoxy and cyano.

 Preferably, A is unsubstituted or substituted with one substituent.

 More preferably, A is unsubstituted or substituted with bromine, methanesulfonyl, fluorine or chlorine.

 Most preferably, A is unsubstituted or substituted with bromine or chlorine.

 Preferably, B is unsubstituted or substituted with one substituent.

 Most preferably, B is unsubstituted.

Preferably, R ¹ is 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; pyridylC _1-3 alkyl; or R ¹ represents a group of the formula —CONHSO ₂ R ^b , where R ^b represents optionally substituted: C _1-6 alkyl, phenyl or 5- or 6-membered heteroaryl.

In particular, R ¹ is a carboxy, tetrazolyl or a group of the formula —CONR ^a R ^a1 , where R ^a is hydrogen and R ^a1 is C _1-6 alkyl optionally substituted with hydroxy or pyridylmethyl; or R ¹ represents a group of the formula —CONHSO ₂ R ^b , where R ^b represents C _1-6 alkyl (optionally substituted with hydroxy or fluorine), phenyl (optionally substituted with acetamido), isoxazolyl (optionally substituted with methyl) or 1,3,4-thiadiazolyl (optionally substituted acetamido).

Most preferably, R ¹ is carboxy, tetrazole or a group of the formula —CONHR ^a1 , wherein 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.

In another aspect of the present invention, R ¹ is carboxy, carbamoyl or tetrazolyl; 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 C _1-6 alkyl optionally substituted with hydroxy, C _2-6 alkenyl; 1-morpholinyl; 1-piperidinyl; 1-pyrrolidinyl; pyridylC _1-3 alkyl; or R ¹ represents a group of the formula —CONHSO ₂ R ^b , where R ^b is C _1-6 alkyl or phenyl.

Preferably, R ² is hydrogen, methyl, ethyl, 2,2,2-trifluoroethyl, cyanomethyl, allyl or 3-propynyl.

More preferably, R ² is hydrogen, methyl, ethyl or propyl.

Even more preferably, R ² is hydrogen or ethyl.

Most preferably, R ² is ethyl.

Preferably R ³ is hydrogen.

Preferably, R ^{4 is} optionally substituted with halogen, hydroxy, C _1-4 alkoxy, amino, carboxy, C _1-4 alkyl S (O) _p (p = 0, 1 or 2), carbamoyl, trifluoromethyl, oxo or cyano.

More preferably, R ^{4 is} optionally substituted with fluorine, chlorine or bromine.

Most preferably, R ^{4 is} optionally substituted with fluorine, trifluoromethyl, cyano or hydroxy.

Preferably R ⁴ is C _1-4 alkyl, C _3-6 cycloalkyl or C _3-6 cycloalkylmethyl.

More preferably, R ⁴ is propyl, isobutyl, butyl, 2-ethylbutyl, 2 (R) methylbutyl, 2 (S) methylbutyl, 2,2,2-trifluoroethyl, cyclopentylmethyl, cyclopropylmethyl, cyclopropyl or cyclopentyl.

Most preferably, R ⁴ is propyl, isobutyl, butyl, 2-ethylbutyl, cyclopentyl, cyclopropylmethyl or cyclopropyl.

где R¹ и R² определены выше; R⁴ представляет С_1-4алкил, С_3-6циклоалкил или С_3-6циклоалкилметил; R⁵ представляет водород или, как определено выше для заместителей кольцевых атомов углерода в А и В, представляет фенил, тиенил, пиридазинил, пиридил или тиазолил.A preferred class of compounds are compounds of formula (II):

where R ¹ and R ^{2 are as} defined above; R ⁴ represents C _1-4 alkyl, C _3-6 cycloalkyl or C _3-6 cycloalkylmethyl; R ⁵ represents hydrogen or, as defined above for substituents of ring carbon atoms in A and B, represents phenyl, thienyl, pyridazinyl, pyridyl or thiazolyl.

 It should be noted that since the compounds of formula (I) as defined above can exist in optically active or racemic forms due to the fact that the compounds of formula (I) contain an asymmetric carbon atom, the definition of the active ingredient of the present invention includes any such optically active or racemic form, which has analgesic properties. The synthesis of such optically active forms can be carried out by standard methods of organic chemistry, well known in the art, for example, by synthesis from optically active starting compounds or by resolution of the racemic form. Similarly, the analgesic properties of the compound can be evaluated using standard laboratory techniques described below.

An in vivo hydrolyzable ester of a compound of formula (I) containing a carboxy group is, for example, a pharmaceutically acceptable ester that hydrolyzes in the human or animal body to form the parent acid, for example, a pharmaceutically acceptable ester formed (C _1-6 ) alcohol, such as methanol, ethanol, ethylene glycol, propanol or butanol, or phenol or benzyl alcohol, such as phenol or benzyl alcohol or substituted phenol or benzyl alcohol, where the substituents are, for example, halogen (t Coy as fluoro or chloro), (C _1-4) alkyl (such as methyl), or (C _1-4) alkoxy (such as ethoxy). The term also includes α-acyloxyalkyl esters and parent compounds which decompose to form the parent hydroxy group. Examples of α-acyloxyalkyl esters are acetoxymethoxycarbonyl and 2,2-dimethylpropionyloxymethoxycarbonyl.

 An in vivo hydrolyzable ester of a compound of formula (I) containing a hydroxy group is, for example, a pharmaceutically acceptable ester that hydrolyzes in the human or animal body to form the parent alcohol. The term includes inorganic esters, such as phosphoric acid esters and α-acyloxyalkyl ethers, as well as the starting compounds, which are formed by in vivo hydrolysis of the ester decomposed to give the starting hydroxy group. Examples of α-acyloxyalkyl ethers are acetoxymethoxy and 2,2-dimethoxypropionyloxymethoxy. Hydroxy-releasing in vivo hydrolyzable ester groups are selected from alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to form alkylcarboxylic acid esters), dialkylcarbamoyl and N- (dialkylaminoethyl) -N-alkyl for the formation of carbamates), dialkylaminoacetyl and carboxyacetyl.

 A suitable in vivo hydrolyzable amide of a compound of formula I containing a carboxy group is, for example, N- (1-6C) alkyl or N, N-di- (1-6C) alkylamide, such as N-methylamide, N-ethylamide, N-propylamide, N, N-dimethylamide, N-ethyl-N-methylamide or N, N-diethylamide.

 A suitable pharmaceutically acceptable salt of a compound of formula (I) is, for example, an acid addition salt of a compound of formula (I), which is sufficiently basic, for example, an acid addition salt formed by an inorganic or organic acid such as hydrochloric, hydrobromic, sulfuric, trifluoroacetic, citric or maleic acid; or, for example, a salt of a compound of formula (I) that is sufficiently acidic, for example, an alkali or alkaline earth metal salt, such as a calcium or magnesium salt, or an ammonium salt, or a salt formed by an organic base, such as methylamine, dimethylamine, trimethylamine, piperidine , morpholine or tris- (2-hydroxyethyl) amine.

где R⁶ представляет R¹ или защищенный R¹; R⁷ представляет R² или защищенный R²; R³, R⁴, А и В являются такими, как они были определены выше; причем любые необязательные заместители являются необязательно защищенными; и кроме того, присутствует, по крайней мере, одна защитная группа;
а затем, если это необходимо:
i) получение фармацевтически приемлемой соли;
ii) получение in vivo гидролизуемого сложного эфира или амида;
iii) преобразование одного необязательного заместителя в другой необязательный заместитель.In another aspect, the present invention relates to a method for producing compounds of formula (I) or their pharmaceutically acceptable salts or their in vivo hydrolyzable amides or esters; moreover, this method involves the removal of protection from the compounds of formula (III):

where R ⁶ represents R ¹ or protected R ¹ ; R ⁷ represents R ² or protected R ² ; R ³ , R ⁴ , A and B are as defined above; wherein any optional substituents are optionally protected; and in addition, at least one protecting group is present;
and then, if necessary:
i) obtaining a pharmaceutically acceptable salt;
ii) in vivo preparation of a hydrolyzable ester or amide;
iii) converting one optional substituent into another optional substituent.

 Protecting groups may be selected from any suitable groups described in the literature and may be introduced by standard methods.

 The protecting groups can be removed by any known method suitable for removing this protecting group, and this method should be chosen so that it effectively removes the protecting group with minimal impact on any other groups in the molecule.

A suitable group for protecting the hydroxy group is, for example, an arylmethyl group (in particular benzyl), a tri- (C _1-4 ) alkylsilyl group (in particular trimethylsilyl or tert-butyldimethylsilyl), an aryldi (C _1-4 ) alkylsilyl group ( in particular dimethylphenylsilyl), diaryl (C _1-4 ) alkylsilyl group (in particular tert-butyl diphenylsilyl), (C _1-4 ) alkyl group (in particular methyl), (C _2-4 ) alkenyl group (in particular , allyl), (C _1-4 ) alkoxymethyl group (in particular methoxymethyl) or tetrahydropyranyl group (in particular tetrahydropyr an-2-yl). The removal conditions of the above protecting groups may vary depending on the choice of protecting group. Thus, for example, an arylmethyl group, such as a benzyl group, can be removed by hydrogenation in the presence of a catalyst, such as palladium-on-charcoal. Alternatively, a trialkylsilyl or aryl dialkylsilyl group, such as a tert-butyldimethylsilyl or dimethylphenylsilyl group, can be removed, for example, by treatment with a suitable acid such as hydrochloric, sulfuric, phosphoric or trifluoroacetic acid, or alkali metal or ammonium fluoride, such as sodium fluoride. preferably fluoride tetrabutylammonium. Alternatively, the alkyl group can be removed, for example, by treatment with (C _1-4 ) alkali metal alkyl sulfide, such as sodium thioethoxide, or, for example, by treatment with alkali metal diaryl phosphide, such as lithium diphenyl phosphide, or, for example, by treatment with boron trihalide or aluminum, such as boron tribromide. Alternatively, the (C _1-4 ) alkoxymethyl group or tetrahydropyranyl group may be removed, for example, by treatment with a suitable acid, such as hydrochloric acid or trifluoroacetic acid.

Alternatively, a suitable protecting group for the hydroxy group is, for example, an acyl group, for example a (C _2-4 ) alkanoyl group (in particular acetyl) or an aroyl group (in particular benzoyl). The removal conditions of the above protecting groups may vary depending on the choice of protecting group. So, for example, an acyl group, such as an alkanoyl or aroyl group, can be removed, for example, by hydrolysis using a base, such as an alkali metal hydroxide, for example lithium or sodium hydroxide.

A suitable protecting group for an amino, imino or alkylamino group is, for example, an acyl group such as a (C _2-4 ) alkanoyl group (in particular acetyl), (C _1-4 ) alkoxycarbonyl group (in particular methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl), an arylmethoxycarbonyl group (in particular benzyloxycarbonyl) or an aroyl group (in particular benzoyl). The removal conditions of the above protecting groups may vary depending on the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl, alkoxycarbonyl or aroyl group can be removed, for example, by hydrolysis using a suitable base, such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an acyl group, such as a tert-butoxycarbonyl group, can be removed, for example, by treatment with a suitable acid, such as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid, and an arylmethoxycarbonyl group, such as a benzyloxycarbonyl group, can be removed, for example, by hydrogenation in the presence of a catalyst such as palladium-on-charcoal.

A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a (C _1-4 ) alkyl group (in particular methyl or ethyl), which can be removed by hydrolysis using a suitable base such as an alkali metal hydroxide, for example lithium hydroxide or sodium; and the tert-butyl group can be removed, for example, by treatment with a suitable acid, such as hydrochloric, sulfuric, phosphoric or trifluoroacetic acid.

b) когда В представляет активированный гетероцикл и R⁷ представляет водород или C_1-6алкил, взаимодействием соединения формулы (V) с соединением формулы (VI):

с) взаимодействием соединения формулы (VII) с соединением формулы (VIII):

d) преобразованием X² в R⁶ в соединении формулы (IX)

е) когда R⁷ не является водородом, взаимодействием соединения формулы R⁷X³ с соединением формулы (X):

f) взаимодействием соединения формулы (XI) с соединением формулы (XII):

g) взаимодействием соединения формулы (XIII) с соединением формулы (XIV):

h) взаимодействием соединения формулы (XV) с соединением формулы Х⁷R⁴:

где R³, R⁴, R⁷, R⁹, А и В определены выше, а Х и X¹ являются уходящими группами, X² является предшественником R⁷; X³ является уходящей группой, X⁴ является удаляемой активирующей группой, X⁵ является уходящей группой, X⁶ является активирующей группой, а X⁷ является уходящей группой;
а затем, если необходимо:
i) удалением любых защитных групп;
ii) получением фармацевтически приемлемой соли;
iii) получением in vivo-гидролизуемого сложного эфира или амида;
iv) преобразованием необязательного заместителя в другой необязательный заместитель.In another aspect of the present invention, compounds of formulas (I) or (III) can be prepared:
a) the restoration of the compounds of formula (IV):

b) when B is an activated heterocycle and R ⁷ is hydrogen or C _1-6 alkyl, by reacting a compound of formula (V) with a compound of formula (VI):

c) reacting a compound of formula (VII) with a compound of formula (VIII):

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

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

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

g) by reacting a compound of formula (XIII) with a compound of formula (XIV):

h) reacting a compound of formula (XV) with a compound of formula X ⁷ R ⁴ :

where R ³ , R ⁴ , R ⁷ , R ⁹ , A and B are defined above, and X and X ¹ are leaving groups, X ² is a precursor of R ⁷ ; X ³ is a leaving group, X ⁴ is a leaving activating group, X ⁵ is a leaving group, X ⁶ is an activating group, and X ⁷ is a leaving group;
and then, if necessary:
i) removal of any protecting 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.

 Particular leaving groups are halogen, for example chlorine, bromine and iodine, sulfonates, for example tosylate, p-bromobenzenesulfonate, p-nitrobenzenesulfonate, methanesulfonate and trifluoroacetate, or phosphoric esters such as diarylphosphoric ester.

где A, R³ и R⁴ определены выше.The compounds of formula (IV) can be reduced using agents such as sodium borohydride or sodium cyanohydride. Compounds of formula (IV) can be prepared by reacting a compound of formula (VII) with a compound of formula (XV):

where A, R ³ and R ^{4 are} defined above.

The interaction between the compounds of formulas (VII) and (XV) can occur under standard conditions, which are usually used to obtain the imine (Schiff base), which can be restored in situ. Thus, for example, imine formation and in situ reduction can be carried out in an inert solvent, such as toluene or tetrahydrofuran, in the presence of a reducing agent, such as sodium cyanoborohydride (NaCNBH ₃ ) under acidic conditions (Synthesis 135, 1975; Org. Prep. Proceed. Int. 11, 201, 1979).

The compounds of formulas (V) and (VI) can be reacted under standard conditions, for example, in an aprotic solvent, such as DMF, in the presence of a weak base at a temperature ranging from room temperature to 180 ^° C. Suitable X are halogen, tosylate, mesylate and trifluoroacetate. In particular, X is chloro or bromo.

The compounds of formulas (VII) and (VIII) can be reacted in an aprotic solvent, such as DMF, in the presence of a base, such as potassium carbonate or sodium hydride, at a temperature of from 0 ^{° C.} to 100 ^° C. Suitable h ¹ are halogen, tosylate, mesylate and trifluoroacetate. In particular, X ¹ is bromine.

The precursor of the R ⁷ group is a group that can be converted to R ⁷ .

Specifically, X ² is cyano, carbamoyl, alkoxycarbonyl, carboxy, and activated carboxy groups, such as acid chloride and activated esters.

The cyano group can be converted into a tetrazole ring by reacting, for example, with ammonium or tin azide in an aprotic solvent, such as DMF, at a temperature of from 100 ^° C to 130 ^° C. Further information on the synthesis of tetrazole can be found in SJ Wittenberger & B. J. Donner JOC, 1993, 58, 4139-4141; BE Huff et al., Tet. Lett, 1993, 50, 8011-8014 and JV Duncia et al., JOC, 1991, 56, 2395-2400.

Alkoxycarbonyl can be converted to a carboxy group by acid or basic hydrolysis. For example, basic hydrolysis can be carried out in an organic solvent, such as methanol or tetrahydrofuran (TTF) at a temperature ranging from room temperature to 100 ^° C. in the presence of sodium hydroxide or potassium hydroxide.

 Acid hydrolysis can be carried out, for example, in pure formic acid or pure trifluoroacetic acid, optionally in an inert solvent such as dichloromethane.

An alkoxycarbonyl or an activated carboxy group, such as an acid chloride or an activated ester, or an acyl group, such as an alkanoyl group, can be converted to an amide group by reaction with an appropriate amine in an inert solvent, such as DMF or dichloromethane, at a temperature of from 0 ^{° C.} to 150 ^{° C.} and preferably at room temperature in the presence of a base such as triethylamine.

The compounds of formulas (X) and R ⁷ X ³ can be reacted in an aprotic solvent, such as DMF, in the presence of a base, such as sodium carbonate or sodium hydride. Suitable for X ³ are halogen, tosylate, mesylate and trifluoroacetate, and especially halogen, such as iodine.

The interaction between the compounds of formulas (XI) and (XII) is usually carried out under mild conditions known as the Mitsunobi reaction, for example, in the presence of di (C _1-4 alkyl) azocarboxylate and triphenylphosphine or 1 ¹ , 1 ¹ - (azodicarbonyl) dipiperidine and tributylphosphine (Tet. Lett, 34, 1993, 1639-1642) in an inert solvent such as toluene, benzene, tetrahydrofuran or diethyl ether, in particular toluene. Examples of removable activating groups are tert-butoxycarbonyl and trifluoroacetyl.

The interaction between the compounds of formulas (XIII) and (XIV) usually occurs in the presence of a strong base, such as sodium hydride, lithium diisopropylamide or LiN (SiMe ₃ ) ₂ , in DMF or an ether solvent, such as ethyl ether or THF, at a temperature within from -78 ^o C to room temperature. Suitable X ⁵ is, for example, halogen, methanesulfonate or tosylate. Examples of activating groups X ⁶ are tert-butoxycarbonyl, halogen and trifluoroacetyl.

The interaction between the compounds of formulas (XV) and X ⁷ R ⁴ can be carried out in an inert organic solvent, such as acetone or DMF, at a temperature ranging from room temperature to 60 ^{° C.} in the presence of a weak base. Suitable leaving groups are tosylate, mesylate, trifluoroacetate and halogen, for example chlorine or bromine. Alternatively, an interphase system may be used. X ⁷ may be a hydroxy group that is activated in situ under the Mitsunobi reaction conditions (O. Synthesis, 1981, 1).

The compounds of formula (XV), where R ⁶ is R ¹ and R ⁷ is R ² , themselves have analgesic properties.

The compounds of formulas (IV), (V), (VIII), (IX), (X), (XI), (XIII) and (XV) can be obtained by the method used to form the lower binding group —OR ⁴ (similar to the method 1) from the corresponding starting compounds.

Compounds of formula (IX) can be prepared by processes a), b), c), e), f), g) or h) from the corresponding starting compound in which R ^{6 is} replaced by X ² .

Compounds of formula (X) can be prepared by one of methods a), b), c), d), f), g) or h) from the corresponding starting compounds, where R ⁷ is hydrogen.

 Compounds of formula (XII) can be readily prepared from compounds of formula (VII).

The compounds of formulas (VI), (VII), (XII) and (XIV) are mainly known compounds, or they can be obtained by the methods described in the examples, or by methods that are commonly used to obtain related compounds. Some compounds of formula (VI) in which X is chloro or bromo can be prepared by converting the oxo group in the ring system to a chloro or bromo group by reacting the oxo ring system with a chlorinating agent such as sulfonyl chloride, phosphorus trichloride, phosphorus pentachloride or P (O ) Cl ₃ , or with a brominating agent, such as phosphorus tribromide or P (O) Br ₃ , in an inert aprotic solvent.

 It is also possible to synthesize some intermediate compounds and even protected compounds using ring synthesis first. For reference, see the short guide, The Chemistry of Heterocyclic Compounds' E.C. Taylor and A. Veissberger (published by John & Sons) and Comprehensive Heterocyclic Chemistry, A.P. Katritsky &. C.W. Rees (published by Pergamon Press).

 Optional substituents may be converted to other optional substituents. Thus, for example, an alkylthio group can be oxidized to form an alkylsulfinyl or alkylsulfonyl group, a nitro group can be reduced to form an amino group, a hydroxy group can be alkylated to form a methoxy group, or a bromine group can be converted to an alkylthio group.

 Various compounds may be introduced into the compounds of the formula (I) and the formula (III) and into the intermediate compounds resulting from the preparation of the compounds of the formulas (I) and (III), if necessary, using conventional methods known in the art. So, for example, an acyl group or an alkyl group can be introduced into the activated benzene ring by the Friedel-Crafts reaction; a formyl group can be introduced by a formylation reaction using titanium tetrachloride and dichloromethyl ether; the nitro group can be introduced by nitration using concentrated nitric and concentrated sulfuric acid, and bromine can be introduced by bromination using bromine or tetra (n-butyl) ammonium tribromide.

 It should be noted that in order to prevent side reactions at some stages of the reaction scheme for obtaining the compounds of formula (I), it may be necessary to protect certain functional groups in the intermediate compounds. Then, if protection is no longer needed, then at the appropriate stage of the reaction scheme, deprotection can be carried out.

As mentioned above, the compounds of formula (I) are antagonists of the analgesic effect of group E prostaglandins and have the ability to eliminate mild or moderate pain accompanying, for example, inflammatory diseases such as rheumatoid arthritis or osteoarthritis. Some properties of the compounds of the present invention can be demonstrated using the tests described below:
(a) an in vitro assay using guinea pig ileum, which is used to evaluate the inhibitory properties of the test compound against PGE ₂ -induced ileum contractions. To do this, the ileum is immersed in an oxygenated Krebs solution containing indomethacin (4 μg / ml) and atropine (1 μM), and kept at 37 ^o C; the ileum is tensioned at 1 g, then a dose-response curve is constructed for the PGE ₂ -induced ileum contraction; after which the test compound (dissolved in dimethyl sulfoxide) is added to the Krebs solution and a dose-response curve is constructed for the PGE ₂ -induced ileum contraction in the presence of the test compound; and then pA _{2 is} calculated for the test compound;
(b) an in vivo assay in mice to evaluate the inhibitory properties of a test compound against an abdominal contraction reaction induced by intraperitoneal administration of a toxic factor such as diluted acetic acid or phenylbenzoquinone (hereinafter referred to as (PBQ); wherein the assay is performed with using the methodology described in European patent application 0218077.

Although the pharmacological properties of the compounds of formula I may vary depending on their structure, the activity of these compounds can generally be demonstrated in one or two of the above Tests (a) and (b) at the following concentrations or doses:
Test (a): pA ₂ >5.3;
Test (b): ED ₅₀ in the range of, for example, 0.01-100 mg / kg orally.

 In test (b), with the administration of the compounds of formula I in doses that are several times higher than their minimum inhibitory dose, no noticeable toxicity or other adverse effects were observed.

Prostaglandin receptors and, in particular, receptors for PGE ₂ have been tentatively characterized by Kennedy et al. (Advances in Prostaglandin, Thromboxane and Leukotriene Research, 1983, 11, 327). The well-known prostaglandin antagonist PGE ₂ SC-19220 blocks the action of PGE ₂ in some tissues, such as the ileum of guinea pigs or dog peritoneum, but this effect is not observed in other tissues, such as the cat's trachea or ileum. It was found that tissues that are susceptible to SC-19220-mediated effects have receptors for EP ₁ . Based on this, it can be argued that the compounds of the present invention having activity in test (a) are EP ₁ antagonists.

 In accordance with another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I), or an in vivo hydrolyzable ester or amide thereof, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.

 This composition may be prepared in a form suitable for oral administration, for example, in the form of a tablet, capsule, aqueous or oily solution, suspension or emulsion; for local use, for example, in the form of a cream, ointment, gel, aerosol, oily or aqueous solution or suspension; for intranasal administration, for example, as a preparation for inhalation through the nose, aerosol or drops in the nose; for vaginal or rectal administration, for example, in the form of a suppository or rectal aerosol; for administration by inhalation, for example, in the form of a fine powder or liquid aerosol; for sublingual and buccal (via the cheek) administration, for example, in the form of a tablet or capsule; or for parenteral administration (including intravenous, subcutaneous, intramuscular, intravascular injection or infusion), for example, in the form of sterile aqueous or oily solutions or suspensions. In general, the above compositions may be prepared by standard methods using standard excipients.

 The amount of active ingredient (i.e., a compound of formula (I) or a pharmaceutically acceptable salt thereof) that is combined with one or more excipients to produce the desired unit dosage form may vary depending on the particular patient being treated, as well as on the route of administration . So, for example, a composition intended for oral administration to humans usually contains from 0.5 mg to 2 g of the active compound, mixed with an appropriate amount of excipients, which can vary from about 5 to about 98% by weight of the total composition.

 In accordance with another aspect, the present invention relates to a compound of formula (I), or an in vivo hydrolyzable ester or amide thereof, or a pharmaceutically acceptable salt thereof, which can be used in the therapeutic treatment of animals (including humans).

 In accordance with another aspect, the present invention relates to a method for alleviating pain in an animal (including humans), comprising administering to the animal an effective amount of a compound of formula I, or an in vivo hydrodizable ester or amide, or a pharmaceutically acceptable salt thereof.

 As indicated above, the compound of formula (I) can be used to eliminate pain, which, for example, is accompanied by inflammatory diseases such as rheumatoid arthritis and osteoarthritis. The daily dose of a compound of formula I used for therapeutic or prophylactic purposes is usually, for example, from 0.1 mg to 75 mg per kg of body weight and may be administered, if necessary, in separate doses. For parenteral administration, generally lower doses are used. So, for example, for intravenous administration, a dose of, for example, from 0.05 to 30 mg per kg of body weight can be used. Similarly, for administration by inhalation, a dose of, for example, from 0.05 mg to 25 mg per kg of body weight may be used.

Although the compounds of formula (I) are usually therapeutic agents intended for administration to warm-blooded animals (including humans), they can be used in all cases in which the inhibition of the action of PGE ₂ in the EP ₁ receptor is required based on test (a). Thus, these compounds can be used as pharmacological standards for the development of new biological tests and new pharmacological agents.

 Due to their ability to relieve pain, the compounds of formula I are effective in treating certain inflammatory and non-inflammatory diseases that are currently being treated with non-steroidal anti-inflammatory drugs (NSAIDs) that inhibit the effects of cyclooxygenases such as indomethacin, ketorolac, acetylsalicylic acid, ibuprofen, sulindac, tolmetin and piroxicam. Co-administration of a compound of Formula I with NSAIDs may reduce the amount of NSAIDs necessary to produce a therapeutic effect. This also reduces the likelihood of side effects caused by NSAIDs, such as gastrointestinal upsets. Thus, in accordance with another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula I, or an in vivo hydrolyzable ester or amide thereof, or a pharmaceutically acceptable salt thereof, in combination or in admixture with a non-steroidal anti-inflammatory agent and a pharmaceutically acceptable diluent or carrier.

 The compounds of the present invention can also be used in combination with other anti-inflammatory agents, such as an inhibitor of the 5-lipoxygenase enzyme (for example, described in European patent applications 0351194, 0375368, 0375404, 0375452, 037547, 0381375, 0385662, 0385663, 0385679, 0385680) .

 The compounds of formula (I) can also be used to treat diseases such as rheumatoid arthritis, when used in combination with anti-arthritis agents such as gold, methotrexate, steroids and penicillinamine; and for the treatment of diseases such as osteoarthritis, they can be used in combination with steroids.

 The compounds of the present invention can also be administered in degenerative diseases, for example, in osteoarthritis, in combination with chondroprotective, antidegenerative and / or reparative agents, such as diacergein, hyaluronic acid preparations such as gualan, rumalon, arteparone, and glucosamine salts such as anthril .

The compositions of the present invention may further comprise one or more other therapeutic agents or prophylactic agents which are known to have an analgesic effect. For example, known opiate painkillers (such as dextropropoxyphene, dehydrocodeine or codeine), or antagonists of other pain mediators or inflammatory mediators, such as bradykinin, takikinin, and calcitonin gene peptides (CGRP) may also be present in the pharmaceutical composition of the present invention ), or an α ₂ -adrenoreceptor agonist, a GABA _B receptor agonist, a calcium channel blocker, an CCK _B receptor antagonist, a neurokinin antagonist or an antagonist and a modulator of the effect of glutamate on the NMDA receptor .

 The compounds of the present invention can also be administered in bone diseases, such as osteoporosis, in combination with calcitonin and bisphosphonates.

In more detail, the present invention is illustrated in the following, but not limiting, examples, in which, unless otherwise indicated:
(i) evaporation was carried out in a rotary vacuum evaporator, and processing procedures were carried out after removal of residual solids by filtration;
(ii) the outputs are given for illustration only and should not be construed as maximum achievable;
(iii) the final products of formula I have satisfactory microanalysis data and their structures have been largely confirmed by analyzes carried out by NMR and mass spectroscopy.

(iv) melting points are uncorrected and were determined using a Mettler SP62 automated special tool or an oil bath appliance; moreover, the melting points for the final products were determined after recrystallization from a standard organic solvent, such as ethanol, methanol, acetone, ether or hexane, taken separately or in a mixture with each other;
(v) the following abbreviations were used:
DMF - N, N-dimethylformamide;
THF - tetrahydrofuran;
DMSO - dimethyl sulfoxide;
TLC - thin layer chromatography;
GHSD - medium-pressure liquid chromatography.

EXAMPLE 1
2- [N- (5-Bromo-2-propoxybenzyl) -N-ethylamino] pyridine-5-carboxylic acid
A solution of methyl 2- [N- (5-bromo-2-propoxybenzyl) -N-ethyl-amino] pyridine-5-carboxylate (comparative example 1) (0.12 g, 0.29 mmol) in THF (3 ml ) and methanol (3 ml) was treated with an aqueous solution of sodium hydroxide (1 N., 1.8 ml). The reaction mixture was heated to 40 ^{° C.} for 18 hours. The solvent was evaporated and the residue was diluted with water (3 ml) and acidified with acetic acid (1 N, 3 ml). The solid product was filtered off and the title compound (0.1 g, 88%) was obtained as a white solid.

MS (CI ⁺ ): 393/395 (M + H) ⁺ .

NMR (200 MHz, DMSO-d ₆ ) δ: 1.0 (t, J = 7Hz, 3H); 1.12 (t, J = 7Hz, 3H); 1.75 (m, 2H); 3.6 (q, J = 7Hz, 2H); 3.98 (t, J = 7Hz, 2H); 4.73 (s, 2H); 6.65 (d, J = 9Hz, 1H); 7.02 (m, 2H); 7.4 (dd, J = 2.9Hz, 1H); 7.92 (dd, J = 2.9Hz, 1H); 8.6 (d, J = 2Hz, 1H).

EXAMPLE 2
2- [N- (5-Bromo-2- (methyl) propoxybenzyl) -N-ethylamino] -5-pyridine-carboxylic acid
The title compound was obtained by a method similar to that described in example 1, except that the corresponding ester was used (comparative example 2).

MS (CI ⁺ ): 407 (M + H) ⁺ .

NMR (250 MHz, DMSO-d ₆ ) δ: 1.0 (d, J = 6Hz, 6H); 1.05 (t, J = 7HZ, 3H); 2.02 (m, 1H); 3.59 (q, J = 7Hz, 2H); 3.8 (d, J = 6Hz, 2H); 4.75 (s, 2H); 6.64 (d, J = 9Hz, 1H); 6.96 (d, J = 9Hz, 1H); 7.05 (d, J = 2Hz, 1H); 7.36 (dd, J = 2.9Hz, 1H); 7.9 (dd, J = 2.9Hz, 1H); 8.61 (d, J = 2Hz, 1H); 12.35 (br s, 1H).

EXAMPLE 3
6- [N- (5-Bromo-2- (cyclopropylmethoxy) benzyl) -N-ethylamino] pyridazine-3-carboxylic acid
The title compound was prepared in a similar manner to that described in Example 1, except that the corresponding butyl ester was used (comparative example 4).

Mp 73-80 ^o C.

MS (FAB ⁺ ): 406 (M + H) ⁺ .

NMR (200 MHz, DMSO-d ₆ + HOAc-d ₄ ) δ: 0.15 (m, 2H); 0.38 (m, 2H); 1.02 (m, 4H); 3.55 (q, J = 7Hz, 2H); 3.7 (d, J = 7Hz, 2H); 4.68 (s, 2H); 6.78 (m, 1H); 7.0 (m, 2H); 7.22 (d, J = 9Hz, 1H); 7.5 (d, J = 9Hz, 1H).

EXAMPLE 4
2- [N- (5-Bromo-2- (cyclopentylmethoxy) benzyl) -N-ethylamino] pyridine-5-carboxylic acid
A solution of methyl 2- [N- (5-bromo-2- (cyclopentylmethoxy) benzyl) -N-ethylamino] pyridine-5-carboxylate (see comparative example 5) (0.37 g, 0.83 mmol) in THF (4 ml) and methanol (4 ml) were treated with 1 N. aqueous sodium hydroxide solution (4 ml). The reaction mixture was heated at 40 ^{° C.} for 18 hours. The solvents were evaporated under reduced pressure, and the residue was acidified with 1N. acetic acid (4 ml) and left to mix for 2 days. The precipitate was filtered, washed with water and dried in vacuo at a temperature of 45 ^{° C.} to give the title compound as a white solid (0.32 g, 89%).

MS (ESP ⁺ ): 433 (M + H) ⁺ .

NMR (200 MHz, DMSO-d ₆ ) δ: 1.2 (t, J = 7Hz, 3H); 1.35 (m, 2H); 1.58 (m, 4H); 1.75 (m, 2H); 2.30 (m, 1H); 3.60 (q, J = 7Hz, 2H); 3.9 (d, J = 7Hz, 2H); 4.74 (s, 2H); 6.65 (d, J = 9Hz, 1H); 6.98 (d, J = 9Hz, 1H); 7.10 (d, J = 2Hz, 1H); 7.88 (dd, J = 2.9Hz, 1H); 7.92 (d, J = 2.9Hz, 1H); 8.62 (d, J = 2Hz, 1H); 12.4 (approx. 1H).

EXAMPLE 5
6- [N- (5-Bromo-2-propoxybenzyl) -N-ethylamino] pyridazine-3-carboxylic acid
The title compound was prepared from butyl-6- [N- (5-bromo-2-propoxybenzyl) -N-ethylamino] pyridazine-3-carboxylate (comparative example 6) in a manner similar to that described in example 1.

MS (ESP ⁺ ): 394/396 (M + H) ⁺ .

NMR (200 MHz DMSO-d ₆ ) δ: 0.97 (t, J = 6.7Hz, 3H); 1.16 (t, J = 6.7Hz, 3H); 1.73 (m, J = 6.7 Hz, 2H); 3.7 (q, J = 6.7Hz, 2H); 3.98 (t, J = 6.7Hz, 2H); 4.82 (s, 2H); 7.0 d, J = 9.3 Hz, 1H); 7.12 (d, J = 9.3Hz, 1H); 7.17 (d, J = 2.0Hz, 1H); 7.40 (dd, J = 2.0, 10.0Hz, 1H); 7.83 (d, J = 10.0Hz, 1H).

EXAMPLE 6
6- [N- (5-Bromo-2-n-butoxybenzyl) -N-ethylamino] pyridazine-3-carboxylic acid
The title compound was prepared from butyl-6- [N- (5-bromo-2-n-butoxybenzyl) -N-ethylamino] pyridazine-3-carboxylate (comparative example 7) in a manner analogous to that described in example 1.

MS (ESP ⁺ ): 408/410 (M + H) ⁺ .

NMR (200 MHz, DMSO-d ₆ ) δ: 0.9 (t, J = 6.7Hz, 3H); 1.14 (t, J = 6.7Hz, 3H); 1.40 (m, J = 6.7Hz, 2H); 1.67 (m, J = 6.7Hz, 2H); 3.67 (q, J = 6.7 Hz, 2H); 4.00 (t, J = 6.7Hz, 2H); 4.8 (s, 2H); 7.0 (d, J = 8.3Hz, 1H); 7.11 (d, J = 10.0Hz, 1H); 7.15 (d, J = 1.7Hz, 1H); 7.40 (dd, J = 1.7, 8.3 Hz, 1H); 7.84 (d, J = 10.0Hz, 1H).

EXAMPLE 7
[N- (3,6-Dimethylisoxazol-4-ylsulfonyl) -6- [N- (5-bromo-2- (cyclopropylmethoxy) benzyl) -N-ethylamino] pyridazine-3-carboxamide
A solution of 6- [N- (5-bromo-2- (cyclopropylmethoxy) benzyl) -N-ethylamino] pyridazine-3-carboxylic acid (example 3) (0.166 g, 0.409 mmol) in DMF (4 ml) was treated with 3.5 dimethyl-4-sulfonamidoisoxazole (0.08 g, 0.455 mmol), dimethylaminopyridine (0.15 g, 1.23 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimidohydrochloride (0.12 g, 0.627 mmol). The reaction mixture was stirred overnight at room temperature. TLC (10% MeOH / CH ₂ Cl ₂ + 1% HOAc) showed that the reaction was not completed. Dimethylaminopyridine (0.05 g, 0.409 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.08 g, 0.418 mmol) were added and the reaction mixture was stirred for 60 hours at room temperature. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried (MgSO ₄ ) and evaporated, and the residue was purified by chromatography (eluent: methanol / dichloromethane / acetic acid) to obtain the title compound as a foam (0.073 g).

MS (ESP ⁺ ): 564 (M + H) ⁺ .

NMR (200 MHz, DMSO-d ₆ ) δ: 0.3 (m, 2H); 0.53 (m, 2H); 1.55 (m, 4H); 2.40 (s, 3H); 2.70 (s, 3H); 3.70 (q, J = 7Hz, 2H); 3.87 (d, J = 7Hz, 2H); 4.85 (s, 2H); 6.98 (d, J = 9Hz, 1H); 7.22 (d, J = 2Hz, 1H); 7.24 (d, J = 9Hz, 1H); 7.39 (dd, J = 2.9Hz, 1H); 7.83 (d, J = 9HZ, 1H).

EXAMPLE 8
The compounds shown in the table (see end of text) were obtained from the corresponding carboxylic acid and the corresponding sulfonamide derivative in a manner analogous to that described in example 7.

Table notes
a) NMR (200 MHz, DMSO-d ₆ ) δ: 0.97 (d, 6H); 1.15 (t, 3H); 2.02 (m, 1H); 2.40 (s, 3H); 2.69 (s, 3H); 3.70 (q, 2H); 3.80 (d, 2H); 4.85 (s, 2H); 7.03 (m, 2H); 7.20 (d, 1H); 7.27 (dd, 1H); 7.82 (d, 1H).

Elemental analysis for C ₂₃ H ₂₈ ClN ₅ O ₅ S + 0.13 mol of toluene:
Theoretical (%): C - 53.8; H 5.5; N - 13.1.

 Found (%): C - 53.4; H 5.5; N - 12.7.

b) NMR (200 MHz, DMSO-d ₆ ) δ: 0.95 (d, 6H); 1.14 (t, 3H); 2.00 (m, 1H); 2.23 (s, 3H); 3.67 (q, 2H); 3.80 (d, 2H); 4.83 (s, 2H); 7.04 (D, J = 8Hz, 1H); 7.14 (d, J = 3Hz, 1H); 7.28 (dd, J = 8, 3HZ, 1H); 7.57 (d, J = 9Hz, 1H); 8.05 (d, J = 9Hz, 1H); 12.84 (s, 1H).

Elemental analysis for C ₂₂ H ₂₆ ClN ₇ O ₅ S ₂ + 0.1 mol CH ₂ Cl ₂ + 0.2 mol H ₂ O:
Theoretical (%): C - 45.8; H 4.6; N - 16.9.

 Found (%): C - 45.4; H 4.5; N - 16.8.

T. pl. 240-242 ^o C.

c) NMR (200 MHz, DMSO-d ₆ ) δ: 1.00 (m, 9H); 1.15 (t, 3H); 1.75 (m, 2H); 2.03 (m, 1H); 3.45 (t, 2H); 3.70 (q, 2H); 3.81 (d, 2H); 4.86 (s, 2H); 7.03 (m, 2H); 7.20 (d, 1H); 7.27 (dd, 1H); 7.87 (d, 1H).

Elemental analysis for C ₂₁ H ₂₉ ClN ₄ O ₄ S:
Theoretical (%): C - 53.8; H 6.2; N - 11.9.

 Found (%): C - 53.9; H 6.2; N - 11.9.

d) MC (ESP ⁺ ): 534/536 (MH ⁺ ).

NMR (200 MHz, DMSO-d ₆ ) δ: 1.13 (t, 3H); 1.65 (wide m); 1.88 (broad m, 2H); 2.38 (s, 3H); 2.68 (s, 3H); 3.65 (q, 2H); 4.76 (s, 2H); 4.85 (m, 1H); 7.00 (d, 1H); 7.03 (d, 1H); 7.18 (d, 1H); 7.24 (dd, 1H); 7.82 (d, 1H).

e) MC (ESP ⁺ ): 507/509 (MH ⁺ ).

NMR (200 MHz, DMSO-d ₆ ) δ: 1.11 (t, 3H); 1.60 (br m, 6H); 1.88 (m, 2H); 3.63 (q, 2H); 4.75 (s, 2H); 4.85 (m, 1H); 7.02 (d, 1H); 7.30 (m, 2H); 7.88 (d, 2H); 8.20 (d, 2H).

f) mp 111-113 ^o C.

NMR (MHz, DMSO-d ₆ ) δ: 0.92 (t, 3H); 1.1 (t, 3H); 1.5-2.2 (m, 8H); 2.65 (m, 1H); 3.25 (m, 2H); 3.68 (q, 2H); 3.95 (d, 2H); 4.8 (s, 2H); 7.0 (m, 2H); 7.15 (d, 1H); 7.25 (dd, 1H); 7.82 (d, 1H).

Elemental analysis for C ₂₂ H ₂₉ ClSN ₄ O ₄ S • 0.75 H ₂ O:
Theoretical (%): C - 53.4; H 6.2; N - 11.3.

 Found (%): C - 53.3; H 5.8; N - 11.4.

g) mp 140-142 ^o C.

NMR (MHz, DMSO-d ₆ ) δ: 1.1 (t, 3H); 1.75-2.2 (m, 6H); 2.25 (s, 3H); 2.55 (s, 3H); 2.70 (m, 1H); 3.65 (q, 2H); 4.0 (d, 2H); 4.75 (s, 2H); 7.0 (m, 3H); 7.25 (dd, 1H); 7.8 (d, 1H).

Elemental analysis for C ₂₄ H ₂₈ SClN ₅ O ₅ • H ₂ O:
Theoretical (%): C - 52.2; H 5.4; N - 12.7.

 Found (%): C - 51.8; H - 5.0; N - 12.5.

EXAMPLE 9
6- [N- (5-Bromo-2- (2-methylpropoxy) benzyl) -N-ethylamino] pyridazine-3-carboxylic acid
Butyl-6- [N- (5-bromo-2- (2-methylpropoxy) benzyl) -N-ethylamino] pyridazine-3-carboxylate (comparative example 10) (0.22 g, 0.47 mmol) in THF ( 3 ml) and methanol (3 ml) were treated with 1 N. aqueous sodium hydroxide solution (3 ml) and left for 1.5 hours at room temperature (after which TLC (diethyl ether / hexane 1: 1) indicated the absence of ester). The reaction mixture was evaporated to a smaller volume, treated with a small amount of water and acidified with acetic acid to give a gum. This resin did not solidify, so it was extracted with ethyl acetate (x2) and the combined extracts were washed with brine, dried (MgSO ₄ ) and evaporated to give a gum. The resin was evaporated from toluene and dichloromethane to give the title compound as a foam (140 mg, 73%).

MS (CI ⁺ ): 408.410 (M + H) ⁺ .

MS (EI ⁺ ): 408.410 (M + H) ⁺ .

NMR (200 MHz, DMSO-d ₆ ) δ: 1.00 (d, J = 10Hz, 6H); 1.16 (t, J = 8.3Hz, 3H); 1.93-2.15 (m, 1H); 3.69 (q, J = 8.3Hz, 2H); 3.80 (d, J = 6.67Hz, 2H); 4.84 (s, 2H); 6.98 (d, J = 10Hz, 1H); 7.12 (m, 2H); 7.40 (dd, J = 2, 8.3 Hz, 1H); 7.84 (d, J = 10Hz, 1H).

EXAMPLE 10
6- [N- (5-Chloro-2- (2-methylpropoxy) benzyl) -N-ethylamino] pyridazine-3-carboxylic acid
The title compound was prepared by hydrolysis of butyl 6- [N- (5-chloro-2- (2-methylpropoxy) benzyl) -N-ethylamino] pyridazine-3-carboxylate (comparative example 12) in a manner similar to that described in example 1 .

NMR (250 MHz, DMSO-d ₆ ) δ: 1.00 (d, 6H); 1.15 (t, 3H); 2.04 (m, 1H); 3.69 (q, 2H); 3.80 (d, 2H); 4.84 (s, 2H); 7.03 (m, 2H); 7.11 (d, 1H); 7.27 (dd, 1H); 7.83 (d, 1H).

MS (ES ⁺ ): 362 (M-H) ^- .

Elemental analysis for C ₁₈ H ₂₂ ClN ₃ O ₃ :
Theoretical (%): C - 59.4; H 6.1; N - 11.5.

 Found (%): C - 59.4; H 5.9; N - 11.4.

Mp 132-134 ^o C.

MS (CI ⁺ ): 181 (M + H) ⁺ .

EXAMPLE 11
6- [N- (5-Bromo-2- (cyclopropylmethoxy) benzyl) -N-ethyl] pyridazine-3-carboxamide
N-Ethyl-5-bromo-2- (cyclopropylmethoxy) benzylamine (comparative example 13) (12.56 g) was dissolved in NMP (59 ml) in an argon atmosphere. 6-Chloropyridazine-3-carboxamide (6.17 g, 3.9 mmol) and sodium bicarbonate (8.24 g, 98 mmol) were added and the mixture was heated at 110 ^{° C.} for 24 hours. Then the mixture was cooled and diluted with ethyl acetate and poured into a mixture of a saturated aqueous solution of ammonium chloride and 1 N. hydrochloric acid (50 ml). The resulting white precipitate was filtered off and washed with ethyl acetate and diethyl ether to give the title compound, which was dried in a vacuum oven at 55 ^° C (11.46 g, 72.1%).

NMR (200 MHz, DMSO-d ₆ ) δ: 0.34 (m, 2H); 0.55 (m, 2H); 1.17 (m, 4H); 3.69 (q, 2H); 3.88 (d, 2H); 4.80 (s, 2H); 6.96 (d, 1H); 7.15 (m, 2H); 7.37 (dd, 1H); 7.42 (br s, 1H); 7.84 (d, 1H); 8.14 (br s, 1H).

MS (ESP ⁺ ): 405 (M + H) ^- .

EXAMPLE 12
5- [6- (N- [5-Bromo-2- (cyclopropylmethoxy) benzyl] -N-ethylamino) pyridazin-3-yl] tetrazole
6- [N- (5-bromo-2- (cyclopropylmethoxy) benzyl] -N-ethylamino] -3-cyanopyridazine (comparative example 14) (1.63 g) was dissolved in dimethylacetamide (DMA) (17 ml) in argon atmosphere Triethylamine hydrochloride (0.87 g, 6.3 mmol) and sodium azide (0.82 g, 12.6 mmol) were added and the mixture was heated at 95-110 ^{° C.} for 3 hours, then cooled and partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with 10% 2N. HCl, saturated aqueous ammonium chloride solution (x 2) and brine (x 2), dried over Na ₂ SO _4, filtered and evaporated. The residue n recrystallized from acetonitrile to give the title compound (1.34 g, 74.0%).

NMR (200 MHz, DMSO-d ₆ ) δ: 0.34 (m, 2H); 0.56 (m, 2H); 1.20 (m, 4H); 3.74 (q, 2H); 3.88 (d, 2H); 4.84 (s, 2H); 6.96 (d, 1H); 7.25 (d, 1H); 7.29 (d, 1H); 7.37 (dd, 1H); 8.03 (d, 1H).

Elemental analysis for C ₁₈ H ₂₀ BrN ₇ O:
Theoretical (%): C - 50.2; H 4.7; N - 22.8.

 Found (%): C - 50.2; H 4.8; N - 22.8.

MS (ESP ⁺ ): 430 (M + H) ⁺ .

EXAMPLE 13
5- (6- [N- (5-Chloro-2- (2-methylpropoxy) benzyl) -N-ethylamino] pyridazin-3-tetrazole
The title compound was prepared from 6- [N- (5-chloro-2- (2-methylpropoxy) benzyl) -N-ethylamino] -3-cyanopyridazine (comparative example 15) by a method similar to that described in example 12.

NMR (200 MHz, DMSO-d ₆ ) δ: 0.99 (d, 6H); 1.18 (t, 3H); 2.04 (m, 1H); 3.72 (q, 2H); 3.82 (d, 2H); 4.86 (s, 2H); 7.04 (d, 1H); 7.09 (d, 1H); 7.27 (m, 2H); 8.03 (d, 1H).

Elemental analysis for C ₁₈ H ₂₂ ClN ₇ O:
Theoretical (%): C - 55.7; H 5.7; N - 25.3.

 Found (%): C - 55.6; H 5.7; N - 24.9.

MS (ES ⁺ ): 388 (M + H) ⁺ .

Mp 204-206 ^o C.

EXAMPLE 14
N-Propanesulfonyl-6- [N- (5-bromo-2- (cyclopropylmethoxy) benzyl] -N-ethylamino] pyridazine-3-carboxamide
6- [N- (5-Bromo-2- (cyclopropylmethoxy) benzyl] -N-ethylamino] pyridazine-3-carboxylic acid (Example 3) (1.0 g, 2.46 mmol) was mixed with propylsulfonamide (0.32 g, 2.6 mmol), 4- (dimethylamino) pyridine (0.90 g, 7.38 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.71 g, 3.7 mmol) argon atmosphere DMF (12.0 ml) was added and the mixture was stirred overnight at room temperature.

The reaction mixture was poured into a saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate (x 2). The combined organic extracts were washed with 5% 2 n HCl in a saturated aqueous solution of ammonium chloride, saturated aqueous sodium bicarbonate (x 1) and brine (x 1), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified using medium pressure liquid chromatography (HPLC) using 2.5% IPA / dichloromethane + 0.2% acetic acid. The fractions containing the title compound were evaporated and the residue was co-distilled with toluene, isohexane and finally ether, whereby the title compound was obtained as a white foam after drying under high vacuum (100 g, 79.4% )

NMR (200 MHz, DMSO-d ₆ ) δ: 0.30 (m, 2H); 0.55 (m, 2H); 1.00 (t, 3H); 1.16 (m, 4H); 1.75 (m, 2H); 3.45 (t, 3H); 3.73 (q, 2H); 3.87 (d, J = 7.5Hz, 2H); 4.85 (s, 2H); 6.97 (d, J = 8.3Hz, 1H); 7.18 (d, J = 3.1Hz, 1H); 7.24 (d, J = 8.7Hz, 1H); 7.39 (dd, J = 8.3, 3.1Hz, 1H); 7.86 (d, J = 8.7Hz, 1H).

Elemental analysis for C ₂₁ H ₂₇ BrN ₄ O ₄ S:
Theoretical (%): C - 49.3; H 5.3; N - 11.0.

 Found (%): C - 49.7; H 5.6; N - 10.7.

EXAMPLE 15
6- [N- (5-Bromo-2- (2-hydroxy-3,3,3-trifluoropropoxy) benzyl) -N-ethylamino] pyridazine-3-carboxylic acid
The title compound was prepared from n-butyl ether (comparative example 16) by a method similar to that described in example 1.

NMR (250 MHz, DMSO-d ₆ ) δ: 1.15 (t, 3H); 3.68 (m, 2H); 4.20 (m, 2H); 4.44 (m, 1H); 4.89 (s, 2H); 7.08 (m, 3H); 7.4 (dd, 1H); 7.83 (d, 1H).

MS: 463 (M + H) ⁺ .

EXAMPLE 16
5- [6- (N- [2- (Cyclopropylmethoxy) -5-methanesulfonylbenzyl] -N-ethylamino) pyridazin-3-yl] tetrazole
The title compound was obtained from the corresponding cyano derivative (comparative example 17) by a method similar to that described in example 12, except that the mixture was heated at 85 ^{° C. for} approximately 20 hours and the reaction progress was monitored by TLC. Yield: 80%.

NMR (200 MHz, DMSO-d ₆ ) δ: 0.36 (m, 2H); 0.57 (m, 2H); 1.14-1.35 (m, 4H); 3.08 (s, 3H); 3.78 (q, 2H); 4.03 (d, J = 6.2Hz, 2H); 4.93 (s, 2H); 7.25 (d, J = 8.3Hz, 1H); 7.35 (d, J = 8.3Hz, 1H); 7.68 (D, J = 2.1Hz, 1H); 7.83 (dd, J = 2.1, 8.3Hz, 1H); 8.05 (D, J = 8.3Hz, 1H).

MS (ESP ⁺ ): 430 (M + H) ⁺ .

EXAMPLE 17
5- [6- (N- [5-Bromo-2-propoxybenzyl] -N-ethylamino) pyridazin-3-yl] tetrazole
6- [N- (5-Bromo-2-propoxybenzyl) -N-ethylamino] -3-cyanopyridazine (comparative example 18) (1.0 g, 2.67 mmol) was dissolved in DMA (15 ml) and treated with sodium azide (520 mg, 8.0 mmol) and then triethylammonium chloride (550 mg, 4.0 mmol) and the mixture was heated for 3 hours at 110 ^° C. The resulting solution was poured into 2M hydrochloric acid (50 ml), extracted with ethyl acetate and dichloromethane (100 ml each) and the combined extracts were washed with water (3x100 ml), dried over MgSO ₄ and concentrated in vacuo. The addition of ether and hexane produced a solid precipitate which was triturated in acetonitrile / toluene to give the title compound (965 mg, 87%).

MS (ESP ⁺ ): 418 (M + H) ⁺ , 390 (M + HN ₂ ) ^- .

Elemental analysis for C ₁₇ H ₂₀ BrN ₇ O:
Calculated: (%) C - 48.8; H 4.82; N, 23.4.

 Found: (%) C - 49.1; H 4.7; N - 23.5.

NMR (250 MHz, DMSO-d ₆ ) δ: 0.99 (t, J = 7Hz, 3H); 1.17 (t, J = 6Hz, 3H); 1.72 (m, 2H); 3.72 (q, J = 6Hz, 2H); 4.0 (t, J = 7Hz, 2H); 4.82 (s, 2H); 6.98 (d, J = 8.5Hz, 1H); 7.22 (d, J = 2Hz, 1H); 7.27 (d, J = 8Hz, 1H); 7.40 (dd, J = 2.8Hz, 1H); 8.03 (d, J = 8.5Hz, 1H).

EXAMPLE 18
6- (N- [5-Bromo-2-propoxybenzyl] -N-ethylamino) pyridazine-3-carboxylic acid
6- [N- (5-Bromo-2-propoxybenzyl] -N-ethylamino] -3-cyanopyridazine (comparative example 18) (1.5 g, 4 mmol) in ethanol (100 ml) was treated with an aqueous solution of sodium hydroxide (20 ml, 2M, 40 mmol) and heated to 70 ^{° C.} for 16 hours. The solvents were evaporated under reduced pressure, the residue was dissolved in water, acidified with acetic acid and extracted four times with ethyl acetate. The combined organic phases were washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The resulting resin was triturated in ether to give the title compounds in the form of a solid product (1.24 g, 79%).

Mp 135-137 ^o C.

MS (ESP ^- ): 392 (MH) ^- .

Elemental analysis for C ₁₇ H ₂₀ BrN ₇ O:
Calculated: (%) C - 51.8; H 5.1; N - 10.7.

 Found: (%) C - 51.9; H 5.3; N - 10.6.

EXAMPLE 19
N-Propyl-6- (N- [5-bromo-2-propoxybenzyl] -N-ethylamino) pyridazine-3-carboxamide
6- (N- [5-Bromo-2-propoxybenzyl] -N-ethylamino) pyridazine-3-carboxylic acid (example 18) (500 mg, 1.27 mmol) was dissolved in dichloromethane (50 ml), 1- hydrochloride was added (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDAC) (365 mg, 2.07 mmol), dimethylaminopyridine (DMAP) (465 mg, 3.81 mmol) and propanesulfonamide (190 mg, 1.54 mmol). The mixture was stirred at room temperature overnight under argon, after which TLC data (5% methanol / dichloromethane) confirmed the completion of the reaction. The reaction mixture was loaded directly onto a GLCS column (silica gel), and elution with 5% methanol / dichloromethane gave the title compound as a foam (380 mg, 60%).

MC (ESP ⁺ ): 499 (M + H) ⁺ .

Elemental analysis for C ₂₀ H ₂₇ BrN ₄ O ₄ S:
Calculated: (%) C - 48.1; H 5.45; N - 11.2.

 Found: (%) C - 48.2; H 5.8; N - 10.8.

NMR (250 MHz, DMSO-d ₆ ) δ: 0.95 (m, 6H); 1.17 (t, J = 6Hz, 3H); 1.7 (m, 2H); 3.37 (t, J = 8Hz, 2H); 3.67 (q, J = 6Hz, 2H); 3.95 (t, J = 6Hz, 2H); 4.82 (s, 2H); 6.98 (d, J = 8.5Hz, 1H); 7.12 (D, J = 2Hz, 1H); 7.17 (d, J = 8Hz, 1H); 7.37 (dd, J = 2.8Hz, 1H); 7.83 (d, J = 8.5Hz, 1H).

EXAMPLE 20
N- (3,5-Dimethylisoxazo-4-ylsulfonyl) -6- (N- [5-bromo-2-propoxybenzyl] -N-ethylamino) pyridazine-3-carboxamide
6- (N- [5-Bromo-2-propoxybenzyl] -N-ethylamino) pyridazine-3-carboxylic acid (Example 18) (500 mg, 1.27 mmol) was dissolved in dichloromethane (50 ml). 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDAC) (365 mg, 2.07 mmol), dimethylaminopyridine (DMAP) (465 mg, 3.81 mmol) and 3,5-dimethyloxazoli-4-ylsulfonamide ( 270 mg, 1.53 mmol). The mixture was stirred at room temperature overnight under argon, after which TLC data (5% methanol / dichloromethane) confirmed the completion of the reaction. The reaction mixture was placed directly on a GLCS column (silica gel) and after elution with 5% methanol / dichloromethane, the title compound was obtained as a gum, which was then purified by trituration in ether to give the desired product as a solid (180 mg, 33%) .

Mp 122-124 ^o C.

MS (ESP ⁺ ): 552 (M + H) ⁺ .

Elemental analysis for C ₂₂ H ₂₆ BrN ₅ O ₅ S • 1.1 H ₂ O:
Calculated: (%) C - 47.8; H 4.7; N - 12.7.

 Found: (%) C - 46.2; H 4.9; N - 12.2.

NMR (250 MHz, DMSO-d ₆ ) δ: 0.95 (m, J = 6Hz, 3H); 1.12 (t, J = 7Hz, 3H); 1.72 (m, 2H); 2.27 (s, 3H); 2.55 (s, 3H); 3.62 (q, J = 7Hz, 2H); 3.95 (t, J = 6Hz, 2H); 4.72 (s, 2H); 6.93 (d, J = 8.5Hz, 1H); 6.97 (d, J = 8Hz, 1H); 7.17 (d, J = 2Hz, 1H); 7.37 (dd, J = 2, 8Hz, 1H); 7.77 (d, J = 8.5Hz, 1H).

EXAMPLE 21
6- [N- (5-Chloro-2- (2-cyclopropylmethoxy) benzyl) -N-ethylamino] pyridazine-3-carboxamide
A mixture of N-ethyl-5-chloro-2- (cyclopropylmethoxy) benzylamine (comparative example 20) (4.4 g, 18.4 mmol), 6-chloropyridazine-3-carboxamide (3.0 g, 19 mmol), diisopropylethylamine (5.0 ml, 29 mmol) and DMF (25 ml) were stirred for 16 hours under reflux. The mixture was cooled and diluted with water (50 ml), the resin was left to settle, the supernatant liquid was drained. The resin was dissolved in dichloromethane and was stirred with the addition of 2 N. hydrochloric acid (50 ml). After 10 minutes, a precipitate formed. The solid product was filtered and washed with dichloromethane (10 ml) and ether (20 ml) to obtain a dark yellow solid product (3.8 g, 61%), so pl. 177-8 ^o C.

MS (ESP ⁺ ): 361/363 (M + H) ⁺ .

NMR (200 MHz, DMSO-d ₆ ) δ: 0.34 (m, 2H); 0.57 (m, 2H); 1.16 (t, J = 7Hz, 3H); 1.25 (m, 1H); 3.70 (q, J = 7Hz, 2H); 3.78 (d, 2H); 4.81 (s, 2H); 7.00 (d, J = 8Hz, 1H); 7.05 (d, J = 2Hz, 1H); 7.17 (d, J = 9Hz, 1H); 7.25 (dd, J = 2, 8Hz, 1H); 7.45 (br s, 1H); 7.85 (d, J = 9Hz, 1H), 8.07 (br s, 1H).

EXAMPLE 22
6- [N- (5-Chloro-2- (cyclopropylmethoxy) benzyl) -N-ethylamino] pyridazine-3-carboxylic acid
The title compound was obtained as a white powder from 6- [N- (5-chloro-2- (cyclopropylmethoxy) benzyl) -N-ethylamino] pyridazine-3-carboxamide (Example 21) by a method similar to that described in Example 26.

 Yield: 86%.

Mp 119-120 ^o C.

MS (ESP ⁺ ): 362/364 (M + H) ⁺ .

NMR (200 MHz, DMSO-d ₆ ) δ: 0.34 (m, 2H); 0.56 (m, 2H); 1.17 (t, J = 7Hz, 3H); 1.22 (m, 1H); 3.72 (q, J = 7Hz, 2H); 3.90 (d, J = 7Hz, 2H); 4.83 (s, 2H); 7.02 (d, J = 8Hz), 7.08 (d, J = 2Hz, 1H); 7.14 (d, J = 9Hz, 1H); 7.26 (dd, J = 2, 8Hz, 1H); 7.84 (d, J = 9Hz, 1H).

Elemental analysis:
Calculated: (%) C - 59.8; H 5.6; N, 11.6; Cl, 9.8.

 Found: (%) C - 59.3; H 5.6; N, 11.7; Cl, 9.9.

EXAMPLE 23
5- [6- (N- [5-Chloro-2-cyclopropylmethoxybenzyl] -N-ethylamino) pyridazin-3-yl] tetrazole
The title compound was prepared from 6- [N- (5-chloro-2-cyclopropylmethoxybenzyl] -N-ethylamino] -3-cyanopyridazine (comparative example 21) in a similar manner to that described in example 12. Yield: 41%.

Mp 190-192 ^o C.

MS (ESP ⁺ ): 386/388 (M + H) ⁺ .

NMR (200 MHz, DMSO-d ₆ ) δ: 0.35 (m, 2H); 0.57 (m, 2H); 1.20 (t, J = 7HZ, 3H); 3.77 (q, J = 7Hz, 2H); 3.90 (D, J = 7Hz, 2H); 4.85 (s, 2H); 7.01 (d, J = 8Hz, 1H); 7.14 (d, J = 2Hz, 1H); 7.25 (dd, J = 2.8Hz, 1H); 7.29 (d, J = 8Hz, 1H); 8.04 (d, J = 8Hz, 1H).

Elemental analysis:
Calculated: (%) C - 56.0; H 5.2; N - 25.4.

 Found: (%) C - 55.9; H 5.3; N - 25.0.

EXAMPLE 24
N-Trifluoromethanesulfonyl-6- [N- (5-chloro-2-cyclopropylmethoxybenzyl) -N-ethylamino] pyridazine-3-carboxamide
The title compound was prepared from 6- [N- (5-chloro-2-cyclopropylmethoxybenzyl) -N-ethylamino] pyridazine-3-carboxylic acid (Example 22) and trifluoromethanesulfonamide in a similar manner to that described in Example 7. Yield: 18%.

Mp 150 ^o C (decomp.).

MS (ESP ⁺ ): 493/495 (M + H) ⁺ .

NMR (200 MHz, DMSO-d ₆ ) δ: 0.35 (m, 2H); 0.57 (m, 2H); 1.15 (t, J = 7Hz, 3H); 3.67 (q, J = 7Hz, 2H); 3.88 (d, J = 7Hz, 2H); 4.80 (s, 2H); 6.95-7.10 (m, H); 7.24 (dd, J = 2, 8Hz, 1H); 7.80 (d, J = 8Hz, 1H).

EXAMPLE 25
6- [N- (5-Chloro-2-cyclopentoxybenzyl) -N-ethylamine] pyridazine-3-carboxamide
N-Ethyl-5-chloro-2-cyclopentoxybenzylamine (comparative example 22; used without further purification) (4.27 g, 16.8 mmol) in dimethylformamide (25 ml) was then treated with 6-chloropyridazine-3-carboxamide (described in comparative example 3) (3.03 g, 19.2 mmol) and ethyldiisopropylamine (5 ml, 29 mmol) and allowed to boil under reflux at 140 ^o C for 16 hours. Water (50 ml) was added and the product was extracted with dichloromethane and ether, dried over anhydrous magnesium sulfate, filtered and purified by column chromatography (2% propan-2-ol in dichloromethane) to give 1.44 g of a yellow gum. Trituration in ether gave the title compound (790 mg, 13%).

MS (ESP ⁺ ): 375/377 (MH ⁺ ).

NMR (200 MHz, DMSO-d ₆ ) δ: 1.08 (t, 3H); 1.60 (m, 6H); 1.87 (m, 2H); 3.62 (q, 2H); 4.74 (s, 2H); 4.85 (m, 1H); 7.03 (m, 2H); 7.13 (d, 1H); 7.24 (dd, 1H); 7.42 (br s, 1H); 7.82 (d, 1H); 8.08 (br s, 1H).

EXAMPLE 26
6- [N- (5-Chloro-2-cyclopentoxybenzyl) -N-ethylamine] pyridazine-3-carboxylic acid
6- [N- (5-Chloro-2-cyclopentoxybenzyl) -N-ethylamine] pyridazine-3-carboxamide (Example 25) (0.75 g, 2.0 mmol) was dissolved in ethanol (50 ml), 2 N was added. . sodium hydroxide (15 ml) and the solution was heated under reflux at 80 ^o C for 16 hours. After cooling, the solvent was removed in vacuo and water (100 ml) was added. The solution was acidified with glacial acetic acid and the title compound was extracted with dichloromethane, washed with water (2 x 100 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated and the product was recrystallized from dichloromethane, ether and hexane when standing (100 mg, 13%).

MS (ESP ⁺ ): 376/378 (MH ⁺ ).

NMR (200 MHz, DMSO-d ₆ , 373K) δ: 0.79 (t, 3H); 1.62 (m, 6H); 1.88 (m, 2H); 3.15 (m, 2H); 4.38 (s, 2H); 4.80 (m, 1H); 6.80 (br s, 1H); 6.95 (d, 1H); 7.22 (dd, 1H); 7.32 (d, 1H); 7.93 (d, 1H).

EXAMPLE 27
5- [6- (N- [5-Chloro-2-cyclopentoxybenzyl] -N-ethylamino) pyridazin-3-yl] tetrazole
The title compound was prepared from 6- (N- [5-chloro-2-cyclopentoxybenzyl] -N-ethylamino) -3-cyanopyridazine (comparative example 23) by a method similar to that described in example 12, except that the reaction mixture was stirred 9 hours at 150 ^o C, the solution was acidified with 1 N. hydrochloric acid and the resulting product was extracted with dichloromethane (2x100 ml), purified by column chromatography (10% propan-2-ol, 0.1% methanoic acid in dichloromethane). Trituration in ether gave the title product (225 mg, 18%).

MS (ESP ⁺ ): 400/402 (MH ⁺ ).

NMR (200 MHz, DMSO-d ₆ ) δ: 1.14 (t, 3H); 1.60 (m, 4H); 1.70 (m, 2H); 1.88 (m, 2H); 3.65 (q, 2H); 4.78 (s, 2H); 4.87 (m, 1H); 7.02 (d, 1H); 7.13 (d, 1H); 7.28 (m, 2H); 8.03 (d, 1H).

EXAMPLE 28
N- (3,5-Dimethylisoxazol-4-ylsulfonyl) -6- [N- (5-bromo-2- (2-methylpropoxy) benzyl) -N-ethylamino] pyridazine-3-carboxamide
The title compound was prepared from 6- [N- (5-bromo-2- (2-methylpropoxy) benzyl) -N-ethylamino] pyridazine-3-carboxylic acid (Example 9) and 3,5-dimethylisoxazole-4- ilsulfonamide in a manner similar to that described in example 14.

NMR (200 MHz, DMSO-d ₆ ) δ: 0.98 (d, 6H); 1.15 (t, 3H); 1.95-2.06 (m, 1H); 2.38 (s, 3H); 2.7 (s, 3H); 3.69 (q, 2H); 3.8 (d, 2H); 4.85 (s, 2H); 6.98 (d, 1H); 7.13 (d, 1H); 7.2 (d, 1H); 7.39 (dd, 1H); 7.8 (d, 1H).

EXAMPLE 29
6- [N- (5-Methanesulfonyl-2- (cyclopropylmethoxy) benzyl) -N-ethylamino] pyridazine-3-carboxylic acid
6- [N- (5-Methanesulfonyl-2- (cyclopropyloxy) benzyl) -N-ethylamino] -3-cyanopyridazine (900 mg, 2.3 mmol) in ethanol (30 ml) and water (6 ml) were treated with granular hydroxide sodium (0.93 g, 23 mmol) and the resulting solution was heated at 80 ^{° C.} overnight (the progress of the reaction was monitored by HPLC). Then the mixture was evaporated to a smaller volume, water was added and the mixture was extracted with ethyl acetate (x 3) (a small amount of insoluble matter was not taken into account). The aqueous layer was acidified with acetic acid and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried and evaporated to the remaining gum. The resin was dissolved in dichloromethane and evaporated to give the title compound as a foam (0.56 g, 60%).

MS (ESP ^- ): 404 (M - H ^- ).

NMR (200 MHz, DMSO-d ₆ ) δ: 0.3-0.4 (m, 2H); 0.52-0.6 (m, 2H); 1.1-1.3 (m + t, 4H); 3.05 (s, 3H); 3.72 (q, 2H); 4.0 (d, 2H); 4.87 (s, 2H); 7.18 (d, 1H); 7.24 (d, 1H); 7.58 (d, 1H); 7.8 (dd, 1H); 7.84 (d, 1H).

EXAMPLE 30
N- (Propanesulfonyl) -6- [N- (5-methanesulfonyl-2- (cyclopropylmethoxy) benzyl) -N-ethylamino] pyridazine-3-carboxamide
The title compound was prepared from 6- [N- (5-methanesulfonyl-2- (cyclopropylmethoxy) benzyl) -N-ethylamino] pyridazine-3-carboxylic acid (Example 29) by a method similar to that described in Example 14.

MS (ESP ⁺ ): 511.2 (M + H) ⁺ .

NMR (200 MHz, DMSO-d ₆ ) δ: 0.29-0.38 (m, 2H); 0.5-0.62 (m, 2H); 0.98 (t, 3H); 1.3-1.1 (m + t, 4H); 1.65-1.82 (m, 2H);
3.05 (s, 3H); 3/43 (t, 2H); 3.75 (q, 2H); 4.0 (d, 2H); 4.9 (s, 2H); 7.23 (d, 1H); 7.27 (d, 1H); 7.56 (d, 1H); 7.8 (dd, 1H); 7.85 (d, 1H).

EXAMPLE 31
N-Propanesulfonyl-6- [N- (5-bromo-2- (2-methylpropoxy) benzyl) -N-ethylamino] pyridazine-3-carboxamide
The title compound was obtained from the corresponding acid (Example 9) in a manner analogous to that described in Example 7.

NMR (250 MHz, DMSO-d ₆ ) δ: 1.00 (m, 9H); 1.15 (t, 3H); 1.75 (m, 2H); 2.03 (m, 1H); 3.45 (m, 2H); 3.70 (q, 2H); 3.80 (d, 2H); 4.86 (s, 2H); 7.0 (d, 1H); 7.13 (d, 1H); 7.21 (d, 1H); 7.40 (dd, 1H); 7.87 (d, 1H).

EXAMPLE 32
N- (3,5-Dimethylisoxazol-4-ylsulfonyl) -6- [N- (5-bromo-2- (3,3,3-trifluoro-2-hydroxypropoxy) benzyl) -N-ethylamino] pyridazin-3- carboxamide
The title compound was prepared from 6- [N- (5-bromo-2- (3,3,3-trifluoro-2-hydroxypropoxy) benzyl) -N-ethyl-amino] pyridazine-3-carboxylic acid (Example 15) in a manner similar to that described in example 7.

NMR (250 MHz, DMSO-d ₆ ) δ: 1.15 (t, 3H); 2.35 (s, 3H); 2.63 (s, 3H); 3.68 (q, 2H); 4.2 (m, 2H); 4.40 (m, 1H); 4.82 (s, 2H); 6.65 (d, 1H); 7.05 (m, 2H); 7.2 (m, 1H); 7.40 (dd, 1H); 7.80 (d, 1H).

MS (ESP ⁺ ): 622 (M + H) ⁺ .

EXAMPLE 33
6- [N- (5-Bromo-2- (cyclobutoxy) benzyl) -N-ethylamino] pyridazine-3-carboxylic acid
The title compound was obtained from the corresponding nitrile (comparative example 24) by a method similar to that described in example 29.

MC (ESP ⁺ ): 406 (M + H) ⁺ .

NMR (250 MHz, DMSO-d ₆ ) δ: 1.15 (t, 3H); 1.73 (m, 2H); 2.00 (m, 2H); 2.42 (m, 2H); 3.69 (q, 2H); 4.72 (quintet, 1H); 4.81 (s, 2H); 6.82 (d, 1H); 7.12 (d, 1H); 7.16 (d, 1H); 7.36 (dd, 1H); 7.83 (d, 1H).

EXAMPLE 34
5- [6- (N- [5-Bromo-2- (3,3,3-trifluoro-2-hydroxypropoxy) benzyl) -N-ethylamino] pyridazin-3-yl] tetrazole
The title compound was obtained from the corresponding nitrile (comparative example 25) by a method similar to that described in example 12.

MS (ESP ⁺ ): 488 (M + H) ⁺ .

NMR (250 MHz, DMSO-d ₆ ) δ: 1.18 (t, 3H); 3.72 (q, 2H); 4.16 (m, 1H); 4.27 (m, 1H); 4.44 (m, 1H); 4.84 (s, 2H); 6.66 (broad d, 1H); 7.08 (d, 1H); 7.19 (d, 1H); 7.25 (d, 1H); 7.41 (dd, 1H); 8.03 (d, 1H).

EXAMPLE 35
2- [N- (5-Bromo-2-cyclopropylmethoxybenzyl) -N-ethylamino] pyridine-5-carboxylic acid
2- [N- (5-Bromo-2-cyclopropylmethoxybenzyl) -N-ethylamino] -5-cyanopyridine (comparative example 26) (7.5 g, 19.43 mmol) was dissolved in ethanol (400 ml) and sodium hydroxide was added (7.8 g, 174 mmol), then water (80 ml). The mixture was refluxed for 16 hours, ethanol was removed in vacuo and the residue was extracted with ethyl acetate (4 x 100 ml). The organic extracts were acidified with acetic acid and washed with water (100 ml) to obtain a solid product (6.8 g). This solid was dissolved in n-butanol (400 ml) and sodium hydroxide (6.75 g, 169 mmol) and water (80 ml) were added. The mixture was refluxed for 72 hours, butanol was removed in vacuo, 100 ml of water was added, and the residue was extracted with ethyl acetate (4 x 100 ml). The organic extracts were acidified with acetic acid and washed with water (100 ml). The combined aqueous layers were then acidified and extracted with ethyl acetate (4 x 100 ml) to give the title compound as a solid (2.4 g, 30%).

Mp 175-177 ^o C.

MS: 404 (M-H) ^-
NMR (MHz, DMSO-d ₆ ) δ: 0.30 (m, 2H); 0.55 (m, 2H); 1.12 (m, 4H); 3.55 (q, 2H); 3.85 (d, 2H); 4.68 (s, 2H); 6.62 (d, 1H); 6.92 (d, 1H); 7.05 (d, 1H); 7.35 (dd, 1H); 7.88 (dd, 1H); 8.58 (d, 1H); 12.30 (s, 1H).

Elemental analysis for C ₁₉ H ₂₁ BrN ₂ O ₃ (%):
Calculated: C - 56.3; H 5.2; N, 6.9.

 Found: C, 56.1; H 5.3; N - 6.8.

EXAMPLE 36
6- [N- (5-Chloro-2-cyclobutylmethoxybenzyl) -N-ethylamino] pyridazine-3-carboxylic acid
The title compound was obtained by a method similar to that described in example 18, by treating 6- [N- (5-chloro-2-cyclobutylmethoxybenzyl) -N-ethylamino] -3-cyanopyridazine (comparative example 27) (2.3 g, 6 46 mmol) with sodium hydroxide (2.6 g, 65 mmol) in water (20 ml) and ethanol (100 ml) to obtain a resin that cures upon trituration in ether (1.15 g, 47%).

Mp 140-142 ^o C.

MS: 374 (M-H) ^- .

NMR (MHz, DMSO-d ₆ ) δ: 1.1 (t, 3H); 1.95 (m, 6H); 2.70 (m, 1H); 3.68 (q, 2H); 4.0 (d, 2H); 4.8 (s, 2H); 7.0 (m, 3H); 7.25 (dd, 1H); 7.82 (d, 1H).

Elemental analysis for C ₁₉ H ₂₂ ClN ₃ O ₃ (%):
Calculated: C - 60.5; H 5.9; N - 11.2.

 Found: C - 60.5; H 6.0; N - 10.9.

EXAMPLE 37
6- [N- (5-Bromo-2-cyclopropylmethoxybenzyl) -N-propylamine] pyridazine-3-carboxylic acid
The title compound was obtained from the corresponding ester [obtained by a method similar to that described in comparative example 3, using propylamine instead of ethylamine, and comparative example 4] by a method similar to that described in example 1. Yield: 20%.

MS (ESP ⁺ ): 420/422 (MH ⁺ ).

NMR (200 MHz, DMSO-d ₆ ) δ: 0.25 (m, 2H); 0.57 (m, 2H); 0.91 (t, 3H); 1.21 (m, 1H); 1.61 (m, 2H); 3.63 (t, 2H); 3.88 (d, 2H); 4.83 (s, 2H); 6.96 (d, J = 8Hz, 1H); 7.13 (d, J = 9Hz, 1H); 7.16 (d, J = 2Hz, 1H); 7.38 (dd, J = 2Hz, 8Hz, 1H); 7.82 (d, J = 9Hz, 1H).

EXAMPLE 38
N- (3,5-Dimethylisoxazol-4-ylsulfonyl) -6- [N- (5-bromo-2-cyclopropylmethoxybenzyl) -N-propylamine] pyridazine-3-carboxamide
The title compound was prepared from 6- [N- (5-bromo-2-cyclopropylmethoxybenzyl) -N-ethylamine] pyridazine-3-carboxylic acid (Example 37) in a manner similar to that described in Example 7, except that as dichloromethane was used in the solvent, and column purification was not necessary. Recrystallization (diethyl ether / hexane) gave the title compound (340 mg, 49%).

MS (ESP ⁺ ): 578/580 (MH ⁺ ).

NMR (250 MHz, DMSO-d ₆ ) δ: 0.33 (m, 2H); 0.54 (m, 2H); 0.88 (t, 3H); 1.19 (m, 1H); 1.60 (m, 2H); 2.40 (s, 3H); 2.68 (s, 3H); 3.60 (t, 2H); 3.87 (d, 2H); 4.84 (s, 2H); 6.96 (d, J = 8Hz, 1H); 7.17 (d, J = 2HZ, 1H); 7.23 (d, J = 9Hz, 1H); 7.38 (dd, J = 2Hz, 8Hz, 1H); 7.81 (d, J = 9Hz, 1H).

EXAMPLE 39
6- [N- (5-Bromo-2-cyclopropylmethoxybenzyl) -N-methylamino] pyridazine-3-carboxylic acid
The title compound was prepared by a method similar to that described in example 37 from the corresponding N-methyl compound.

MS (ESP ⁺ ): 392/394 (MH ⁺ ).

NMR (250 MHz, DMSO-d ₆ ) δ: 0.33 (m, 2H); 0.55 (m, 2H); 1.19 (m, 1H); 3.38 (d, 2H); 4.86 (s, 2H); 6.97 (d, J = 8Hz, 1H); 7.17 (d, J = 10Hz, 1H); 7.20 (d, J = 2Hz, 1H); 7.37 (dd, J = 8Hz, 2Hz, 1H); 7.84 (d, J = 10Hz).

EXAMPLE 40
N- (3,5-Dimethylisoxazol-4-ylsulfonyl) -6- [N- (5-bromo-2-cyclopropylmethoxybenzyl) -N-methylamino] pyridazine-3-carboxamide
The title compound was prepared from the corresponding carboxylic acid in a manner similar to that described in Example 38.

MS (ESP ⁺ ): 550/552 (MH ⁺ ).

NMR (250 MHz, DMSO-d ₆ ) δ: 0.30 (m, 2H); 0.52 (m, 2H); 1.16 (m, 1H); 2.39 (s, 3H); 2.69 (s, 3H); 3.22 (s, 3H); 3.85 (d, 2H); 5.87 (s, 2H); 6.95 (d, J = 8Hz, 1H); 7.20 (d, J = 2Hz, 1H); 7.27 (d, 1H); 7.39 (dd, J = 2Hz, 8Hz, 1H); 7.84 (d, 1H).

Comparative Example 1
Methyl 2- [N- (5-bromo-2-propoxybenzyl) -N-ethylamino] pyridine-5-carboxylate
6-Chloronicotinic acid (100 g, 0.63 mol) was treated with ethylamine (70% in water, 500 ml). The reaction mixture was loaded into an autoclave, sealed, and heated at 170 ^{° C.} for 6 hours. The reaction mixture was evaporated, partially neutralized with concentrated HCl and adjusted to pH 5 with glacial acetic acid. The solid was filtered and dried in vacuo for 18 hours to give 6- (ethylamino) nicotinic acid (87.8 g, 84% yield).

MS (CI ⁺ ): 167 (M + H) ⁺ .

NMR (250 MHz, DMSO-d ₆ ) δ: 1.15 (t, J = 7Hz, 3H); 3.3 (q, J = 7Hz, 2H); 6.45 (d, J = 9Hz, 1H); 7.25 (br t, 1H); 7.78 (dd, J = 2, 9Hz, 1H); 8.54 (d, J = 2Hz, 1H); 11.6 (br s, 1H).

A suspension of 6- (ethylamino) nicotinic acid (50 g, 0.3 mmol) in methanol (500 ml) was treated with concentrated H ₂ SO ₄ (30 ml). The reaction mixture was heated under reflux for 18 hours. Then the reaction mixture was evaporated, poured into ice water (1 L) and adjusted to pH 8 with solid sodium bicarbonate (with the formation of a foam). The aqueous mixture was extracted with ethyl acetate (3 × 300 ml) and the organic layers were combined, dried (MgSO ₄ ) and evaporated to give methyl 6- (ethylamino) -nicotinoate as an off-white solid (45.5 g, 84%).

NMR (200 MHz, DMSO-d ₆ ) δ: 1.14 (t, J = 7Hz, 3H); 3.3 (q, J = 7Hz, 2H); 3.76 (s, 3H); 6.46 (d, J = 9Hz, 1H); 7.39 (br t, 1H); 7.80 (dd, J = 3, 9Hz, 1H); 8.56 (d, J = 3Hz, 1H).

A solution of 5-bromosalicylaldehyde (12.0 g, 59.7 mmol) in DMF (50 ml) was treated with K ₂ CO ₃ (16.5 g, 120 mmol) and benzyl bromide (11.2 g, 65.6 mmol). The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate and filtered. The filtrate was washed with HCl (0.05 M), saturated aqueous sodium hydrogencarbonate and brine. The organic phase was dried (Na ₂ SO ₄ ) and evaporated, the residue was triturated in hexane / diethyl ether. The product was filtered and 2-benzyloxy-5-bromobenzaldehyde was obtained as a white solid (15.8 g, 90%), mp. 70-72 ^o C.

MS (CI ⁺ ): 291 (M + H) ⁺ .

NMR (200 MHz, DMSO-d ₆ ) δ: 5.38 (s, 2H); 7.5 (m, 6H); 7.9 (m, 2H); 10.41 (s, 1H).

A suspension of 2-benzyloxy-5-bromobenzaldehyde (14.5 g, 50.2 mmol) in absolute ethanol (250 ml) was treated with sodium borohydride (2.6 g, 68.8 mmol). The reaction mixture was stirred and the temperature was slowly raised to 33 ^o C. After 1 hour, the reaction mixture was evaporated and the residue was dissolved in ethyl acetate and poured into a mixture of ice water (200 ml) and 1 N. Hcl (25 ml). The organic layer was separated, washed with an aqueous sodium hydrogen carbonate solution, brine, dried (Na ₂ SO ₄ ) and evaporated to give 2-benzyloxy-5-bromobenzyl alcohol as a pale yellow oil (14.85 g, quantitative yield).

MS (CI ⁺ ): 292 (M ⁺ ).

NMR (200 MHz, DMSO-d ₆ ) δ: 4.52 (d, J = 5Hz, 2H); 5.12 (s, 2H); 5.17 (t, J = 5Hz, 1H); 6.98 (d, J = 9Hz, 1H); 7.4 (m, 6H); 7.5 (d, 2H, 1H).

A solution of 2-benzyloxy-5-bromobenzyl alcohol (14.75 g, 50.2 mmol) in anhydrous ethyl ether (150 ml) was cooled to 4 ^° C. A solution of PBr ₃ (13.68 g, 50 mmol) in was added dropwise. anhydrous ether (40 ml), maintaining the temperature below 10 ^o C. the Reaction mixture was allowed to warm to room temperature and was stirred for 1 hour. The reaction mixture was filtered through silica gel (200 g). Silica gel was washed with ethyl ether to remove all products. The filtrate was washed with water (1x150 ml), saturated aqueous sodium hydrogen carbonate solution (1x150 ml) and brine (1x150 ml). The organic layer was dried (Na ₂ SO ₄ ) and evaporated to give 2-benzyloxy-5-bromobenzyl bromide (15.2 g, 85%) as a pale yellow oil, which crystallized upon standing.

MS (EI ⁺ ): 354 (M ⁺ ).

NMR (200 MHz, DMSO-d ₆ ) δ: 4.65 (s, 2H); 5.2 (s, 2H); 7.05 (D, J = 9HZ, 1H); 7.4 (m, 6H); 7.66 (d, J = 3Hz, 1H).

A solution of methyl 6-ethylaminonicotinoate (15.2 g, 84.4 mmol) in DMF (50 ml) was cooled to 0 ^° C and treated with sodium hydride (60%, 75 mmol). The reaction mixture was stirred for 1 hour and a solution of 2-benzyloxy-5-bromobenzyl bromide (25 g, 70.2 mmol) in DMF (50 ml) was added. The reaction mixture was allowed to warm to room temperature and was stirred for 18 hours. The reaction was quenched with water and extracted with ethyl acetate (three times). The organic layers were combined, washed with water and brine twice, dried (MgSO ₄ ) and evaporated to give a white solid. Recrystallization from ethyl acetate / hexane gave methyl 2- [N- (2-benzyloxy-5-bromobenzyl) -N-ethylamino] pyridine-5-carboxylate (22.7 g, 71%).

MS (CI ⁺ ): 455/457 (M + H) ⁺ .

NMR (200 MHz, DMSO-d ₆ ) δ: 1.1 (t, J = 7Hz, 3H); 3.5 (q, J = 7Hz, 2H); 3.78 (s, 3H); 4.77 (s, 2H); 5.18 (s, 2H); 6.55 (d, J = 9Hz, 1H); 7.08 (m, 2H); 7.4 (m, 6H); 7.9 (dd, J = 2, 9Hz, 1H); 8.62 (d, 1H).

A solution of methyl 2- [N- (2-benzyloxy-5-bromobenzyl) -N-ethyl-amino] pyridine-5-carboxylate (10.0 g, 22 mol) in dichloromethane (950 ml) was treated with boron dimethyl sulfide trichloride complex (40 ml, 2M, 80 mmol). The reaction mixture was stirred at room temperature for 48 hours. A saturated aqueous sodium hydrogen carbonate solution was added and the layers were washed with dichloromethane. The organic layers were combined, dried (MgSO ₄ ) and evaporated to give an off-white solid which was chromatographed (eluent: ethyl acetate / hexane) to give methyl 2- [N- (5-bromo-2-hydroxybenzyl) -N- ethyl amino] pyridine-5-carboxylate (6.02 g, 75%).

MS (CI ⁺ ): 365 (M + H) ⁺ .

NMR (250 MHz, DMSO-d ₆ ) δ: 1.14 (t, J = 7Hz, 3H); 3.61 (q, J = 7Hz, 2H); 3.78 (s, 3H); 4.66 (s, 2H); 6.65 (d, J = 9Hz, 1H); 6.8 (d, J = 9Hz, 1H); 7.02 (D, J = 2Hz, 1H); 7.2 (dd, J = 2, 9Hz, 1H); 7.93 (dd, J = 2, 9Hz, 1H); 8.64 (d, J = 2Hz, 1H); 10, 13 (s, 1H).

 1-Bromopropane (0.12 g, 0.69 mmol) was treated with a solution of methyl 2- [N- (5-bromo-2-hydroxybenzyl) -N-ethylamino] -5-pyridylcarboxylate (0.2 g, 0.55 mmol) in DMF (4 ml). Potassium carbonate (230 mg, 1.7 mmol) was added to this solution, and the reaction mixture was stirred for 18 hours. The solvent was evaporated and the residue was treated with water (4 ml) and extracted with ethyl acetate (3 × 3 ml). The combined extracts were evaporated and the residue was chromatographed (eluent: ethyl acetate / hexane) to give the title compound as a pale yellow oil (0.122 g, 54%), which was used in the next step without further purification.

Reference Example 2
Methyl 2- [N- (5-bromo-2- (2-methylpropoxy) benzyl) -N-ethylamino] pyridine-5-carboxylate
A solution of methyl 2- [N- (5-bromo-2- (hydroxybenzyl) -N-ethylamino] pyridine-5-carboxylate (comparative example 1, paragraph 7) (0.5 g, 1.37 mmol) in THF ( 15 ml) was treated with triphenylphosphine (0.39 g, 1.49 mmol) and diazoethyl dicarboxylate.The reaction mixture was stirred for five minutes at room temperature and then isobutyl alcohol (0.152 g, 2.06 mmol) was added. Then the reaction mixture was stirred for 18 hours at room temperature, partitioned between ethyl acetate and water and the aqueous layer was washed with ethyl acetate (x 2). The organic layers were combined by washing water and brine, dried (MgSO ₄ ) and evaporated.The residue was chromatographed (eluent: ethyl acetate / hexane) to give the title compound (0.35 g, 60%) as an off-white solid.

MS (CI ⁺ ): 421 (M + H) ⁺ .

NMR (250 MHz, DMSO-d ₆ ) δ: 1.0 (d, J = 6Hz, 3H); 1.12 (t, J = 7Hz, 6H); 2.04 (m, 1H); 3.6 (q, J = 7Hz, 2H); 3.78 (s, 3H); 3.80 (s, 2H); 4.75 (s, 2H); 6.66 (d, J = 9Hz, 1H); 6.97 (d, J = 9Hz, 1H); 7.05 (d, J = 2Hz, 1H); 7.37 (dd, J = 2, 9Hz, 1H); 7.93 (dd, J = 2, 9Hz, 1H); 8.73 (d, J = 2Hz, 1H).

Reference Example 3
Butyl-6- [N- (5-bromo-2-hydroxybenzyl) -N-ethylamino] pyridazine-3-carboxylate
A solution of 6-oxo-1,6-dihydropyridazin-3-carboxylic acid (British Patent 856409) (52 g, 0.33 mmol) in n-BuOAc (80 ml) and butanol (80 ml) was treated with concentrated sulfuric acid (5 ml ) The mixture was heated with a Dean-Stark trap. After 5 hours, the formation of water ceased. The reaction mixture was allowed to cool to room temperature and after standing overnight, the precipitate was filtered, washed with diethyl ether and dried to give butyl 6-oxo-1,6-dihydropyridazine-3-carboxylate as a white solid (55.2 g, 85 %), mp 81-83 ^o C.

A solution of the above butyl ether (55.2 g, 0.28 mol) in acetonitrile (220 ml) was carefully added to POCl ₃ (55.2 ml, 0.60 mol). The resulting solution was stirred at 100 ^{° C.} for 2 hours. The reaction mixture was cooled and evaporated under reduced pressure. The residue was dissolved in dichloromethane (280 ml) and added to a cold stirred solution of sodium carbonate (55 g) in water (280 ml). The resulting mixture was stirred until gas bubbles were completely stopped, then the layers were separated and the organic layer was dried (MgSO ₄ ) and filtered through a pad of silica gel. The solution was evaporated to give butyl 6-chloropyridazine-3-carboxylate as a pale pink solid (51 g, 85%).

 A solution of the chloropyridazine compound from the previous step (51 g, 0.238 mol) in THF (375 ml) was treated with methanol ammonia (sat., 80 ml). The reaction mixture was left to stand overnight at room temperature. The precipitate was filtered and dried to give 6-chloropyridazine-3-carboxamide as a pink solid (18.2 g, 49%). [Additionally, the product can be obtained by evaporating the filtrate (under reduced pressure) and treating the residue with THF (100 ml) with methanol ammonia (40 ml). The product was isolated, as above, to give a pink solid (17.4 g). Total yield (35.6 g, 95%)].

 A suspension of 6-chloropyridazine-3-carboxamide (28.5 g, 0.18 mol) in methanol (200 ml) was treated with an aqueous solution of ethylamine (70% solution, 77 ml). The reaction mixture was heated under reflux for 3.5 hours. The reaction mixture was allowed to cool to room temperature and left overnight. The precipitate formed was filtered and washed with a small volume of water and dried to obtain 6- (ethylamino) pyridazine-3-carboxamide as a pink solid (8.9 g). [The filtrates were evaporated to a small volume, diluted with cold water (100 ml) and an additional amount of the desired solid product was filtered off, washed with water and dried (12.8 g). Total yield (21.7 g, 72%)].

A solution of 6- (ethylamino) pyridazine-3-carboxamide (21.7 g, 0.131 mol) in n-butanol (109 ml) and BF ₃ • Et ₂ O (54 ml) was heated under air cooler (allowing Et ₂ O to evaporate) at 120 ^o C for 18 hours. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in ice water (400 ml) and neutralized with solid sodium bicarbonate with stirring. An oily residue was extracted with dichloromethane (250 ml) containing methanol (50 ml). The extracts were dried (MgSO ₄ ) and evaporated (in vacuo) to give a slightly viscous solid, which was recrystallized from ethyl acetate (~ 250 ml) to obtain butyl 6- (ethylamino) pyridazine-3-carboxylate as an off-white solid ( 22.0 g, 75%).

A suspension of butyl ether of the previous step (21 g, 0.094 mol) in acetic acid (400 ml) was treated with 4-bromophenol (65.5 g, 0.378 mol) and paraformaldehyde (3.15 g, 0.105 mol). The reaction mixture was heated at 100 ^{° C.} for 4.5 hours and another portion of paraformaldehyde (6.3 g, 0.21 mol) was added and the reaction mixture was heated at 100 ^{° C.} for 16 hours. The resulting dark colored reaction mixture was evaporated to give a dark oil. Chromatography (eluent: diethyl ether / hexane) gave fast-moving products as a brown oil. This oil was dissolved in ethyl acetate (~ 70 ml) and allowed to stand overnight at room temperature to give a white solid, which was filtered and washed with ethyl acetate and dried to give butyl-6- [N- (5-bromo-2-hydroxybenzyl) -N -ethylamino] pyridazine-3-carboxylate as a product (12.3 g, 32%).

Reference Example 4
Butyl-6- [N- (5-bromo-2-cyclopropylmethoxybenzyl) -N-ethylamino] pyridazine-3-carboxylate
A solution of n-butyl-6- [N- (5-bromo-2-hydroxybenzyl) -N-ethylamino] pyridazine-3-carboxylate (comparative example 3) (0.286 g, 0.69 mmol) in DMF (3.5 ml ) was treated with bromomethylcyclopropane (0.1 g, 0.78 mmol) and potassium carbonate (0.473 g, 3.4 mmol). The reaction mixture was allowed to stir at room temperature for 60 hours. The solvent was evaporated under reduced pressure (vacuum pump) and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2x10 ml). The organic layers were combined, dried (MgSO ₄ ) and evaporated. The residue was purified by chromatography (eluent: ethyl acetate / hexane) to obtain the title compound as a pale yellow oil (0.3 g, 94%).

MS (ESP ⁺ ): 462 (M + H) ⁺ .

NMR (200 MHz, DMSO-d ₆ ) δ: 0.32 (m, 2H); 0.55 (m, 2H); 0.93 (t, J = 7Hz, 3H); 1.15 (m, 4H); 1.42 (m, 2H); 1.7 (m, 2H); 3.7 (q, J = 7Hz, 2H); 3.89 (d, J = 7Hz, 2H); 4.3 (t, J = 7Hz, 2H); 4.84 (s, 2H); 6.98 (d, J = 8Hz, 1H); 7.15 (m, 2H); 7.4 (dd, J = 3.9Hz); 7.82 (d, J = 8Hz, 1H).

Reference Example 5
Methyl 2- [N- (5-bromo-2- (cyclopentylmethoxy) benzyl) -N-ethylamino] pyridine-5-carboxylate
The title compound was obtained by a method similar to that described in comparative example 2 (from phenol in comparative example 1, paragraph 7), using cyclopentylmethanol instead of isobutyl alcohol (yield: 60%).

MS (ESP ⁺ ): 447 (M + H) ⁺ .

NMR (200 MHz, DMSO-d ₆ ) δ: 1.11 (t, J = 7Hz, 3H); 1.35 (m, 2H); 1.58 (m, 4H); 1.77 m, 2H); 2.3 (m, 1H); 3.6 (q, J = 7Hz, 2H); 3.79 (s, 3H); 3.9 (d, J = 7Hz, 2H); 4.75 (s, 2H); 6.68 (d, J = 9Hz, 1H); 6.8 (d, J = 9Hz, 1H); 7.07 (d, J = 2Hz, 1H); 7.38 (dd, J = 2, 9Hz, 1H); 7.94 (dd, J = 2, 9Hz, 1H); 8.65 (d, J = 2H, 1H).

Reference Example 6
Butyl-6- [N- (5-bromo-2-propoxybenzyl) -N-ethylamino] pyridazine-3-carboxylate
The title compound was prepared by reacting 1-iodopropane with butyl-6- [N- (5-bromo-2-hydroxybenzyl) -N-ethylamino] pyridazine-3-carboxylate (comparative example 3) in a manner similar to that described in comparative example 4 .

MS (ESP ¹⁺ ): 450/452 (M + H) ⁺ .

Reference Example 7
Butyl-6- [N- (5-bromo-2-butoxybenzyl) -N-ethylamino] pyridazine-3-carboxylate
The title compound was prepared by reacting 1-iodobutane with butyl-6- [N- (5-bromo-2-hydroxybenzyl) -N-ethylamino] pyridazine-3-carboxylate in a manner similar to that described in comparative example 4.

MC (ESP ⁺ ): 464/466 (M + H) ⁺ .

Reference Example 8
6- [N- (5-Bromo-2-hydroxybenzyl) -N-ethylamino] pyridazine-3-carboxylic acid
A solution of butyl 6- [N- (5-Bromo-2-hydroxybenzyl) -N-ethylamino] pyridazine-3-carboxylate (comparative example 3) (0.36 g, 1.0 mmol) in THF (4 ml) and methanol (4 ml) was treated with 1 N. aqueous sodium hydroxide solution (4 ml) and kept for 1.5 hours at room temperature. The reaction mixture was evaporated to a small volume, diluted with water and acidified with acetic acid. After standing for 18 hours, the precipitate was filtered, washed with water and ether and dried (MgSO ₄ ) to obtain the title compound as a white solid (0.26 g, 71%).

MS (ESP ⁺ ): 352/354 (M + H) ⁺ .

NMR (200 MHz, DMSO-d ₆ ) δ: 1.15 (t, J = 6.67 Hz, 3H); 3.68 (q, J = 6.67Hz, 2H); 4.75 (s, 2H); 6.83 (d, J = 8.34Hz, 1H); 7.10 (d, J = 8.34Hz, 1H); 7.13 (d, J = 2.33Hz, 1H); 7.25 (dd, J = 10.00, 2.33Hz, 1H); 7.83 (d, J = 10.00Hz, 1H).

Reference Example 9
2- [N- (5-Bromo-2-hydroxybenzyl) -N-ethylamino] pyridine-5-carboxylic acid
A solution of methyl 2- [N- (5-bromo-2-hydroxybenzyl) -N-ethylamino] pyridine-5-carboxylate (see comparative example 1) (10.2 g, 0.55 mmol) in THF (3 ml ) and methanol (5 ml) were treated with 1 N. aqueous sodium hydroxide solution (2.7 ml) and heated to 40 ^{° C.} for 24 hours. The solvents were evaporated under reduced pressure, the residue was treated with 1 N. acetic acid (2.7 ml) and the precipitate was filtered, washed with water and dried with air to obtain the title compound (0.17 g, 92%).

MS (FAB ⁺ ): 351 (M + H) ⁺ .

NMR (200 MHz, DMSO-d ₆ ) δ: 1.12 (t, J = 7Hz, 3H); 3.6 (q, J = 7Hz, 2H); 4.64 (s, 2H); 6.6 (d, J = 9Hz, 1H); 6.83 (d, J = 9Hz, 1H); 7.06 (d, J = 2Hz, 1H); 7.23 (dd, J = 2, 9Hz, 1H); 7.92 (dd, J = 2, 9Hz, 1H); 8.59 (d, J = 2Hz, 1H).

Reference Example 10
Butyl-6- [N- (5-bromo-2- (2-methylpropoxy) benzyl) -N-ethylamino] pyridazine-3-carboxylate
Butyl-6- [N- (5-bromo-2-hydroxybenzyl) -N-ethylamino] pyridine-3-carboxylate (see comparative example 3) (1.12 g, 2.76 mmol) in dimethylformamide (16 ml) treated with potassium carbonate and then 1-bromo-2-methylpropane (0.16 ml, 770 mg, 5.6 mmol) and stirred overnight at room temperature. TLC indicated that the reaction was not completed, and additional potassium carbonate (1.12 g) and 1-bromo-2-methylpropane were added to the reaction mixture. The resulting mixture was stirred at room temperature for 2 days. The mixture was then evaporated to a smaller volume and the residue was purified directly by HPLC to give the title compound as a colorless gum. Yield: 98% (1.26 g).

NMR (250 MHz, DMSO-d ₆ ) δ: 0.90 (m, 9H); 1.15 (t, 3H); 1.42 (m, 2H); 1.70 (m, 2H); 2.03 (m, 1H); 3.73 (q, 2H); 3.80 (d, 1H); 4.28 (t, 2H); 4.82 (s, 2H); 6.97 (d, 1H); 7.1 (m, 2H); 7.38 (dd, 1H); 7.81 (d, 1H).

Reference Example 11
Butyl-6- [N- (5-bromo-2-hydroxybenzyl) -N-ethylamino] pyridazine-3-carboxylate
The title compound was prepared from butyl 6- (ethylamino) pyridazine-3-carboxylate and 4-chlorophenol in a manner similar to that described in comparative example 3, except that 0.4 equivalent of trifluoroacetic acid was added to the reaction mixture.

NMR (250 MHz, DMSO-d ₆ ) δ: 0.94 (t, 3H); 1.17 (t, 3H); 1.43 (m, 2H); 1.70 (m, 2H); 3.7 (q, 2H); 4.28 (t, 2H); 4.75 (s, 2H); 6.85 (d, 1H); 6.97 (d, 1H); 7.1 (m, 2H); 7.82 (d, 1H); 10.1 (br s, 1H).

Reference Example 12
Butyl-6- [N- (5-bromo-2- (2-methoxypropoxy) benzyl) -N-ethylamino] pyridazine-3-carboxylate
The title compound was prepared by reacting butyl-6- [N- (5-chloro-hydroxybenzyl) -N-ethylamino] pyridazine-3-carboxylate (comparative example 11) and 1-bromo-2-methylpropane in a manner similar to that described in comparative example 4.

NMR (200 MHz, DMSO-d ₆ ) δ: 0.95 (m, 9H); 1.15 (t, 3H); 1.43 (m, 2H); 1.70 (m, 2H); 2.03 (m, 1H); 3.68 (q, 2H); 3.80 (d, 2H); 4.28 (t, 2H); 4.83 (s, 2H); 6.99 (d, 1H); 7.04 (d, 1H); 7.10 (d, 1H); 7.26 (dd, 1H); 7.83 (d, 1H).

MS (ES ⁺ ): 420 (M + H) ⁺ .

Reference Example 13
N-Ethyl-5-bromo-2- (cyclopropylmethoxy) benzylamine
1-Methyl-2-pyrrolidinone (90 ml) (NMP) was added to anhydrous potassium carbonate (27.6 g, 0.2 mol) in an argon atmosphere. 5-Bromosalicylaldehyde (20.1 ml, 0.1 mol) was added portionwise to the stirred mixture and the mixture was stirred for 10 minutes. Bromomethylcyclopropane (14.4 ml, 0.15 mol) was dissolved in NMP and added dropwise over 15 minutes at a temperature below 30 ^o C. The reaction temperature was raised to 35-40 ^o C for 3 hours, and then increased to 70 ^o C for 1 hour and then cooled to 35 ^o C. Ethylamine hydrochloride (13.85 g, 0.17 mol) was dissolved in methanol (60 ml) and quickly added to the mixture, which was then heated at a temperature of 35-40 ^o C for 3 hours and stirred overnight (to cool to room temperature). After that, the reaction mixture was cooled on ice. To this reaction mixture was added dropwise sodium borohydride (5.3 g, 0.14 mol) dissolved in NMP (58 ml) [evolution of gas bubbles and heating to 15 ^{° C.} ], and the mixture was heated at 40-45 ^{° C.} within 2 hours. To this mixture was added 2N dropwise. hydrochloric acid (250 ml), while maintaining the temperature below 30 ^o C. the resulting mixture was transferred to a separatory funnel and was extracted with ethyl acetate (x 2). The combined organic layers were washed with 20% saline / water (x 3) and brine (x 1), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was dissolved in ethyl acetate (100 ml) and cooled on ice. Then, gaseous hydrogen chloride was bubbled into the stirred solution. The title compound as a hydrochloride salt was precipitated, filtered, washed with ethyl acetate (x 2) and dried under high vacuum (12.6 g, 28.5%).

NMR (200 MHz, DMSO-d ₆ ) δ: 0.37 (m, 2H); 0.58 (m, 2H); 1.27 (m, 4H); 2.95 (q, 2H); 3.89 (d, 2H); 4.07 (s, 2H); 7.02 (d, J = 8.0Hz, 1H); 7.53 (dd, J = 8.0, 2.9Hz, 1H); 7.73 (d, J = 2.9Hz, 1H); 9.25 (br s, 2H).

MS (ESP ⁺ ): 284 (M + H) ⁺ .

Reference Example 14
6- [N- (5-Bromo-2- (cyclopropylmethoxy) benzyl) -N-ethylamino] -3-cyanopyridazine
6- [N- (5-Bromo-2- (cyclopropylmethoxy) benzyl) -N-ethylamino] pyridazine-3-carboxamide (Example 11) (2.03 g) was suspended in pyridine (25 ml) and cooled under argon under 4 ^° C. Methanesulfonyl chloride (4.6 ml, 59.5 mmol) was added dropwise to the suspension (reaction with heat evolution to -8 ^° C), followed by pyridine (20 ml). The reaction mixture was heated and stirred overnight. After removal of the pyridine under reduced pressure, the residue was partitioned between ethyl acetate and 1N. hydrochloric acid. The organic layer was washed with 50% 1 N. HCl / saturated aqueous ammonium chloride (x 1), saturated aqueous sodium bicarbonate (x 1) and brine (x 1), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by column chromatography (eluent: 2.5% ethyl acetate / dichloromethane), and the fractions containing the title product were evaporated to a gum (1.65 g, 85.0%).

NMR (200 MHz, DMSO-d ₆ ) δ: 0.30 (m, 2H); 0.54 (m, 2H); 1.15 (m, 4H); 3.69 (q, 2H); 3.85 (d, 2H); 4.80 (s, 2H); 6.95 (d, 1H); 7.20 (m, 2H); 7.38 (dd, 1H); 7.80 (d, 1H).

MS (ESP ^- ): 386.8 (M-H) ^- .

Reference Example 15
6- [N- (5-Chloro-2- (2-methylpropoxy) benzyl) -N-ethylamino] -3-cyanopyridazine
6- [N- (5-Chloro-2- (2-methylpropoxy) benzyl) -N-ethylamino] pyridazine-3-carboxylic acid (Example 10) (2.0 g) was dissolved in pyridine (30 ml) under argon atmosphere and cooled to 4 ^° C. Methanesulfonyl chloride (0.75 ml, 9.7 mmol) was added, the mixture was stirred for 1.5 hours at a temperature of 4 ^{° C.} and a dark purple solution was obtained. Ammonia gas was bubbled into the solution for 2 minutes (warming up to +15 ^° C) and a dark red solution was obtained, which was then evaporated under reduced pressure. The residue was dissolved in pyridine (30 ml) and cooled in an argon stream to 4 ^° C. After adding methanesulfonyl chloride (5.1 ml, 66 mmol) dropwise (warming to 10 ^{° C.} ), the resulting brown suspension was stirred overnight at room temperature. Then the brown solution was evaporated and the residue was partitioned between a saturated aqueous solution of ammonium chloride and ethyl acetate. The organic layer was washed with 10% 2 N. HCl / saturated aqueous ammonium chloride (x 2), saturated aqueous sodium bicarbonate (x 1) and brine (x 1), dried over Na ₂ SO ₄ , filtered and evaporated. The title product was isolated by column chromatography using 20% ethyl acetate / isohexane (1.18 g, 62.2%) as eluent. [OPPI 14: 396-9 (1982)].

NMR (200 MHz, DMSO-d ₆ ) δ: 0.97 (d, 6H); 1.12 (t, 3H); 2.00 (m, 1H); 3.67 (q, 2H); 3.79 (d, 2H); 4.85 (s, 2H); 7.05 (m, 2H); 7.19 (d, 1H); 7.29 (dd, 1H); 7.84 (d, 1H).

MS (ES ⁺ ): 345 (M + H) ⁺ .

Reference Example 16
n-Butyl-6- [N- (5-bromo-2- (2-hydroxy-3,3,3-trifluoropropoxy) benzyl) -N-ethylamino] pyridazine-3-carboxylate
The title compound was prepared by reacting 3-bromo-1,1,1-trifluoropropan-2-ol and butyl-6- [N- (5-bromo-2-hydroxybenzyl) -N-ethylamino] pyridazine-3-carboxylate by the method similar to that described in comparative example 4.

NMR (250 MHz, DMSO-d ₆ ) δ: 0.95 (t, 3H); 1.15 (t, 3H); 1.42 (m, 2H); 1.68 (m, 2H); 3.7 (q, 2H); 4.20 (m, 4H); 4.42 (m, 1H); 4.83 (s, 2H); 6.65 (d, 1H); 7.1 (m, 3H); 7.42 (dd, 1H); 7.63 (d, 1H).

Reference Example 17
6- [N- (2- (Cyclopropylmethoxy) -5-methanesulfonylbenzyl) -N-ethylamino] -3-cyanopyridazine
4-Methyl mercaptophenol (8.96 g, 64 mmol) was suspended in toluene (80 ml) and added to a solution of magnesium methylate in methanol (5.5 ml, 8%, 41.4 mmol) and the reaction mixture was stirred for 1 hour at heating under reflux. After that, the yellow solution was treated with toluene (80 ml) and methanol was distilled off from the reaction mixture until the temperature of the reaction mixture reached approximately 95 ^° C. A small amount of solid precipitate formed. Paraformaldehyde (5.84 g, 194 mmol) in toluene (60 ml) was added to the mixture, which was stirred for 3.5 hours under argon under reflux (the temperature should be at least 95 ^° C). The reaction mixture containing a small amount of solid product was cooled and treated with 2 N. sulfuric acid (80 ml), toluene (80 ml), was stirred for 15 minutes and separated. The organic layer was washed with water (x 3), dried and evaporated to a residue as an orange oil (9.6 g). This oil was purified by HPLC using 5% ether / isohexane to give 2-hydroxy-5-methylthiobenzaldehyde (3.3 g).

NMR (200 MHz, DMSO-d ₆ ) δ: 2.45 (s, 3H); 6.98 (d, J = 9Hz, 1H); 7.48 (dd, J = 2.3, 9.0Hz, 1H); 7.55 (d, J = 2.3Hz, 1H); 10.25 (s, 1H); 10.67 (s, 1H).

MS (CI ⁺ ): 168 (M ⁺ ).

 2-Hydroxy-5-methylthiobenzaldehyde was alkylated with bromomethylcyclopropane in a similar manner to that described in comparative example 4 to give 2-cyclopropylmethoxy-5-methylthiobenzaldehyde.

NMR (200 MHz, DMSO-d ₆ ) δ: 0.36 (m, 2H); 0.6 (m, 2H); 1.26 (m, 1H); 2.46 (s, 3H); 4.0 (d, J = 8.25 Hz, 2H); 7.2 (d, J = 9.2Hz, 1H); 7.52-7.62 (m, 2H); 10.38 (s, 1H).

MS (CI ⁺ ): (M + H) ⁺ 223.3.

 N-Ethyl-2-cyclopropylmethoxy-5-methylthiobenzylamine was obtained by reductive amination of 2-cyclopropylmethoxy-5-methylthiobenzylamine in a manner similar to that described in comparative example 19 (1).

NMR (200 MHz, DMSO-d ₆ ) δ: 0.32 (m, 2H); 0.55 (m, 2H); 1.03 (t, J = 7.3Hz, 3H); 1.30-1.13 (m, 1H); 2.4 (s, 3H); 2.53 (q, J = 7.3Hz, 2H); 3.65 (s, 2H); 3.82 (d, J = 6.25Hz, 2H); 6.88 (d, J = 8.3Hz, 1H); 7.10 (dd, J = 2.5, 8.3Hz, 1H); 7.25 (d, J = 2.5Hz, 1H).

MS (ESP ⁺ ): 252.4 (M + H) ⁺ .

 N-Ethyl-2-cyclopropylmethoxy-5-methylthiobenzylamine was reacted with 3-chloro-6-cyanopyridazine (obtained in comparative example 18) by a method similar to that described in example 11, whereby 6- [N- (2-cyclopropylmethoxy) was obtained -5-methylthiobenzyl) -N-ethylamino] -3-cyanopyridazine.

NMR (200 MHz, DMSO-d ₆ ) δ: 0.28 (m, 2H); 0.52 (m, 2H); 1.20-1.08 (m, 4H); 2.35 (s, 3H); 3.70 (q, 2H); 3.84 (d, J = 8.3Hz, 2H); 4.8 (s, 2H); 6.95 (d, J = 8.3Hz, 1H); 7.03 (d, J = 2.1Hz, 1H); 7.19 (dd, J = 10.4, 2.1Hz, 2H); 7.8 (d, J = 10.4Hz).

MS (ESP ⁺ ): 355 (M + H) ⁺ .

6- [N- (2-Cyclopropylmethoxy-5-methylthiobenzyl) -N-ethylamino] -3-cyanopyridazine (201 mg, 0.57 mmol) in dichloromethane (5 ml) was cooled on ice to about -10 ^° C and treated with 50 % m-chloroperbenzoic acid (196 mg, 0.57 mmol). The reaction mixture was stirred for 1 hour at a temperature of from -10 ^{° C.} to 0 ^{° C.} , then diluted with dichloromethane and extracted with saturated aqueous sodium bicarbonate (x 2). The organic extracts were dried and evaporated to give a pale brown foam (180 mg). Foam (180 mg, 0.49 mmol) in dichloromethane (5 ml) was cooled to -10 ^° C, treated with m-chloroperbenzoic acid (170 mg, 0.49 mmol) and stirred for 1.25 hours, raising the temperature to 0 ^o C. An additional amount of dichloromethane was added, the mixture was extracted with aqueous saturated sodium bicarbonate (x 2), dried and evaporated to give a foam, which was purified using HPLC using 2: 1 ethyl acetate / hexane as the eluent to obtain the title product (100 mg, 53%).

NMR (200 MHz, DMSO-d ₆ ) δ: 0.32 (m, 2H); 0.54 (m, 2H); 1.27-1.08 (m, 4H); 3.08 (s, 3H); 3.7 (q, 2H); 3.98 (d, J = 8.3Hz, 2H); 4.88 (s, 2H); 7.22 (d, J = 10.4Hz, 1H); 7.26 (d, J = 10.4Hz, 1H); 7.61 (d, J = 2.1Hz, 1H); 7.77-7.78 (m, J = 10.21 Hz, 2H).

MS (ESP ⁺ ): (M + H) ⁺ 387.2.

Reference Example 18
6- [N- (5-Bromo-2-propoxybenzyl) -N-ethylamino] -3-cyanopyridazine
(1) A mixture of 6-chloropyridazine-3-carboxamide (described in comparative example 3) (15 g, 95.5 mmol) and pyridine (22.6 g, 23.1 ml, 286.6 mmol) was suspended in dichloromethane and cooled to -30 ^o C in an argon atmosphere. TFAA was added dropwise to the stirred mixture, keeping the internal temperature below -20 ^° C. The reaction mixture was stirred for 19.5 hours to warm to room temperature. The mixture was poured into water (500 ml) and washed with water (4x500 ml) until the aqueous phase turned a light yellow hue. The organic phase was dried over MgSO ₄ , filtered through a pad of silica gel (diameter 50 mm, depth 30 mm) and concentrated in vacuo. The resulting solid product was purified by HPLC (40% dichloromethane / 20% ethyl acetate / hexane) to give 3-chloro-6-cyanopyridazine as a colorless solid (5.25 g, 59%).

MS (EI ⁺ ): 139 (M ⁺ ).

NMR (250 MHz, CDCl ₃ ) δ: 7.71 (d, J = 8Hz, 1H); 7.83 (d, J = 8 Hz, 1H).

(2) A solution of 5-bromosalicylaldehyde (20 g, 100 mmol) in NMP (100 ml) was treated with K ₂ CO ₃ (41.4 g, 300 mmol) for 30 minutes at a temperature of 40 ^° C. N-propyl iodide (25) was added. 5 g, 150 mmol) and the reaction mixture was stirred for 19 hours at 40 ^° C. A solution of ethylamine hydrochloride (11.41 g, 140 mmol) in ethanol (50 ml) was added, the mixture was stirred for another 3 hours at 40 ^{° C.} and then a solution of sodium borohydride (5.292 g, 140 mmol) in NMP (20 ml) was added dropwise over 1 hour. (Caution: a large amount of foam is formed). The reaction mixture was stirred for 19 hours at 40 ^{° C.} , cooled to room temperature, and 5 M hydrochloric acid (500 ml) was added. Then, the solution was treated with 5M sodium hydroxide solution to pH 14 and extracted with ethyl acetate (3 × 300 ml). The combined organic phases were washed with water (4 x 500 ml), dried over potassium carbonate and dry HCl gas was passed through the solution. The suspension was concentrated in vacuo to give a yellow solid, which was recrystallized from acetonitrile / toluene, whereby N-ethyl-2-propoxy-5-bromobenzylamine hydrochloride was obtained as a white solid (15.47 g, 50%).

MS (ESP): 375 (MH ^- ).

NMR (250 MHz, CDCl ₃ ) δ: 1.02 (t, J = 7Hz, 3H); 1.25 (t, J = 6Hz, 3H); 1.80 (m, 2H); 3.77 (q, J = 6Hz, 2H); 3.92 (t, J = 7Hz, 2H); 4.80 (br s, 2H); 6.67 (d, J = 8.5Hz, 1H); 6.75 (d, J = Hz, 1H); 7.12 (d, J = 2Hz, 1H); 7.34 (dd, J = 8, 2Hz, 1H); 7.38 (d, J = 8.5Hz, 1H).

(3) N-Ethyl-2-propoxy-5-bromobenzylamine hydrochloride 2 (5.17 g, 16.8 mmol) and 3-chloro-6-cyanopyridazine (2.65 g, 16.8 mmol) were dissolved in NMP ( 25 ml) and sodium bicarbonate (3.54 g, 42.1 mmol) was added. The resulting mixture was heated at 110 ^{° C.} under argon for 7.5 hours, then allowed to cool to room temperature. The mixture was poured into ethyl acetate (200 ml), washed with water (5x200 ml) and brine (200 ml), the organic phase was dried over MgSO ₄ and concentrated in vacuo. The residue was purified by HPLC (20% ethyl acetate / hexane) and then crystallized from ether / hexane to give the title product (4.80 g, 76%).

MS (ESP): 272 (MH ⁺ ), 227 (M-EtNH ₂ ) ⁺ .

NMR (250 MHz, DMSO-d ₆ ) δ: 0.99 (t, J = 6Hz, 3H); 1.26 (t, J = 7Hz, 3H); 1.78 (m, 2H); 2.92 (q, J = 7Hz, 2H); 3.95 (t, J = 6Hz, 2H); 4.02 (s, 2H); 7.02 (d, J = 8Hz, 1H); 7.52 (dd, J = 8.2Hz, 1H); 7.75 (d, J = 2Hz, 1H); 9.32 (br s, 2H).

Reference Example 19
6- [N- (5-Bromo-2-hydroxybenzyl) -N-ethylamino] -3-cyanopyridazine
(1) A solution of 5-bromosalicylaldehyde (20.1 g, 0.1 mmol) in THF (150 ml) was treated with a solution of ethylamine in methanol (2M, 70 ml, 0.14 mmol). The reaction mixture was stirred for 1.5 hours at room temperature. After cooling in an ice bath, sodium borohydride (5.3 g, 0.14 mmol) was added portionwise. The reaction mixture was kept overnight at room temperature. Water was added and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water, the organic layer was dried over MgSO ₄ and acidified with gaseous HCl. N-ethyl-5-bromo-2-hydroxybenzylamine hydrochloride was collected by filtration to give a white solid (17.53 g, 66%).

NMR (250 MHz, DMSO-d ₆ ) δ: 1.23 (t, 3H); 2.94 (q, 2H); 4.60 (t, 2H); 6.96 (d, 1H); 7.37 (dd, 1H); 7.63 (d, 1H); 9.02 (br s, 1H); 10.59 (s, 1H).

MS (ESP ⁺ ): 230/232 (M + H) ⁺ .

 (2) The title compound was obtained by reacting N-ethyl-5-bromo-2-hydroxybenzylamine hydrochloride with 3-chloro-6-cyanopyridazine in a manner similar to that described in comparative example 18, except that eluent was used in chromatography 2% diethyl ether / dichloromethane (yield: 50%).

NMR (250 MHz, DMSO-d ₆ ) δ: 1.15 (t, 3H); 8.37 (q, 2H); 4.75 (s, 2H); 6.81 (d, 1H); 7.07 (d, 1H); 7.15 (d, 1H); 7.25 (dd, 1H); 7.82 (d, 1H); 10.12 (br s, 1H).

Reference Example 20
N-Ethyl-5-chloro-2- (cyclopropylmethoxy) benzylamine
The title compound was prepared by reacting 5-chloro-2-hydroxybenzaldehyde with bromomethylcyclopropane in a manner similar to that described in comparative example 4.

MS (CI ⁺ ): 240/242 (M + H) ⁺ .

NMR (200 MHz, CDCl ₃ ) δ: 0.34 (m, 2H); 0.63 (m, 2H); 1.13 (t, J = 7Hz, 23H); 1.26 (m, 1H); 2.65 (q, J = 7Hz, 2H); 3.78 (d, 2H); 3.80 (d, 2H); 6.72 (d, J = 8Hz, 1H); 7.13 (dd, J = 2, 8Hz, 1H); 7.21 (d, J = 2Hz, 1H).

Reference Example 21
6- [N- (5-Chloro-2- (cyclopropylmethoxy) benzyl) -N-ethylamino] -3-cyanopyridazine
To a stirred mixture of 6- [N- (5-Chloro-2- (cyclopropylmethoxy) benzyl) -N-ethylamino] pyridazine-3-carboxamide (3.5 g, 9.7 mmol) in pyridine (120 ml) at a temperature of 20 ^o C, methanesulfonyl chloride (10.0 ml, 124 mmol) was added dropwise over 20 minutes. The resulting mixture was stirred at a temperature of 20 ^{° C.} for 60 hours and poured onto ice (300 g), 10 N was added. hydrochloric acid (100 ml) and this mixture was vigorously stirred, after which it was extracted with ether (500 ml). The organic layer was washed with 1 N. hydrochloric acid (500 ml) was dried over anhydrous magnesium sulfate and evaporated, whereby the title product was obtained as a light brown gum (3.3 g, 99%).

MS (ESP ⁺ ): 343/345 (M + H) ⁺ .

NMR (200 MHz, CDCl ₃ ) δ: 0.32 (m, 2H); 0.60 (m, 2H); 1.20 (m, 1H); 1.25 (t, J = 7Hz, 3H); 3.82 (d, 2H); 3.85 (q, J = 7Hz, 2H); 4.85 (s, 2H); 6.78 (d, J = 8Hz, 1H); 7.06 (d, J = 8Hz, 1H); 7.09 (d, J = 2Hz, 1H); 7.22 (dd, J = 2, 8Hz, 1H); 7.52 (d, J = 8Hz, 1H).

Reference Example 22
N-Ethyl-5-chloro-2- (cyclopentoxy) benzylamine
Anhydrous potassium carbonate (23.4 g, 169 mmol) was added to 5-chlorosalicylaldehyde (20.3 g, 130 mmol) and bromocyclopentane (22.0 g, 148 mmol) in dimethylformamide (100 ml) and the solution was stirred for 16 hours at 50 ^° C. The inorganic solid was extracted and the solvent was removed in vacuo. The resulting product was extracted with dichloromethane from water (200 ml) and the organic layer was successively dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The dissolved product was purified on a column of silica gel by washing with dichloromethane and 2 N. sodium hydroxide solution (3 • 100 ml), whereby 5-chloro-2-cyclopentoxybenzaldehyde (19.22 g, 66%) was obtained.

MS (CI ⁺ ): 225/227 (MH ⁺ ).

NMR (200 MHz, DMSO-d ₆ ) δ: 1.80 (m, 8H); 4.98 (m, 1H); 7.24 (d, J = 8Hz, 1H); 7.58 (d, J = 2Hz, 1H); 7.62 (dd, J = 2.8Hz, 1H); 10.28 (s, 1H).

5-Chloro-2-cyclopentoxybenzaldehyde (9.35 g, 41.6 mmol) and ethylamine hydrochloride (18.6 g, 229 mmol) in methanol (100 ml) were stirred for 30 minutes at room temperature, and then sodium cyanoborohydride (5 , 6 g, 88 mmol) and the reaction mixture was heated under reflux at 70 ^{° C.} for 70 hours with periodic acidification with glacial acetic acid to pH 6. Normal hydrochloric acid (100 ml) was added dropwise and the resulting mixture was made basic with a 2 N hydroxide solution. sodium to pH 11, the product was extracted with dichloromethane (250 ml x 2) and ethyl acetate (250 ml x 2). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and the solvent was removed to obtain the title compound (8.5 g, 80%).

Reference Example 23
6- (N- [5-Chloro-2- (cyclopentoxy) benzyl] -N-ethylamino) -3-cyanopyridazine
The title compound was obtained by reacting the compounds of comparative example 22 and 3-chloro-6-cyanopyridazine (comparative example 18 (1)) in a manner similar to that described in comparative example 18 (3).

Reference Example 24
6- (N- [5-Bromo-2- (cyclobutyloxy) benzyl] -N-ethylamino) -3-cyanopyridazine
The title compound was obtained by alkylation of the corresponding nitrile (comparative example 18) with bromocyclobutane using a method similar to that described in comparative example 4, except that the reaction mixture was stirred for 10 days at room temperature.

MS (ESP ⁺ ): 387 (M + H) ⁺ .

NMR (250 MHz, DMSO-d ₆ ) δ: 1.14 (t, 3H); 1.73 (m, 2H); 1.98 (m, 2H); 2.40 (m, 2H); 3.68 (q, 2H); 4.72 (quintet, 1H); 4.81 (s, 2H); 6.82 (d, 1H); 7.2 (m, 2H); 7.37 (dd, 1H); 7.83 (d, 1H).

Reference Example 25
6- [N- (5-Bromo-2- (3,3,3-trifluoro-2-hydroxypropoxy) benzyl] -N-ethylamino) -3-cyanopyridazine
The title compound was prepared by reacting 6- [N- (5-bromo-2-hydroxybenzyl) -N-ethylamino] -3-cyanopyridazine with 1,1,1-trifluoro-3-bromopropan-2-ol in a similar manner described in comparative example 4.

MS (ESP ⁺ ): 445 (M + H) ⁺ .

NMR (250 MHz, DMSO-d ₆ ) δ: 1.15 (t, 3H); 3.68 (q, 2H); 4.16 (m, 1H); 4.25 (m, 1H); 4.4 (m, 1H); 4.85 (s, 2H); 6.65 (d, 1H); 7.14 (m, 3H); 7.43 (dd, 1H); 7.83 (d, 1H).

Reference Example 26
2- [N- (5-Bromo-2-cyclopropylmethoxybenzyl) -N-ethylamino] -5-cyanopyridine
The title compound was prepared by reacting N-ethyl-5-bromo-2-cyclopropylmethoxybenzylamine (comparative example 13) with 2-chloro-5-cyanpyridine in a manner similar to that described in comparative example 18.

MS: 386 (M + H) ⁺ .

NMR (MHz, DMSO-d ₆ ) δ: 0.33 (m, 2H); 0.55 (m, 6.70 (d, 1H); 6.95 (d, 1H); 7.05 (d, 1H); 7.35 (dd, 1H); 7.75 (dd, 1H) ; 8.45 (d, 1H).

Reference Example 27
6- [N- (5-Chloro-2-cyclobutylmethoxybenzyl] -N-ethylamino) -3-cyanopyridazine
Cyclobutanomethanol (5 g, 58 mmol) was dissolved in dichloromethane (150 ml) and cooled in an ice water bath. Triethylamine (10.5 ml, 75.6 mmol) was added to the solution, and then a solution of tosyl chloride (13.3 g, 69.8 mmol) in dichloromethane (50 ml) was added dropwise. After removing the cooling bath, the mixture was allowed to warm to room temperature for more than 16 hours. The mixture was washed with water (2x100 ml), dried (MgSO ₄ ) and concentrated in vacuo to give cyclobutanomethanol tosylate as a yellow oil, which was used without further purification.

MS: 241 (M + H) ⁺ .

5-Chlorosalicylaldehyde (7.7 g, 49.4 mmol) was dissolved in DMF (20 ml) with potassium carbonate (7.5 g, 54.1 mmol) and cyclobutanomethanol tosylate (13 g, 54.1 mmol). The mixture was stirred for 16 hours under argon at 50 ^° C. It was poured into water (500 ml), extracted with ethyl acetate (4 x 100 ml) and the combined organic fractions were washed with 1 M sodium hydroxide solution (100 ml), water (100 ml), saturated brine solution (100 ml), dried (MgSO ₄ ) and concentrated in vacuo to give 5-chloro-2- (cyclobutylmethoxy) benzaldehyde as a brown oil (13 g), which was used without further purification.

MS: 225 (M + H) ⁺ .

5-Chloro-2- (cyclobutylmethoxy) benzaldehyde (13 g) was dissolved in DMF (100 ml), potassium carbonate (16 g, 116 mmol) and ethylamine hydrochloride (9.5 g, 117 mmol) were added. The mixture was heated for 1 hour at 40 ^{° C.} , then cooled in an ice water bath, and a solution of sodium borohydride (4.3 g, 116 mmol) in a minimum amount of DMF was added dropwise. After completion of the addition, the cooling bath was removed and the reaction mixture was heated at 40 ^{° C.} for 16 hours. The reaction mixture was cooled to room temperature and 5M hydrochloric acid was carefully added until the mixture became pH 2. Solid sodium hydroxide was added to the resulting mixture to pH 14 and the mixture was extracted with ethyl acetate (3 × 300 ml), the combined organic fractions were washed with water (100 ml), brine (100 ml), dried (MgSO ₄ ) and concentrated in vacuo to give an oil (15 g). This oil was purified by HPLC (5% methanol / dichloromethane) to give N-ethyl-5-chloro-2- (cyclobutylmethoxy) benzylamine as a gum which crystallized upon standing (2.1 g, 17%).

MS: 254 (M + H) ⁺ .

NMR (MHz, DMSO-d ₆ ) δ: 1.05 (t, 3H); 1.95 (m, 6H); 2.50 (m, 1H); 2.75 (q, 2H); 3.65 (s, 2H); 3.92 (d, 2H); 6.95 (d, 1H); 7.20 (dd, 1H); 7.28 (d, 1H).

 N-Ethyl-5-chloro-2- (cyclobutylmethoxy) benzylamine (2.1 g, 8.3 mmol) was coupled with 3-chloro-5-cyanopyridazine (1.3 g, 8.25 mmol) using bicarbonate sodium (0.71 g, 8.45 mmol) in NMP (10 ml), in a manner analogous to that described in comparative example 18. The title compound was purified by HPLC (dichloromethane, 1% MeOH / dichloromethane) (2.3 g, 78%) to obtain a solid product.

MS: 357 (M + H) ⁺ .

NMR (MHz, DMSO-d ₆ ) δ: 1.1 (t, 3H); 1.95 (m, 6H); 2.60 (m, 1H); 3.65 (q, 2H); 3.95 (d, 2H); 4.8 (s, 2H); 6.95 (d, 1H); 7.00 (d, 1H); 7.18 (d, 1H); 7.26 (dd, 1H); 7.82 (d, 1H).

Reference Example 28
N-Ethyl-5-bromo-2- (cyclopropylmethoxy) benzylamine
Anhydrous potassium carbonate (36.8 g, 266 mmol) and bromomethylcyclopropane (9 ml, 93 mmol) were added to 5-bromosalicylaldehyde (15.0 g, 74 mmol) in dimethylformamide, and the solution was stirred for 60 hours at 50 ^° C. Then propylamine (26.5 g, 450 mmol) was added and the solution was allowed to stir at room temperature for 2 hours, after which diethyl ether (50 ml) and sodium borohydride (2.6 g, 68 mmol) were added and the solution was kept for 1 hours. After adding dropwise 6 n. hydrochloric acid (150 ml) the solution was left to mix for 16 hours. The impurities were extracted with diethyl ether (200 ml x 2), the solution was made basic with caustic soda liquid and the product was extracted with diethyl ether (250 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was removed in vacuo to give the title compound (4.8 g, 22%).

MS (EI ⁺ ): 298/300 (MH ⁺ ).

NMR (200 MHz, DMSO-d ₆ ) δ: 0.34 (m, 2H); 0.56 (m, 2H); 0.88 (t, 3H); 1.22 (m, 1H); 1.44 (m, 2H); 2.47 (t, 2H); 3.66 (s, 2H); 3.82 (d, 2H); 6.86 (d, J = 8Hz, 1H); 7.31 (dd, J = 2Hz, 8Hz, 1H); 7.46 (d, J = 2Hz, 1H).

Claims (11)

1. Aromatic compounds of formula I

where A is optionally substituted phenyl provided that the —CH (R ³ ) N (R ² ) BR ¹ and —OR ⁴ groups are in the 1,2-position relative to each other on the ring carbon atoms and the ring atom located in the ortho position with respect to the OR ⁴ -adhesive group (and therefore in the 3-position with respect to the -CHR ³ NR ² -binding group) is unsubstituted; and wherein said optional substituents on the ring carbon atoms are selected from halogen, trifluoromethyl, nitro, hydroxy, amino, C _1-4 alkylamino, diC _1-4 alkylamino, cyano, C _1-6 alkoxy, C _1-6 alkylS (O) _p ( p = 0, 1 or 2), C _1-6 alkyl (optionally substituted with hydroxy, amino, halogen, nitro or cyano), CF ₃ S (O) _p (p = 0, 1 or 2), 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 alkanesulfonylamido, benzenesulfonylamido, aminosulfonyl, C _1-4 alkyl minosulfonyl, C _1-4 alkanoylaminosulfonyl, di (C _1-4 alkyl) aminosulfonyl, C _1-4 alkoxycarbonyl, C _1-4 alkanoyloxy, C _1-6 alkanoyl, formylC _1-4 alkyl, trifluoro C _1-3 alkyl sulfonyl , gidroksiiminoS _1-6 alkyl, C _1-4 alkoksiiminoS _1-6 alkyl and C _1-6 alkilkarbamoilamino;
B is pyridyl or pyridazinyl;
R ¹ is on ring B at the 1,3- or 1,4-position with respect to the —CHR ³ NR ² -binding group and is a 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, or R ¹ is a group of the formula —CONHSO ₂ R ^b , where R ^b is C _1-6 alkyl, trifluoromethyl or 5-membered heteroaryl, where The 5-membered heteroaryl is selected from isoxazolyl and thiadiazolyl optionally substituted with a C _1-6 alkyl or a C _1-4 alkanoylamino group;
R ² is C _1-6 alkyl;
R ³ is hydrogen;
R ⁴ is C _1-4 alkyl, C _3-7 cycloalkyl C _1-3 alkyl or C _3-7 cycloalkyl, wherein said C _1-6 alkyl is optionally substituted with hydroxy or halogen,
or a pharmaceutically acceptable salt thereof, or an in vivo hydrolyzable ester, wherein the in vivo hydrolyzable carboxylic ester is selected from a pharmaceutically acceptable ester formed of a C _1-6 alcohol, phenol or benzyl alcohol substituted with phenol or benzyl alcohol, wherein the substituent is C _1-4 alkyl or C _1-4 alkoxy; or α-acyloxyalkyl ester;
in vivo hydrolyzable ester of the hydroxy group is selected from alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to obtain esters of alkyl carbonate), dialkylcarbamoyl and N- (dialkylaminoethyl) -N-alkylcarbamoyl (to obtain carbamoacetate; and with the exception of 2- [2-methoxybenzylamino] pyridine-5-carboxylic acid. 2. The compound of claim 1, wherein R ² is methyl, ethyl or propyl. 3. The compound according to claim 1 or 2, where R ¹ is carboxy, tetrazolyl or a group of the formula —CONHR ^a1 , where R ^a1 is C _1-4 alkyl 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. 4. The compound according to any one of paragraphs. 1-3, where A is substituted by halogen, nitro, trifluoromethyl, cyano, amino, C _1-6 alkoxy, carbamoyl, C _1-4 alkylcarbamoyl, di (C _1-4 alkyl) carbamoyl, C _1-4 alkanoylamino, C _{1- 6} alkyl S (O) _p , C _1-4 alkanesulfonamido, benzenesulfonamido, C _1-6 alkanoyl, C _1-4 alkoxyimino C _1-4 alkyl or hydroxyimino C _1-4 alkyl. 5. The compound according to any one of paragraphs. 1-4, where R ⁴ is C _1-4 alkyl, C _3-6 cycloalkylmethyl, C _3-6 cycloalkyl, wherein said C _1-4 alkyl is optionally substituted with hydroxy or halogen.  6. The compound according to claim 1, which is 6- [N- (5-chloro-2-isobutoxybenzyl) -N-ethylamino] -N- (3,5-dimethylisoxazol-4-ylsulfonyl) -pyridazine-3-carboxamide, or N-propanesulfonyl-6- [N- (5-bromo-2- (cyclopropylmethoxy) benzyl) -N-ethylamino] pyridazine-3-carboxamide, or a pharmaceutically acceptable salt thereof.  7. The compound according to claim 1, which is 6- [N- (5-bromo-2- (cyclopropylmethoxy) benzyl) -N-ethylamino] pyridazine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof, or an in vivo hydrolyzable complex ether.  8. A pharmaceutical composition for eliminating pain, which contains an effective amount of a compound according to any one of claims. 1-7 and a pharmaceutically acceptable carrier.  9. A method of eliminating pain by administering to the patient an effective amount of a compound of formula (I) according to claims 1-7. 10. The method of producing aromatic compounds of formula I according to claim 1, in which R ^{1 is a} carboxy, carbamoyl or a group of the formula —CONR ^a R ^a1 or the formula —CONHSO ₂ R ⁶ , where R ^a , R ^a1 and R ^b are as defined in claim 1, or their pharmaceutically acceptable salts, or their in vivo hydrolyzable esters as defined in claim 1, characterized in that in the compound of formula III

in which R ⁶ means a protected carboxy group;
R ⁷ has the meanings indicated for R ² in paragraph 1 of the formula;
R ³ , R ⁴ , A and B have the meanings indicated in paragraph 1,
the carboxy protecting group is removed to give a compound of formula I, where R ¹ is carboxy, followed by optionally converting the resulting compound to a compound of formula I, where R ¹ is carbamoyl, or —CONR ^a R ^a1 , or CONHSO ₂ R ⁶ , and conversion, if necessary, of the obtained compounds into a pharmaceutically acceptable salt or in vivo hydrolyzable ester. 11. Aromatic compounds of formula III

where R ⁶ means a carboxy group protected by an esterifying C _1-4 alkyl group;
R ⁷ has the meanings indicated for R ² in paragraph 1 of the formula;
R ³ , R ⁴ , A and B have the meanings indicated in paragraph 1. Priority on points and signs:
06/20/1995 PP 1-4 for compounds where R ⁴ is unsubstituted C _1-6 alkyl; according to claim 5, where R ⁴ is unsubstituted C _1-4 alkyl; p. 8, where the pharmaceutical composition contains the above compounds; p. 9 where these compounds are used, and p. 10 a method for producing these compounds;
01/25/1996 PP 1-4 for compounds where R ⁴ is C _1-6 alkyl substituted with hydroxy and halogen, or C _3-7 cycloalkyl; according to claim 5, wherein R ⁴ is C _1-4 alkyl substituted with hydroxy and halogen, or C _3-6 cycloalkyl; p. 8, where the pharmaceutical composition contains these compounds; p. 9 using these compounds and p. 10 in terms of obtaining these compounds;
06/17/1996 (according to the filing date of the application PCT / GB 96/01442) according to paragraphs. 1-4 for compounds wherein R ⁴ is C _3-7 cycloalkylC _1-3 alkyl; according to claim 5, where R ⁴ is C _3-6 cycloalkylmethyl; by pp. 6 and 7, p. 8, where the pharmaceutical composition contains these compounds; according to claim 9, where these compounds are used; p. 10, where they receive these compounds and p. 11.

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