HK1027557B

HK1027557B - Aryl sulfonamides and analogues thereof and their use in the treatment of neurodegenerative diseases

Info

Publication number: HK1027557B
Application number: HK00106900.6A
Authority: HK
Inventors: J‧米藤多夫; J‧德雷塞尔; M‧马茨克; J‧克尔德尼希; K‧H‧莫尔斯; S‧拉达茨; J‧弗朗兹; P‧斯普雷耶; V‧弗林格; J‧舒马赫尔; M‧H‧罗克; E‧霍尔瓦斯; A‧弗里德尔; F‧毛勒; J‧M‧V‧德弗赖; R‧乔克
Original assignee: Bayer Intellectual Property Gmbh
Priority date: 1997-02-21
Filing date: 1998-02-10
Publication date: 2009-12-18

Description

Aryl sulfonamides and analogues thereof and their use in the treatment of neurodegenerative diseases

The present invention relates to novel aryl sulfonamides and analogues thereof, methods for their preparation and their use in the prevention and treatment of neurodegenerative disorders, in particular cerebral stroke and craniocerebral trauma.

Δ⁹-tetrahydrocannabinol (Δ)⁹-THC), to a lesser extent, also Δ⁸-THC is bioavailable in extracts of cannabis sativa (marihuana), cannabis indica (hashish) plantsAnd act on the Central Nervous System (CNS) of the human brain. Potential historical and modern therapeutic uses of cannabis preparations include, inter alia, the treatment of pain, emesis, anorexia, glaucoma and movement disorders.

To date, two subtypes of cannabinoid receptors and one splice variant have been identified. The CB1 receptor (Nature 1990, 346, 561) and a splice variant CB1a (j. biol. chem.1995, 270, 3726) are located mainly in the central nervous system. CB2 receptors are found mainly in peripheral tissues, particularly leukocytes, spleen and macrophages (eur.j. biochem.1995, 232, 54).

The CB1 and CB2 receptors have 7 transmembrane domains and belong to the G protein receptor family. Both receptors pass through G_i/G_oProteins negatively couple to adenylate cyclase and possibly to presynaptically released glutamate (j. neurosci.1996, 16, 4322). The CB1 receptor also positively couples potassium channels and also negatively couples N-and Q-type calcium channels.

Four classes of CB1 receptor agonists are known today; classical cannabinoids such as delta⁹-THC, non-classical cannabinoids, aminoalkylindoles and eicosanoids. The latter includes the generally accepted endogenous CB1 receptor agonist anandamide.

It is also known that cerebral strokes are a consequence of sudden circulatory disturbances in the brain region of a human being, with consequent loss of function, with corresponding neurological and/or physiological symptoms. Cerebral stroke is caused by cerebral hemorrhage (e.g., after vascular rupture due to hypertension, arteriosclerosis, and aneurysm) and ischemia (e.g., due to a hypotensive crisis or embolism). Loss of brain function leads to degeneration or destruction of brain cells (Journal of cereal Blood Flow and Metabolism 1981, 1, 155; chem. Eng. News 1996(May 13), 41; Trends Pharmacol. Sci.1996, 17, 227). Craniocerebral trauma refers to both closed and open cranial trauma involving the brain.

The present invention relates to compounds of the general formula (I):

R¹-A-D-E-G-L-R² (I)

wherein

R¹Is represented by (C)₆-C₁₀) -aryl, quinolinyl, isoquinolinyl or a group of formula:

wherein a represents 1 or 2, or a salt thereof,

R³represents a hydrogen atom or (C)₂-C₆) -alkenyl, (C)₁-C₆) -alkyl or (C)₁-C₆) -acyl, and all the above ring systems and groups may optionally be substituted, if appropriate geminally substituted, by one or more, identical or different substituents selected from the following:

halogen, carboxyl, hydroxyl, phenyl, (C)₁-C₆) -alkoxy, (C)₁-C₆) -alkoxycarbonyl group, (C)₁-C₈) Alkyl, to which the radical may be substituted by halogen, (C)₁-C₆) Alkylsulfonyloxy, azido, amino, mono (C)₁-C₆) Alkylamino, di (C)₁-C₆) -alkylamino or hydroxy substitution;

formula- (CO)_b-NR⁴R⁵The radical(s) is (are),

wherein b represents a number of 0 or 1,

R⁴and R⁵The same or different, independently represent a hydrogen atom, a phenyl group, or a group (C)₁-C₆) -acyl, ring (C)₄-C₇) -acyl, benzoyl or (C)₁-C₆) Alkyl, optionally substituted by amino, mono (C)₁-C₆) Alkylamino, di (C)₁-C₆) -an alkyl-amino substitution,

or R⁴And R⁵Together with the nitrogen atom, form a 5-or 6-membered saturated heterocyclic ring, which may optionally contain one or more further heteroatoms selected from S and O and/or one or more compounds of formula-NR⁸The group of (a) or (b),

wherein R is⁸Represents a hydrogen atom or (C)₁-C₆) -alkyl or (C)₁-C₆) -an acyl group;

and the formula-NR⁶-SO₂-R⁷The group of (a) or (b),

wherein R is⁶Represents a hydrogen atom, a phenyl group, or (C)₁-C₆) -alkyl or (C)₁-C₆) -an acyl group,

R⁷represents phenyl or (C)₁-C₆) -an alkyl group;

a and E are the same or different and represent a bond or (C)₁-C₄) -an alkylene group,

d represents an oxygen atom or a group of the formula-S (O)_C-or-N (R)⁹) -a group of,

wherein c represents 0, 1 or 2,

R⁹represents a hydrogen atom or (C)₁-C₆) -alkyl or (C)₁-C₆) -an acyl group,

g represents a double bond (C)₆-C₁₀) -aryl or a two-bonded 5-to 7-membered heteroaromatic ring containing up to 3 heteroatoms selected from S, N and/or O, both aryl and heteroaromatic rings being optionally substituted by one or more, identical or different substituents selected from the group consisting of:

hydroxy, trifluoromethyl, carboxy, halogen, (C)₁-C₆) Alkyl, hydroxy (C)₁-C₆) Alkyl radicals, (C)₁-C₆) -alkoxy, (C)₁-C₆) -an alkoxycarbonyl group, a carbonyl halide group,

and a group of the formula:

-CO-O-(CH₂)_d-NR¹⁰R¹¹、-NR¹²-SO₂R¹³、

-(CH₂)_e-(CO)_f-NR¹⁴R¹⁵and-OR¹⁶，

Wherein d represents 1, 2, 3 or 4,

e and f are identical or different and denote 0 or 1,

R¹⁰and R¹¹And the above-mentioned R⁴And R⁵Are the same, and they may be the same or different,

R¹²and the above-mentioned R⁶Are the same, and they may be the same or different,

R¹³and the above-mentioned R⁷Are the same, and they may be the same or different,

R¹⁴and R¹⁵And the above-mentioned R⁴And R⁵Are the same, and they may be the same or different,

or independently of one another, represent a group of formula:

-(CH₂)_g-NR¹⁷R¹⁸，

wherein g represents 1, 2, 3 or 4,

and R is¹⁷And R¹⁸And the above-mentioned R⁴And R⁵Are the same, and they may be the same or different,

R¹⁶is represented by (C)₆-C₁₀) -an aryl group,

l represents a group of the formula:

-O-、-NH-、

wherein the bonding of the group to G is at the left bond,

and wherein R is¹⁹、R²⁰、R²¹、R²²、R²³、R²⁴、R²⁵、R²⁶And R²⁷Are the same or different and represent a hydrogen atom or (C)₁-C₄) -an alkyl group,

or R¹⁹Is represented by the formula-SO₂R²The group of (a) or (b),

R²is represented by (C)₆-C₁₀) -aryl or a 5 to 7 membered saturated aromatic heterocycle containing up to 3 heteroatoms selected from S, N and/or O, both aryl and aromatic heterocycle being optionally substituted by one or more, identical or different substituents selected from the group consisting of:

halogen, trifluoromethyl, nitro, amino and (C)₁-C₆) An alkyl group, a carboxyl group,

or represents a group of the formula:

or a morpholine, or a mixture of morpholine,

or represents C₃-C₈-a cycloalkyl group,

or represents (C)₁-C₁₂) Alkyl radicals, (C)₂-C₁₂) -alkenyl or (C)₂-C₁₂) -alkynyl, wherein each group is optionally substituted with one or more, the same or different substituents selected from the group consisting of:

halogen, trifluoromethyl, hydroxy, cyano, azido, (C)₁-C₆) -alkoxy, (C)₁-C₆) Perfluoroalkoxy, partially fluorinated (C)₁-C₆) -alkoxy radicalA group of the formula

-NR²⁸R²⁹，

Wherein R is²⁸And R²⁹And the above-mentioned R⁴And R⁵Are the same as defined above, and they are the same or different;

phenyl optionally substituted with one or more, the same or different substituents selected from the group consisting of:

halogen, nitro, hydroxy, (C)₁-C₆) Alkyl radicals, (C)₁-C₆) -alkoxy and of the formula-NR³⁰R³¹The group of (a) or (b),

wherein R is³⁰And R³¹Are the same or different and represent a hydrogen atom or (C)₁-C₆) -alkyl or (C)₁-C₆) -an acyl group;

and 5 to 6 membered ring containing up to 3 heteroatoms selected from S, N and/or O, optionally substituted with one or more, the same or different substituents selected from the group consisting of:

wherein R is³⁰And R³¹The definition is as above-mentioned,

alternatively, the first and second electrodes may be,

l and R²Together represent a group of the formula.

Preferred compounds of formula (I) are the following compounds and salts thereof:

wherein

R¹Represents phenyl, naphthyl, quinolyl, isoquinolyl or a group of formula:

wherein a represents 1 or 2, or a salt thereof,

R³represents a hydrogen atom or (C)₂-C₄) -alkenyl, (C)₁-C₄) -alkyl or (C)₁-C₄) -acyl, and all the above ring systems and groups may optionally be substituted, if appropriate geminally substituted, by one or more, identical or different substituents selected from the following:

halogen, carboxyl, hydroxyl, phenyl, (C)₁-C₄) -alkoxy, (C)₁-C₅) -alkoxycarbonyl group, (C)₁-C₆) Alkyl, to which the radical may be substituted by halogen, (C)₁-C₄) Alkylsulfonyloxy, azido, amino, mono (C)₁-C₄) Alkylamino, di (C)₁-C₄) -alkylamino or hydroxy substitution;

formula- (CO)_b-NR⁴R⁵The radical(s) is (are),

wherein b represents a number of 0 or 1,

R⁴and R⁵The same or different, independently represent a hydrogen atom, a phenyl group, or a group (C)₁-C₄) -acyl, ring (C)₄-C₇) -acyl, benzoyl or (C)₁-C₄) Alkyl, optionally substituted by amino, mono (C)₁-C₄) Alkylamino, di (C)₁-C₄) -an alkyl-amino substitution,

or R⁴And R⁵Together with the nitrogen atom, form a morpholine, piperidine or N-methylpiperazine ring;

and the formula-NR⁶-SO₂-R⁷The group of (a) or (b),

wherein R is⁶Represents a hydrogen atom, a phenyl group, or (C)₁-C₄) -alkyl or (C)₁-C₄) -an acyl group,

R⁷represents phenyl or (C)₁-C₅) -an alkyl group;

wherein c represents 0, 1 or 2,

R⁹represents a hydrogen atom or (C)₁-C₄) -alkyl or (C)₁-C₄) -an acyl group,

g represents a two-bonded phenyl, naphthyl, pyrimidinyl, pyridazinyl or pyridinyl group, each of which is optionally substituted by one or more, identical or different substituents selected from the following:

hydroxy, trifluoromethyl, carboxy, halogen, (C)₁-C₄) Alkyl, hydroxy (C)₁-C₄) Alkyl radicals, (C)₁-C₄) -alkoxy, (C)₁-C₄) -an alkoxycarbonyl group, and a group of formula:

-CO-O-(CH₂)_d-NR¹⁰R¹¹、-NR¹²-SO₂R¹³、

-(CH₂)_e-(CO)_f-NR¹⁴R¹⁵and-OR¹⁶，

Wherein d represents 1, 2, 3 or 4,

e and f are identical or different and denote 0 or 1,

or independently of one another, represent a group of formula:

-(CH₂)_g-NR¹⁷R¹⁸，

wherein g represents 1, 2 or 3,

and R is¹⁷And R¹⁸And the above-mentioned R¹⁰And R¹¹Are the same, and they may be the same or different,

R¹⁶represents a phenyl group or a naphthyl group,

l represents a group of the formula:

wherein the bonding of the group to G is at the left bond,

and wherein R is¹⁹、R²⁰、R²¹、R²²、R²³、R²⁴、R²⁵、R²⁶And R²⁷Are the same or different and represent a hydrogen atom or (C)₁-C₃) -an alkyl group,

or R¹⁹Is represented by the formula-SO₂R²The group of (a) or (b),

R²represents phenyl, naphthyl, pyridyl, furyl, thienyl or pyrimidinyl, each of which is optionally substituted by one or more, identical or different substituents selected from the following:

halogen, amino, trifluoromethyl, nitro and (C)₁-C₄) An alkyl group, a carboxyl group,

or represents a group of the formula:

or a morpholine, or a mixture of morpholine,

or represents cyclopropyl, cyclohexyl or cyclopentyl,

or represents (C)₁-C₁₀) Alkyl radicals, (C)₂-C₁₀) -alkenyl or (C)₂-C₁₀) -alkynyl, wherein each group is optionally substituted with one or more, the same or different substituents selected from the group consisting of:

halogen, trifluoromethyl, hydroxy, azido, (C)₁-C₄) -alkoxy, (C)₁-C₅) Perfluoroalkoxy, partially fluorinated (C)₁-C₄) -alkoxy, a group of formula

and-NR²⁸R²⁹，

halogen, nitro, hydroxy, (C)₁-C₄) Alkyl radicals, (C)₁-C₄) -alkoxy and of the formula-NR³⁰R³¹The group of (a) or (b),

wherein R is³⁰And R³¹Are the same or different and represent a hydrogen atom or (C)₁-C₄) -alkyl or (C)₁-C₄) -an acyl group;

pyridinyl and pyrimidinyl, optionally substituted with one or more, the same or different substituents selected from the group consisting of:

wherein R is³⁰And R³¹The definition is as above-mentioned,

alternatively, the first and second electrodes may be,

l and R²Together represent a group of the formula,

particularly preferred compounds of formula (I) are the following compounds and salts thereof:

wherein

R¹Represents phenyl, naphthyl, quinolyl, isoquinolyl or a group of formula:

wherein a represents 1 or 2, or a salt thereof,

R³represents a hydrogen atom or (C)₂-C₃) -alkenyl, (C)₁-C₃) -alkyl or (C)₁-C₃) -acyl, and all the above ring systems and groups may optionally be substituted, if appropriate geminally substituted, by one or more, identical or different substituents selected from the following:

chlorine, fluorine, carboxyl, hydroxyl, phenyl, (C)₁-C₃) -alkoxy, (C)₁-C₄) -alkoxycarbonyl group, (C)₁-C₄) -alkyl, for which the group may be substituted by chloro, methanesulfonyloxy or hydroxy;

formula- (CO)_b-NR⁴R⁵The radical(s) is (are),

wherein b represents a number of 0 or 1,

R⁴and R⁵The same or different, independently represent a hydrogen atom, (C)₁-C₃) -acyl, ring (C)₄-C₆) -acyl, benzoyl or (C)₁-C₃) Alkyl, optionally substituted by amino, mono (C)₁-C₃) Alkylamino, di (C)₁-C₃) -an alkyl-amino substitution,

and the formula-NR⁶-SO₂-R⁷The group of (a) or (b),

wherein R is⁶Represents a hydrogen atom or (C)₁-C₃) -alkyl or (C)₁-C₃) -an acyl group,

R⁷represents phenyl or (C)₁-C₄) -an alkyl group;

a and E are the same or different and represent a bond or (C)₁-C₃) -an alkyl group,

wherein c represents 0, 1 or 2,

R⁹represents a hydrogen atom or (C)₁-C₃) -alkyl or (C)₁-C₃) -an acyl group,

hydroxy, trifluoromethyl, carboxy, fluoro, chloro, bromo, (C)₁-C₃) Alkyl, hydroxy (C)₁-C₃) Alkyl radicals, (C)₁-C₃) -alkoxy, (C)₁-C₃) -an alkoxycarbonyl group, and a group of formula:

-CO-O-(CH₂)_d-NR¹⁰R¹¹、-NR¹²-SO₂R¹³、

-(CH₂)_e-(CO)_f-NR¹⁴R¹⁵、-CH₂OH and-OR¹⁶，

Wherein d represents 1, 2 or 3,

e and f are identical or different and denote 0 or 1,

R¹⁰and R¹¹Represents a hydrogen atom or a methyl group,

R¹²represents a hydrogen atom, and is represented by,

R¹³is represented by (C)₁-C₄) -an alkyl group,

or independently of one another, of the formula- (CH)₂)_g-NR¹⁷R¹⁸，

Wherein g represents 1, 2 or 3,

and R is¹⁷And R¹⁸Represents a hydrogen atom or a methyl group,

or R¹⁴And R¹⁵Together with the nitrogen atom form a radical of the formula

R¹⁶Represents a phenyl group or a naphthyl group,

l represents a group of the formula:

wherein the bonding of the group to G is at the left bond,

and wherein R is¹⁹、R²⁰、R²¹、R²²、R²³、R²⁴、R²⁵、R²⁶And R²⁷Identical or different and represent a hydrogen atom, a methyl or ethyl group,

or R¹⁹Is represented by the formula-SO₂R²The group of (a) or (b),

R²represents phenyl, furyl or pyridyl, each of which is optionally substituted by one or more, identical or different substituents selected from the group consisting of:

fluorine, chlorine, bromine or trifluoromethyl,

or represents a group of the formula:

or a morpholine, or a mixture of morpholine,

or represents a cyclopentyl or cyclohexyl radical,

or represents (C)₁-C₈) Alkyl radicals, (C)₂-C₈) -alkenyl or (C)₂-C₈) -alkynyl, wherein each group is optionally substituted with one or more, the same or different substituents selected from the group consisting of:

fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, azido, (C)₁-C₃) -alkoxy, (C)₁-C₄) -perfluoroalkoxy, trifluoromethyl-substituted (C)₁-C₄) -alkoxy, a group of formula

and-NR²⁸R²⁹，

Wherein R is²⁸And R²⁹Represents a hydrogen atom or a methyl group;

phenyl, pyridinyl and pyrimidinyl, optionally substituted with one or more, the same or different substituents selected from the group consisting of:

fluorine, chlorine, bromine, nitro, hydroxy, (C)₁-C₃) Alkyl radicals, (C)₁-C₃) -alkoxy and of the formula-NR³⁰R³¹The group of (a) or (b),

wherein R is³⁰And R³¹Identical or different and represent a hydrogen atom, a methyl group or a methylcarbonyl group;

alternatively, the first and second electrodes may be,

l and R²Together represent a group of the formula,

the invention also relates to compounds of formula (I) and salts thereof:

wherein

R¹Is represented by (C)₆-C₁₀) -aryl, quinolinyl or a group of formula:

wherein a represents 1 or 2, or a salt thereof,

all the above ring systems and radicals may optionally be substituted, if appropriate geminally, by one or more, identical or different substituents selected from the following:

halogen, carboxyl, hydroxyl, (C)₁-C₆) -alkoxy, (C)₁-C₆) -alkoxycarbonyl group, (C)₁-C₈) -alkyl, for which the group may be substituted by halogen or hydroxy;

formula- (CO)_b-NR⁴R⁵The radical(s) is (are),

wherein b represents a number of 0 or 1,

R⁴and R⁵The same or different, independently of each other, represents a hydrogen atom, a phenyl group or (C)₁-C₆) -an alkyl group,

and the formula-NR⁶-SO₂-R⁷The group of (a) or (b),

wherein R is⁶Represents a hydrogen atom, a phenyl group or (C)₁-C₆) -an alkyl group,

R⁷represents phenyl or (C)₁-C₆) -an alkyl group;

d tableRepresents an oxygen atom or the formula-S (O)_C-or-NH-groups,

wherein c represents 0, 1 or 2,

g represents a double bond (C)₁-C₆) -aryl or a two-bonded 5-to 7-membered heteroaromatic ring containing up to 3 heteroatoms selected from S, N and/or O, both aryl and heteroaromatic rings being optionally substituted by one to three, identical or different substituents selected from the group consisting of:

hydroxy, carboxy, halogen, (C)₁-C₆) Alkyl, hydroxy (C)₁-C₆) Alkyl radicals, (C)₁-C₆) -alkoxy, (C)₁-C₆) -an alkoxycarbonyl group, and a group of formula:

-CO-O-(CH₂)_d-NR¹⁰R¹¹、-NR¹²-SO₂R¹³and-CO-NR¹⁴R¹⁵，

Wherein d represents 1, 2, 3 or 4,

R¹⁴and R¹⁵And the above-mentioned R⁴And R⁵Are the same as defined above, and they may be the same or different, or together with the nitrogen atom form a 5-to 6-membered saturated heterocyclic ring which may optionally contain a further heteroatom selected from S and O or a group of formula-NH-,

l represents a group of the formula:

wherein the bonding of the group to G is at the left bond,

and wherein R is¹⁹、R²⁰、R²¹、R²²、R²³And R²⁴Are the same or different and represent a hydrogen atom or (C)₁-C₄) -an alkyl group,

R²represents phenyl optionally substituted by halogen, trifluoromethyl, nitro, amino or (C)₁-C₆) -an alkyl substitution,

R²a group represented by the formula:

or morpholine, or represents perfluoroalkyl containing up to 12 fluorine atoms,

or represents (C)₁-C₁₂) -alkyl or (C)₂-C₁₂) -alkynyl, wherein each group is optionally substituted by halogen, trifluoromethyl, hydroxy, azido or by a group of formula

or-NR²⁸R²⁹，

and/or optionally substituted by phenyl or by a 5-to 6-membered aromatic heterocycle, wherein the aromatic heterocycle contains up to 3 heteroatoms selected from S, N and/or O, the phenyl and aromatic heterocycles are substituted up to 2 times, and the substituents, identically or differently, are halogen, nitro, hydroxy, (C)₁-C₆) -alkanesBase, (C)₁-C₆) Alkoxy and may be of the formula-NR³⁰R³¹Is substituted with a group (b) of (a),

wherein R is³⁰And R³¹The same or different and represent a hydrogen atom, (C)₁-C₆) -alkyl or (C)₁-C₆) -an acyl group,

l and R²Together represent a group of the formula.

Very particularly preferred compounds of the formula (I) according to the invention are the following compounds and their salts:

wherein

R¹Represents optionally substituted by (C)₁-C₆) -alkyl-substituted naphthalen-1-yl, wherein alkyl is substituted by hydroxy, (C)₁-C₆) -amido, amino or (C)₁-C₆) -alkoxy substitution; or by hydroxy (C)₁-C₆) Alkyl-substituted 1, 2-indan-4-yl,

a group represented by the formula:

wherein R is³Is (C)₁-C₆) -an alkyl group,

e and A represent a chemical bond,

d represents an oxygen atom, and D represents an oxygen atom,

g represents 1, 3-phenylene, 1, 4-phenylene or 2, 5-pyridylene, each of which is optionally substituted by halogen,

l represents formula-NH-SO₂-or-O-SO₂-, and

R²is represented by (C)₁-C₆) -alkyl optionally substituted by chloro, trifluoromethyl, of formula-O-CH₂-CF₃The group, phenyl or pyridyl, and phenyl and pyridyl may be substituted with a bromine or chlorine atom.

In particular, the most preferred compounds worth mentioning are the following:

racemates and enantiomers

Racemates and enantiomers

The compounds of the invention may also be present in the form of their salts. In general, mention may be made here of salts with organic or inorganic bases or acids.

In the present invention, physiologically acceptable salts are preferred. Physiologically acceptable salts of the compounds of the invention may be salts of the substances of the invention with mineral acids, carboxylic acids or sulfonic acids. Particularly preferred salts are, for example, those with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Physiologically acceptable salts can also be metal or ammonium salts of the compounds of the invention. For example, sodium, potassium, magnesium or calcium salts are particularly preferred, as well as ammonium salts prepared from ammonia or organic amines, for example ethylamine, di-or triethylamine, di-or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.

The invention also includes ammonium compounds prepared from free amines by alkylation reactions.

In the present invention, the substituents generally have the following meanings:

(C₁-C₁₂) Alkyl generally represents, depending on the substituents mentioned above, a straight-chain or branched hydrocarbon radical having from 1 to 12 carbon atoms. Examples which may be mentioned are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl and isooctyl.

Preferably containing 1 to 8 carbon atoms₁-C₈) Alkyl, for example, preferably nonyl, decyl, undecyl, dodecyl.

(C₂-C₁₂) Alkenyl generally denotes, depending on the substituents mentioned above, a straight-chain or branched hydrocarbon radical having 2 to 6 and 2 to 20 carbon atoms and having one or more and preferably one or two double bonds. Lower alkyl groups containing 2 to 4 and 2 to 10 carbon atoms and one double bond are preferred. Alkenyl groups having 2 to 3 and 2 to 8 carbon atoms and a double bond are particularly preferred. Examples which may be mentioned are allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, isohexenyl, heptenyl, isoheptenyl, octenyl and isooctenyl.

(C₂-C₁₂) Alkynyl generally denotes, depending on the substituents mentioned above, a straight-chain or branched hydrocarbon radical having from 2 to 12 carbon atoms and one or more and preferably one or two triple bonds. Hydrocarbyl groups containing from 2 to about 10 carbon atoms and a triple bond are preferred. Hydrocarbyl groups having 2 to 8 carbon atoms and a triple bond are particularly preferred. Examples which may be mentioned are ethynyl, 2-butynyl, 2-pentynyl and 2-hexynyl.

(C₁-C₆) Acyl generally represents, depending on the substituents mentioned above, a lower alkyl group, straight or branched, containing from 1 to 6 carbon atoms, bonded via a carbonyl group. Alkyl groups containing up to 4 carbon atoms are preferred. For example, alkyl groups containing up to 3 carbon atoms are particularly preferred. Examples which may be mentioned are acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl and isobutylcarbonyl.

(C₁-C₆) Alkoxy in general represents, according to the substituents mentioned aboveA chain or branched, hydrocarbon group containing 1 to 6 carbon atoms bonded through one oxygen atom. Lower alkoxy groups having 1 to 4 carbon atoms are preferred. Alkoxy groups having 1 to 3 carbon atoms are particularly preferred. Examples which may be mentioned are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy, isoheptoxy, octoxy or isooctoxy.

(C₁-C₆) The alkoxycarbonyl group can be represented by, for example, the following formula,

wherein "Alkyl" represents a straight or branched chain hydrocarbon group having 1 to 6 carbon atoms. Lower alkoxycarbonyl groups with alkyl moieties containing 1 to 4 carbon atoms are preferred. Examples which may be mentioned are the following alkoxycarbonyl groups: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.

(C₃-C₈) Cycloalkyl generally denotes a cyclic hydrocarbon radical containing from 3 to 8 carbon atoms. Cyclopropyl, cyclopentyl and cyclohexyl are preferred. Examples which may be mentioned are cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Ring (C)₄-C₇) Acyl generally represents, depending on the substituents mentioned above, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl or cyclohexylcarbonyl.

(C₆-C₁₀) Aryl generally denotes an aromatic radical containing from 6 to 10 carbon atoms. Preferred aromatic groups are phenyl and naphthyl.

(C₁-C₆) Perfluoroalkoxy represents, in the context of the present invention, an alkoxy group having from 1 to 6 carbon atoms and from 3 to 13 fluorine atoms. Alkoxy groups having 1 to 5 carbon atoms and 3 to 9 fluorine atoms are preferred.

(C₁-C₆) Partially fluorinated alkoxy in the context of the present invention means an alkoxy group containing from 1 to 6 carbon atoms and from 3 to 5 fluorine atoms. Alkoxy groups having 1 to 4 carbon atoms and 3 fluorine atoms are preferred. Alkoxy having 1 to 3 carbon atoms and which is substituted by trifluoromethyl is particularly preferred.

Halogen in the present invention denotes fluorine, chlorine, bromine and iodine atoms.

In the context of the present invention, aromatic, saturated and unsaturated heterocycles, depending on the abovementioned substituents, generally denote 5-to 7-membered or 5-to 6-membered, preferably 5-to 6-membered, heterocycles which may contain up to 3 heteroatoms from the group S, N and/or O and which may optionally also be bonded via a nitrogen atom. Examples which may be mentioned are pyridyl, thienyl, furyl, pyrrolyl, pyrrolidinyl, piperazinyl, pyrimidinyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl or piperidinyl. Pyridyl, furyl, morpholinyl, piperidyl and piperazinyl are preferred.

In the context of the present invention, a leaving group is a group which can be displaced by a nucleophile in a nucleophilic displacement reaction (Streittwieser, A., Jr.; Heathcock, C.H. OrganischeChemie, Verlag Chemie, 1980, p.1699 ff). Preferred leaving groups are halogen and sulfonate/anhydride. A particularly preferred leaving group is chloro.

In the present invention, (C)₃-C₆) -ketone means a saturated or unsaturated ketone containing from 3 to 6 carbon atoms. Examples which may be mentioned are acetone, butanone, but-1-en-3-one, but-1-yn-3-one, pent-2-one, pent-1-en-3-one, pent-1-yn-3-one, pent-1, 4-dien-3-one, 3-methylbut-2-one, cyclopropylmethyl ketone, cyclopentanone, hex-2-one, hex-3-one, cyclohexanone, 2-methylcyclopentanone, 2-ethylcyclobutanone.

In the present invention, (C)₁-C₆) Aldehyde represents a saturated or unsaturated aldehyde containing from 1 to 6 carbon atoms. Examples which may be mentioned are formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, isobutyraldehyde, cyclopropylformaldehyde, but-2-enal, but-2-ynal, valeraldehyde, isovaleraldehyde, pivalaldehyde, cyclobutylformaldehyde, 2-methylcyclo-butyraldehydePropylformaldehyde, pent-2-enal, pent-4-enal, hexanal, 2-cyclobutylformaldehyde.

The compounds of the invention may exist in stereoisomeric forms which may or may not be mirror images (enantiomers). The present invention relates to enantiomers and diastereomers and respective mixtures thereof. Mixtures of these enantiomers and diastereomers can be resolved in known manner into stereoisomeric individual components.

A process has also been found for preparing the compounds of the general formula (I) according to the invention, which is characterized in that

[A] A compound of the general formula (II)

R¹-A-D-E-G-M-H (II)

Wherein R is¹A, D, E and G are as defined in claim 1, and

m represents an oxygen atom or-N (R)³²)-，

R³²Is a hydrogen atom or (C)₁-C₄) -an alkyl group,

with compounds of the general formula (III) in an inert solvent, if appropriate in the presence of a base,

R³³-Q-R² (III)

wherein R is²As defined in claim 1, wherein,

R³³represents halogen, preferably chlorine or iodine,

q represents a group-SO₂-、-SO-、-CO-、-P(O)(OR²⁷) -or a single bond,

wherein R is²⁷The definition is as above-mentioned,

to give compounds of the general formula (Ia)

R¹-A-D-E-G-M-Q-R² (Ia)

Wherein R is¹A, D, E, G, M, Q and R²As defined above.

Alternatively, the first and second electrodes may be,

[B] the compound of formula (II) is first reacted with trialkylsilyl chlorosulphonate, preferably trimethylsilyl chlorosulphonate, treated with acid and then reacted with a chlorinating agent, preferably phosphorus pentachloride, to give the compound of formula (IV)

R¹-A-D-E-G-M-SO₂-Cl (IV)

Wherein R is¹A, D, E, G and M are as defined above,

then reacting with a compound of the general formula (V),

H-T-R² (V)

wherein R is²As defined in claim 1, wherein,

and T represents an oxygen atom or a nitrogen atom,

the reaction is carried out in Bzl-NEt in an inert solvent₃ ⁺Cl^-And in the presence of a base, and,

to give compounds of the general formula (Ib)

R¹-A-D-E-G-M-SO₂-T-R² (Ib)

Wherein R is¹A, D, E, G, M, T, and R²As defined above.

Alternatively, the first and second electrodes may be,

[C] a compound of the general formula (VI)

R¹-A-D’-H (VI)

Wherein R is¹And A is as defined above, and,

d' represents an oxygen atom, a sulfur atom or-N (R)⁹) -, and

R⁹definition of sameIn accordance with claim 1, wherein,

with a compound of the general formula (VII),

R³⁴-E-G-SO₂-NH-R² (VII)

wherein E, G and R²Is as defined above, and

R³⁴represents a leaving group, preferably halogen, particularly preferably fluorine, chlorine or bromine,

to give a compound of the formula (Ic)

R¹-A-D′-E-G-SO₂-NH-R² (Ic)

Wherein R is¹A, D', E, G and R²The definition is as above-mentioned,

alternatively, the first and second electrodes may be,

[D] a compound of the formula (Id)

R³⁷-A-D-E-G-L-R² (Id)

Wherein A, D, E, G, L and R²Is as defined above, and

R³⁷represents a group of the formula

Wherein R is⁴¹Is represented by (C)₁-C₆) -an alkyl group,

reaction with a chloroformate, preferably 1- (1-chloro) ethyl chloroformate or methyl chloroformate, and then with an alcohol, preferably methanol, if appropriate in the presence of a base, to give a compound of the formula (Ie)

R³⁸-A-D-E-G-L-R² (Ie)

Wherein A, D, E, G, L andR²is as defined above, and

R³⁸represents a group of the formula

Alternatively, the first and second electrodes may be,

[E] a compound of the formula (Ie)

And (C)₁-C₆) -ketone or (C)₁-C₆) An aldehyde reaction in the presence of a reducing agent, preferably sodium cyanoborohydride, If appropriate in the presence of an acid, to give the compounds of the general formula (If)

R³⁹-A-D-E-G-L-R² (If)

Wherein A, D, E, G, L and R²The definition is as above-mentioned,

and R is³⁹Is represented by (C)₃-C₆) -alkenyl or (C)₁-C₆) -an alkyl group,

alternatively, the first and second electrodes may be,

[F] reacting a compound of formula (Ie) with a compound of formula (VIII),

R³⁵-R³ (VIII)

wherein R is³As defined in claim 1, wherein,

R³⁵represents a leaving group, preferably a halogen,

the reaction is carried out in an inert solvent, if appropriate in the presence of a base, to give the compounds of the general formula (Ig)

R⁴⁰-A-D-E-G-L-R² (Ig)

Wherein A, D, E, G, L and R²The definition is as above-mentioned,

and R is⁴⁰Represents a group of the formula

Wherein R is³The definition is as above-mentioned,

alternatively, the first and second electrodes may be,

[G] a compound of the formula (Ih)

Wherein A, D, E, G, L and R²The definition is as above-mentioned,

by free radical bromination in an inert solvent, e.g. with N-bromosuccinimide, to compounds of formula (Ii)

Wherein A, D, E, G, L and R²The definition is as above-mentioned,

then reacting it with a compound of the general formula (IX) or (X),

CH₂(CO₂R⁴²)₂ (IX)

H₂N-R³ (X)

wherein R is⁴²Is represented by (C)₁-C₆) -an alkyl group,

and R is³The definition is as above-mentioned,

the reaction is carried out in an inert solvent, if appropriate in the presence of a base, to give the compounds of the general formula (Ij)

R⁴³-A-D-E-G-L-R² (Ij)

Wherein A, D, E, G, L and R²The definition is as above-mentioned,

and R is⁴³To represent

Wherein R is⁴²And R³The definition is as above-mentioned,

and, if appropriate, the above-mentioned substituents are introduced and derivatized in accordance with conventional methods,

and if D is-SO-or-SO₂The oxidation is carried out in a conventional manner starting from the corresponding thioether (D ═ S),

in the case of ammonium compounds, the alkylation reaction is carried out starting from the corresponding amine.

The process of the present invention can be illustrated by the following reaction scheme:

suitable solvents are ethers, such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, or hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, trichloroethane or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. Mixtures of the above solvents may also be used. Dichloromethane is preferred.

Suitable bases are generally alkali metal hydrides or alcoholates, e.g. sodium hydride or potassium tert-butoxide, or cyclic amines, e.g. piperidine, pyridine, dimethylaminopyridine, or C₁-C₄Alkylamines, such as triethylamine. Preference is given to triethylamine, sodium hydride, pyridine and/or dimethylaminopyridine.

Suitable bases also include the usual inorganic bases. Preference is given to alkali metal hydroxides or alkaline earth metal hydroxides, for example sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates such as sodium carbonate or potassium carbonate or sodium bicarbonate, or alkali metal alcoholates such as sodium methylate, sodium ethylate, potassium methylate, potassium ethylate or potassium tert-butylate. Potassium carbonate and sodium hydroxide are particularly preferred.

In one variation, the reaction is carried out in pyridine, and a catalytic amount of DMAP is added thereto. If appropriate, toluene can also be added.

The process is generally carried out at atmospheric pressure. However, it is also possible to carry out under elevated pressure or under reduced pressure (for example at 0.5 to 5 bar).

The invention also relates to compounds of the general formula (II)

R¹-A-D-E-G-M-H (II)

Wherein R is¹A, D, E, G and M are as defined above.

Preferred compounds of the formula (II) are the following compounds:

wherein

R¹Represents an optional quilt (C)₁-C₆) Naphthalene-1-yl substituted by alkyl, which is substituted by hydroxy, (1-C)₆) -amido, amino or (C)₁-C₆) -alkoxy substitution; by hydroxy (C)₁-C₆) Alkyl substituted indenesA group of-4-,

a group represented by the formula:

wherein R is³Is (C)₁-C₆) -an alkyl group,

e and A represent a chemical bond,

d represents an oxygen atom, and D represents an oxygen atom,

l represents formula-NH-SO₂-or-O-SO₂-, and

R²is represented by (C)₁-C₆) -alkyl optionally substituted by chloro, trifluoromethyl, of formula-O-CH₂-CF₃The group, phenyl or pyridyl, and phenyl and pyridyl may be substituted by a bromine or chlorine atom,

and M represents an oxygen atom or-N (R)³²)-，

Wherein R is³²Is a hydrogen atom or (C)₁-C₄) -an alkyl group.

For example, the compound of formula (II) can be prepared by the following method:

[A] a compound of the general formula (VI)

R¹-A-D′-H (VI)

Wherein R is¹A and D' are as defined in claim 7,

with a compound of the formula (XI) in an inert solvent, if appropriate in the presence of a base,

R⁴⁴E-G-NO₂ (XI)

wherein E and G are as defined in claim 1,

and R is⁴⁴Is a leaving group, preferably a halogen,

then, it is reacted with a conventional reducing agent, preferably H₂Reaction of/Pd/C in an inert solvent or with hydrazine hydrate and Pd/C, if appropriate with simultaneous hydrogenation of the (C-C) multiple bond, to give compounds of the formula (IIa)

R¹-A-D′-E-G-NH₂ (IIa)

Wherein R is¹A, D', E and G are as defined above,

alternatively, the first and second electrodes may be,

[B] a compound of the formula (IIb)

R¹-A-D-E-G-NH₂ (IIb)

Wherein R is¹A, D, E and G are as defined in claim 1, with a nitrosating reagent, preferably an aqueous solution of sulfuric acid and sodium nitrite, and subsequently heated, preferably to 60 to 100 ℃, to give a compound of formula (IIc)

R¹-A-D-E-G-OH (IIc)

Wherein R is¹A, D, E and G are as defined above,

alternatively, the first and second electrodes may be,

[C] a compound of the formula (XII)

R¹-R³⁶ (XII)

Wherein R is¹The definition is as above-mentioned,

and R is³⁶As leaving group, preferably halogen, particularly preferably bromine atom,

with compounds of the general formula (XIII)

HO-G-O-R⁴⁵ (XIII)

Wherein G is as defined above, and wherein,

R⁴⁵is represented by (C)₁-C₆) The alkyl group, preferably the methyl group,

the reaction is carried out in an inert solvent, preferably dimethylformamide or pyridine, if appropriate in the presence of a base, preferably potassium carbonate, and if appropriate in the presence of a copper (I/II) salt, preferably copper (II) oxide or copper (I) iodide, at a temperature of from 0 to 200 ℃, preferably from 80 to 150 ℃ and under normal pressure, to give the compounds of the formula (Ik)

R¹-O-G-O-R⁴⁵ (Ik)

Wherein R is¹G and R⁴⁵The definition is as above-mentioned,

and then reacted in the presence of an acid, preferably hydrobromic acid, to give a compound of formula (IId)

R¹-O-G-OH (IId)

Alternatively, the first and second electrodes may be,

[D] a compound of the general formula (VI)

R¹-A-D′-H (VI)

Wherein R is¹A and D' are as defined in claim 7,

with a compound of the general formula (XIV),

R⁴⁶-E-G′-R⁴⁷ (XIV)

wherein R is⁴⁶And R³⁶Are as defined, they may be the same or different,

e is defined as above-mentioned in the specification,

g' represents a two-bonded 5-to 7-membered aromatic heterocyclic ring containing up to 3 heteroatoms selected from sulfur, nitrogen and/or oxygen atoms, which may optionally be substituted by one or more, identical or different substituents as defined for G in claim 1,

and R is⁴⁷Represents a halogen, preferably a chlorine or bromine atom,

to give a compound of the formula (XV)

R¹-A-D′-E-G′-R⁴⁷ (XV)

Wherein R is¹A, D ', E, G' and R⁴⁷The definition is as above-mentioned,

the reaction is carried out in an inert solvent, if appropriate in the presence of a base, and is then converted with potassium amide in liquid ammonia into the corresponding free amine of the formula (IIe)

R¹-A-D′-E-G′-NH₂ (IIe)

Wherein R is¹A, D ', E and G' are as defined above.

DOS (German patent publication) 1942264 describes the preparation of fluoroalkylsulfonyl chlorides, and US5149357 describes in particular the preparation of 4, 4, 4-trifluorobutanesulfonamide, but does not disclose the preparation of the corresponding sulfonyl chloride.

This fluorosulfonyl chloride is prepared analogously to DOS (Germany) 1942264.

The invention likewise relates to compounds of the general formula (XV)

R⁴⁸-SO₂-(CH₂)_h-U-(CH₂)_i-CR⁴⁹R⁵⁰-CF₂-R⁵¹ (XV)

Wherein R is⁴⁸Is a leaving group which is a substituent of the group,

u is an oxygen atom or a single bond,

R⁴⁹and R⁵⁰Identical or different and denotes H, F, Cl or trifluoromethyl,

R⁵¹is H, F, Cl or Br, and is,

h is 1 or 2, and the compound is,

and i is either 0 or 1, and,

the following compounds are excluded:

u is a single bond, and U is a single bond,

R⁴⁹and R⁵⁰Are identical and represent H or F,

and R is⁵¹The expression "F" is used to indicate that,

the following compounds are also excluded:

u is an oxygen atom, and U is an oxygen atom,

R⁴⁹and R⁵⁰Represents a compound represented by the formula (I) Cl,

and i represents 0.

The invention also relates to compounds of the general formulae (XVI) and (XVII)

R⁴⁸-SO₂-CH₂-CH₂-CH₂-CF₃ (XVI)

Or

R⁴⁸-SO₂-CH₂-CH₂-CH₂-CF₂-CF₃ (XVII)

Wherein R is⁴⁸Is a leaving group.

R⁴⁸Compounds which are chlorine atoms are preferred.

Suitable bases are generally alkali metal hydrides or alcoholates, e.g. sodium hydride or potassium tert-butoxide, or cyclic amines, e.g. piperidine, pyridine, dimethylaminopyridine, or C₁-C₄Alkylamines, such as triethylamine. Sodium hydride, pyridine and/or dimethylaminopyridine are preferred.

The base is used in an amount of 1 to 20 equivalents, preferably 2 to 10 equivalents, in each case based on 1 equivalent of the compounds of the formulae (X) and (XII).

The process is generally carried out at a temperature of from 0 to 200 ℃ and preferably from room temperature to 140 ℃.

The compounds of the formulae (III), (V), (VIII), (IX), (X) and (XII) are known to the person skilled in the art or can be prepared by customary methods.

The alkylation reaction to prepare the ammonium compounds is generally carried out with alkylating agents such as alkyl halides, sulfonates or substituted or unsubstituted dialkyl or diaryl sulfates, preferably using methyl iodide or dimethyl sulfate.

The alkylation reaction is generally carried out in one of the above-mentioned solvents, preferably dimethylformamide, at a temperature of from 0 to 70 ℃, preferably from 0 to 30 ℃ and under normal pressure.

Surprisingly, these novel arylsulfonamides and analogs thereof exhibit unpredictable, useful pharmacological effects.

They are remarkably potent agonists of the CB1 receptor and in some cases also of the CB2 receptor. They can be used alone or in combination with other agents for the treatment and/or prevention of neuronal damage caused by a variety of causes, for example, as follows: ischemia, thrombosis and/or thromboembolism and hemorrhagic stroke, as well as symptoms following direct or indirect damage to the brain or cranial area, can also be used to treat and/or prevent cerebral ischemia following surgery on the brain or peripheral organs or body parts, and associated or pre-emergent pathological conditions or allergies that can lead to primary or secondary neuronal damage. Likewise, the compounds of the invention are also suitable for the treatment of primary or secondary pathological conditions of the brain, such as hypoxia or anoxia, perinatal asphyxia, autoimmune diseases, metabolic and organic disorders which can accompany brain injury and which also damage the brain to cause primary brain disorders, such as convulsions and atherosclerosis and/or arteriosclerosis, for the treatment of chronic or psychiatric disorders, for example depression, neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease or Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, neurodegenerative reactions caused by acute and/or chronic viral or bacterial infections, and multiple infarct dementia.

In addition, they can be used in medicaments for the treatment of pain, emesis, nausea, glaucoma, asthma, anorexia, spasticity, rheumatism, sedation and movement disorders.

The substances according to the invention are also suitable for the treatment of diseases caused by bacterial and/or viral infections, which are based on direct and/or indirect changes in the immune system or on immunoregulatory disorders in which the immune system is involved, such as, for example, local or systemic autoimmune diseases (e.g. all variants of lupus erythematosus), inflammatory and/or autoimmune-related joint diseases (e.g. primary chronic polyarthritis, inflammation associated with trauma), inflammatory and/or autoimmune-related bone and muscle diseases, inflammatory and/or autoimmune-related pathological processes of the internal organs (e.g. Crohn's disease, glomerulonephritis), pathological processes of the external organs (e.g. allergic reactions due to the inhalation of antigens in the air), pathological processes of the central nervous system (e.g. multiple sclerosis, Alzheimer's disease, inflammatory disorders of the immune system (e.g. inflammatory disorders of the immune, Psychosis), and pathological processes of primary and/or secondary and/or autoimmune diseases of the sensory organs, hematopoietic system, and pathological processes of the immune system itself (such as rejection, AIDS), as well as inflammatory and/or immunological skin diseases of humans or animals. These substances also act on the secondary symptoms of these diseases, such as pain.

Their use for the treatment of cerebral ischemia and craniocerebral trauma is preferred.

CB 1-luciferase receptor Gene assay

1. Cloning of the murine cannabinoid receptor CB1

All RNA was isolated from murine brain (this tissue was taken from freshly sacrificed animals and shock-frozen in liquid nitrogen) by extraction with acidic guanidine thiocyanate/phenol/chloroform (j.biol. chem.1979, 18, 5294) and converted to cDNA by reverse transcriptase and random primers (all from Invitrogen). Polymerase chain reaction (PCR, conditions: 4 minutes at 94 ℃, 1 ×; 1 minute at 94 ℃, 2 minutes at 53 ℃, 1 minute at 72 ℃, 50 cycles; 1 minute at 94 ℃, 2 minutes at 53 ℃, 4 minutes at 72 ℃, 1 ×) was performed with Taq polymerase (Perkin Elmer) in a Perkin Elmer thermal cycler; the oligonucleotide primers used (bases 99 to 122: 5 ' → 3 ', "Down '; 1556-. A portion of the PCR reaction was separated on a 1% strength agarose gel in 1 XTBE buffer and then stained with ethidium bromide, with only one band having the expected visible length (about 1.5 kb). This PCR product was subcloned into a TA cloning vector (Invitrogen) and the nucleotide sequence of the insert was determined by dideoxynucleotide termination reaction with T7DNA polymerase (Aequoransw, USA/Amersham). This insert was 1477 base pairs in length and contained an open reading frame of 1419 base pairs corresponding to a protein of 473 amino acids. The number of base pairs, the position of the open reading frame and the number of amino acids correspond to the published sequence. Computer analysis was performed with the aid of the GCG software package (Genetic Computer Group). After partial digestion with HindIII and NotI (Biolabs), the cDNA insert was subcloned into the expression vector pRc/CMV (Invitrogen). This construct (plasmid CMV-RH) was used for transfection experiments.

2.CHOluc₉Stable transfection of recipient cells

Adding CHOluc₉The cells were cultured in 50% Dulbecco's modified Eagle's Medium/50% F-12(DMEM/F12) containing 10% Fetal Calf Serum (FCS). Transfection was performed in 6-well plates. CMV-RH plasmid DNA was purified using the DOTAP transfection system according to the protocol given by the manufacturer (Boehringer Mannheim) by adding 7.5. mu.l Qiagen per 105 cells. Transfected cells were picked with 1mg/ml G418 and individual clones were obtained by limiting dilution in 96-well plates. Cell lines expressing cannabinoid receptors were identified by inhibition of receptor gene expression following incubation with cannabinoid receptor agonist WIN-55212-2 in the presence of forskolin. Several stably transfected and subcloned cell lines were further defined by RT-PCR as described under item 1.

Experimental optimization and pharmacological characterization of the CHOCB1 receptor cell line

The luciferase assay was optimized by varying several assay parameters, such as cell density, growth phase and assay incubation time, forskolin concentration, media composition, with high sensitivity and reproducibility, low denaturation and high suitability for automated systems. The following experiments were used for pharmacological characterization of cells and computer-assisted substance screening: stock cultures were grown in 50% Dulbecco's modified Eagle Medium/50% E-12(DMEM/F12) with 10% FCS at 37 ℃ under 10% carbon dioxide, and split 1: 10 in each case after 2 to 3 days. Experimental cultures were seeded at 5000 cells per well in 96-well plates and incubated at 37 ℃ for 70 hours. Then, the culture was carefully washed with phosphate buffered saline and reconstituted with serum free Ultra-CHO medium (Bio-Whittaker). This material dissolved in DMSO was diluted 1 x in culture medium and added to the experimental culture (final DMSO concentration in this experimental batch was 0.5%). After 20 minutes, forskolin was added, and the culture was then incubated in an incubator at 37 ℃ for 3 hours. Then, the supernatant was removed and the cells were lysed by adding 25. mu.l of lysis reagent (25mM triphosphate, pH7.8, 2mM DTT, 10% glycerol, 3% Triton X100). Thereafter, a luciferase substrate solution (2.5mM ATP, 0.5mM fluorescein, 0.1mM coenzyme A, 10mM wheat brass, 1.35mM magnesium sulfate, 15mM DTT, pH7.8) was directly added, and the mixture was briefly shaken and the luciferase activity was detected using a Hamamatsu photographic system.

To inactivate G_iProtein, the experimental cultures were treated with 5mg/ml (final concentration) of brevitoxin for 16 hours prior to the experiment.

Using GraphPadprism^TMProgram (Hill equation, specially for: one-point competition) for computing IC₅₀The value is obtained.

Activity in the murine CB1 receptor luciferase Gene assay

Examples	IC(nmol/l)
Examples	IC(nmol/l)	1	15
33	10	1	15
33	10	51	0.9
65	13	51	0.9
65	13	99	2.9

hCB 2-luciferase receptor gene assay

Stable transfection of CHOluc with human CB2 receptor₉A cell. Transfection, clone selection and experiments were performed in analogy to the study of the murine CB1 receptor. The following protocol was used for the pharmacological characterization of these cells and the test substances.

Stock cultures were grown in 50% Dulbecco's modified Eagle Medium/50% E-12(DMEM/F12) with 10% FCS at 37 ℃ under 10% carbon dioxide, and split 1: 10 in each case after 2 to 3 days. The experimental cultures were seeded at 5000 cells per well in 96-well plates with DMEM/F12 medium and incubated for 70 hours at 37 ℃. This medium was then removed from the culture and replaced with serum-free Ultra-CHO medium (Bio-Whittaker). This material (200 × final concentration) dissolved in DMSO was added to the experimental culture (final concentration of DMSO in this experimental batch was 0.5%), after 20 minutes forskolin was added. This culture was then incubated at 37 ℃ for 3.5 hours in an incubator. Then, the supernatant was removed and the cells were lysed by adding 25. mu.l of lysis reagent (25mM triphosphate, pH7.8, 2mM DTT, 10% glycerol, 3% Triton X100). Thereafter, 50. mu.l of a luciferase substrate solution (5mM ATP, 1mM fluorescein, 0.2mM coenzyme A, 10mM wheat brass, 1.35mM magnesium sulfate, 15mM DTT, pH7.8) was directly added, the mixture was briefly shaken, and the luciferase activity was detected with a photomultiplier tube photographic detection system (Hamamatsu).

Using GraphPad Prism^TMProgram (Hill equation, specially for: one-point competition) for computing IC₅₀The value is obtained.

Binding studies of murine cortical membranes

Membrane proteins are prepared from different tissues or cells by standard methods. Buffer, labeled ligand, DMSO or test substance were added together, then 100 μ g protein was added, and the mixture was mixed well and incubated in a water bath at 30 ℃ for 60 minutes. After the incubation period, the reaction was stopped by adding ice-cold buffer to each tube. After filtration, the cells were washed with 3/4ml incubation buffer. The filters were transferred to vials and radioactivity was measured in a scintillation counter.

Affinity for the CB1 receptor (murine plasma membrane)

Examples	K(nmol/l)
Examples	K(nmol/l)	1	590
33	420	1	590
33	420	51	41
65	250	51	41

Inhibition of glutamate Release

After decapitation of the rat, the skull was opened, and the brain was isolated and cut along the median suture. The hippocampus was exposed, separated from other tissues, and 350 μm thick sections were prepared and incubated in a stainer at 37 ℃ for 60 minutes. After determining the basal value and stimulation 1 value with 75mM KCl (S1), the sections were incubated with the test compound and then stimulated with KCl and test compound (S2). The glutamate concentration of the samples studied was then determined by enzymatic action (GLDH) and fluorescence detection of NADH. The glutamic acid content of the sample was determined using the calibration curve, and the glutamic acid content per mg protein was calculated from the protein content. Comparing the S2/S1 ratios; glutamate release inhibitors reduce this ratio in a concentration dependent manner.

Temperature reduction

1. Agitation test

Administration of the test substance (i.v.) was performed 5 minutes after the basal temperature was determined with an esophageal thermometer. The control group received only the solvent for the test substance, again i.v.. Body temperature was measured 7.5, 15, 30 and 60 minutes after i.v. administration. Each dose group included 5-7 animals (mice).

Rat cooling-agitation experiment

Examples	ED[mg/kg]
Examples	ED[mg/kg]	1	1.0
33	0.6	1	1.0
33	0.6	51	0.1
65	1.0	51	0.1
65	1.0	99	0.6

a) Effective dose for reducing body temperature of 1 DEG C

b) The use of the specific CB1 antagonist SR141716A significantly reduced hypothermia (see methods for antagonism experiment)

2. Antagonism experiment

The specific CB1 antagonist SR141716A was administered intraperitoneally 60 minutes before the test substance and the control group was given solvent only (Solutol/0.9% NaCl). Basal body temperature was measured with an esophageal thermometer 5 minutes before using SR141716A 5. Other methods correspond to "agonistic testing" methods. Each dose group included 5-7 animals (mice).

Permanent focal cerebral ischemia (MCA-O) in mice

Under isoflurane anesthesia, one end of the middle cerebral artery is exposed and the other end and its branches are irreversibly sealed by electrocoagulation. As a result, cerebral infarction occurs. During surgery, the body temperature of the animals was maintained at 37 ℃. After the wound was closed and the anesthetic effect disappeared, the animals were again placed in cages. The administration of the test substances is carried out after the wound has been closed according to different time schedules and by different administration routes (intravenous, intraperitoneal). The size of the infarct was determined 7 days later. For this purpose, the brain is removed, processed histologically and the infarct volume is determined with the aid of a computer-aided analysis system.

Activity in model of permanent focal cerebral ischemia (MCA-O)

Examples	Reduction in infarct volume%	Dosage form
Examples	Reduction in infarct volume%	Dosage form	1	35	0.03mg/kg/h
33	33	0.1mg/kg	1	35	0.03mg/kg/h
33	33	0.1mg/kg	51	24	0.1mg/kg
65	37(47)	0.03mg/kg/h (0.01mg/kg/h)	51	24	0.1mg/kg

a) In each case, the substances to be tested are applied directly in the form of an intravenous bolus injection 2 to 4 hours after wound closure

b) Administering the substance directly as an intravenous continuous infusion within not more than 4 hours after wound closure

Subdural hematoma of mouse (SDH)

Under anesthesia, the animal's own blood was injected to one side of the dura mater. Infarction develops under this hematoma. According to different time schedules and by different routes of administration (intravenous, intraperitoneal). Infarct size was determined as used in the murine model of permanent focal ischemia (MCA-O).

Activity in the model of murine subdural hematoma (SDH)

Examples	Reduction in infarct volume%	Dosage form
Examples	Reduction in infarct volume%	Dosage form	1	54(84)	0.1mg/kg (1.0mg/kg
33	42	0.1mg/kg	1	54(84)	0.1mg/kg (1.0mg/kg
33	42	0.1mg/kg	51	54	0.01mg/kg/h
65	53(65)	0.1mg/kg (0.3mg/kg/h )	51	54	0.01mg/kg/h

The novel active compounds can be converted in a known manner into the customary formulations, such as tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, nontoxic, pharmaceutically suitable excipients or solvents. In this case, the therapeutically active compound should be present in a concentration of about 0.5 to 90% by weight of the total mixture in each case, i.e. in an amount sufficient to achieve the dosage range indicated.

For example, these formulations are prepared by expanding the active compound with solvents and/or excipients, if appropriate with emulsifiers and/or dispersants, for example, if water is used as diluent, optionally with organic solvents as auxiliary solvents.

Administration is carried out in a conventional manner, preferably orally, transdermally or parenterally (especially sublingually or intravenously).

When administered intravenously, it is generally advantageous to administer about 0.01 to 10mg/kg, preferably about 0.1 to 10mg/kg, of body weight, in order to achieve effective results.

Nevertheless, amounts other than those described above may be required if appropriate, i.e., depending on body weight or route of administration, on individual response to the drug, manner of formulation, and time or period of administration. Thus, in some cases it may be appropriate to use less than the minimum dosage mentioned above, while in other cases the upper limit mentioned above must be exceeded. In the case of larger quantities, it is advisable to divide them into several single doses during the course of the day.

Abbreviations used

Me methyl group

Et Ethyl group

NPr n-propyl group

NBu n-butyl

NPent n-amyl

NHex n-hexyl

Noct n-octyl

PE Petroleum Ether

Tol toluene

EA Ethyl acetate

Et₂O Ether

Solvent(s)

I PE∶Et₂O 10∶1

II PE∶Et₂O 5∶1

II PE to dichloromethane 5: 1

IV Tol∶EA 10∶1

V cyclohexane to dichloromethane 5: 1

VI Tol∶EA 5∶1

VII Tol∶EA 1∶1

VIII Tol∶EA 5∶3

IX PE: dichloromethane 1: 1

X Tol∶EA 20∶1

XI PE∶EA 5∶1

XII Tol∶EA 8∶1

XIII EA acetone 20: 1

XIV PE∶EA 10∶1

XV dichloromethane: formic acid 40: 1

XVI Tol∶EA 3∶1

XVII dichloromethane: Et₂O 10∶1

XVIII Tol∶EA 1∶2

XIX EA acetone 20: 3

XXEA acetone 10: 1

XXI Dichloromethane formic acid 10: 1

XXII Tol: EA: formic acid 10: 1: 0.05

XXIII dichloromethane, methanol and concentrated ammonia water 10: 1: 0.5

XXIV dichloromethane ethanol 20: 1

XXV dichloromethane methanol 10: 1

XXVI Dichloromethane methanol 5: 1

XXVII Tol∶EA 2∶1

XXVIII Hexane: EA 4: 1

XXIX Tol∶EA 15∶1

XXX toluene

XXXI toluene EA 30: 1

XXXII dichloromethane methanol 19: 1

XXXIII dichloromethane methanol 9: 1

XXXIV dichloromethane methanol 4: 1

XXXV Ethyl acetate

XXXVI cyclohexane Ethyl acetate 3: 1

XXXVII cyclohexane, Ethyl acetate methanol 10: 2: 1

XXXVIII n-hexane: ethyl acetate 2: 1

XXXIX dichloromethane methanol 3: 1

XL ethyl acetate/methanol 4: 1

XLI Dichloromethane 95: 5 methanol

XLII EA isooctane 1: 1

XLIII EA cyclohexane 8: 2

XLIV EA cyclohexane 3: 7

XLV dichloromethane methanol triethylamine 9: 1: 0.1

XLVI methylene chloride methanol 98: 2

Mass spectrometry method

A EI

B DCI，NH₃

C ESI

D FAB

E DCI, isobutane

Starting compounds

Example 1A

1- (naphthyl-1-oxy) -4-nitrobenzene

A solution of 1-naphthol (102g, 0.709mol) in DMF (800ml) was treated with potassium carbonate (97.9g, 0.709mol) and stirred at room temperature for 2 h. After dropwise addition of a solution of 4-fluoro-1-nitrobenzene (100g, 0.709mol) in DMF (200ml), the reaction mixture was stirred at room temperature overnight. The solvent was then distilled off in vacuo and the residue was treated with ethyl acetate (600 ml). After filtration, most of the solvent was evaporated in vacuo. The precipitated product is filtered off, washed with a small amount of ethyl acetate and dried in vacuo. 107g of product are obtained.

25g of product were also obtained by further evaporation of the mother liquor.

The total yield is as follows: 132g (69% of theory).

M.p.：143℃

MS(EI)：m/e 265(M)

The compounds prepared in analogy to example 1A are shown in Table I.

a) Starting materials:

b) reaction at 140 deg.C

c) The starting material is 1-naphthylthiophenol

d) Reaction of 1-aminonaphthalene and 4-fluoro-1-nitrobenzene was carried out analogously to J.chem.Soc.Perkin Trans I, 1988, 1331

e) Starting materials:

f) the starting material was 1-hydroxy-6-methoxycarbonylnaphthalene, prepared according to j.chem.soc.1923, 123, 1649 and subsequently esterified.

Example 25A

1- (naphthyl-1-methoxy) -4-nitrobenzene

A solution of 4-nitrophenol (15.7g, 113mol) in DMF (300ml) was treated with potassium carbonate (30.8g, 223mol) and stirred at room temperature for 1 hour. After addition of 1-naphthyl-methyl bromide (25.0g, 113mol), the reaction mixture was stirred at 50 ℃ overnight. The solvent was distilled off in vacuo and the residue was recovered with ethyl acetate (600ml) and water (250 ml). After filtration, the phases were separated and the aqueous phase was extracted with ethyl acetate (3X 300 ml). The combined organic phases were washed with water (200ml), dried over magnesium sulphate and highly concentrated in vacuo. The crude precipitate is filtered off with suction, stirred in ethyl acetate/petroleum ether, filtered off with suction again and dried. The product was purified by recrystallization from dichloromethane/methanol.

Yield: 15.7g (50% of theory)

M.p.：145-146℃

MS(DCI，NH₃)：m/e＝297(M+NH₄)

R_f＝0.83(IV)

The examples shown in Table II were prepared in analogy to example 25A:

examples 1A-29A reduction of the Nitro groups

Method A

Example 29A

1-amino-4- (2, 3-dimethylphenyl-1-oxy) benzene

A suspension of example 5A (13.5g, 55.6mmol) and 10% palladium on activated carbon (1.45g) in methanol (132ml) was heated to reflux under argon. After dropwise addition of hydrazine hydrate (5.4ml, 111mmol), the mixture is stirred under reflux for a further 2 hours. The reaction mixture was filtered through celite, washed with methanol, and then concentrated in vacuo. The residue is chromatographed on silica gel, eluting with toluene: ethyl acetate (10: 1).

Yield: 0.33(IV)

MS(DCI，NH₃)：m/e＝231(M+NH₄)

Method B

Example 30A

N-butyl 5- (4-aminophenyl-1-oxy) naphthalene-1-carboxylate

A solution of example 8A (10.96g, 30.0mmol) in THF (100ml) was treated with 10% palladium on activated carbon (0.25g) and hydrogenated at normal pressure for 5 h. The reaction mixture was filtered through silica gel, washed with THF and concentrated in vacuo. The residue was stirred in ether, filtered and dried in vacuo.

Yield: 8.38g (83% of theory)

M.p.：104-105℃

R_f＝0.31(IV)

MS(ESI)：m/e＝336(M+H)

Method C

Example 31A

1-amino-4- (5, 8-dihydro-naphthyl-1-oxy) benzene

A solution of 15% titanium (III) chloride in 10% hydrochloric acid (212ml, 243mmol) was added dropwise to a solution of the compound from example 7A (10.7g, 40.0mmol) in glacial acetic acid (380ml) and water (80ml) and the mixture was stirred overnight. The solvent was evaporated in vacuo and the residue was recovered in ethyl acetate/water. The pH was adjusted to 9-10 by addition of 3N sodium hydroxide solution, the phases were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed 2 times with water, dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel, eluting with toluene/ethyl acetate (20: 1).

Yield: 2.1g (22% of theory)

R_f＝0.25(X)

MS(DCI，NH₃)：m/e＝238(M+H)

The examples shown in Table III were prepared analogously to examples 29A-31A:

example 56A

4- (naphthyl-1-oxy) phenol

Adding NaNO at 0 deg.C₂A solution of (7.6g, 110mmol) in water (45ml) was added dropwise to a suspension of compound 51A (25.8g, 110mmol) in 50% strength sulfuric acid (400ml) and stirred for 10 min. The reaction mixture was then heated at 100 ℃ for 2.5 h, cooled and extracted with dichloromethane (3X 150 ml). The combined organic phases were washed with water (1 × 100ml), dried (sodium sulphate) and concentrated in vacuo. The residue is chromatographed on silica gel eluting with dichloromethane.

Yield: 6.1g (24% of theory)

R_f＝0.39(IV)

MS(DCI，NH₃)：m/e＝237(M+H)

Example 57A

3-methyl-4- (naphthyl-1-oxy) phenol

Preparation was carried out in analogy to the preparation of example 56A, starting from example 39A (5.0 g; 20 mmol).

Yield: 2.1g (42% of theory)

R_f＝0.36(IV)

MS(DCI，NH₃)：251(M+H)

Example 58A

[4- (naphthyl-1-oxy) phenyl ] sulfamic acid

Triethylamine (6.44g, 63.8mmol) was added dropwise to a cyclohexane solution of trimethylchlorosilane (6.93g, 63.8mmol) under argon atmosphere at 5 ℃ and the mixture was stirred under ice cooling for 1 hour. The compound from example 51A (15.0g, 63.8mmol) was dissolved in cyclohexane (350ml) with heating and the solution was added dropwise to a solution of trimethylchlorosilane/triethylamine at 5 ℃. The reaction mixture was stirred at room temperature overnight and the precipitated triethylammonium chloride was filtered off. Washed with cyclohexane and the filtrate was concentrated in vacuo. The residue was recovered in dichloromethane (120ml) and trimethylsilyl chlorosulfonate (12.0g, 63.8mmol) was added dropwise at-15 ℃ over 40 minutes under argon. The reaction mixture was stirred at-15 ℃ overnight, then filtered under argon, treated dropwise with trifluoroacetic acid (7.3g, 63.8mmol) at-15 ℃ and stirred at-15 ℃ for a further 3 h. The precipitated product is filtered off, washed with dichloromethane and dried in vacuo.

Yield: 5.6g (28% of theory)

M.p.：220℃

MS(FAB)：m/e＝316(M+H)

Example 59A

4-amino-2- (naphthyl-2-oxy) -pyridines

A suspension of 4-amino-2-chloropyridine (4.20g, 32.7mmol), 1-naphthol (7.06g, 49.0mmol) and potassium carbonate (6.77g, 49.0mmol) in pyridine (50ml) was heated to reflux and treated with copper (II) oxide (5.8g, 73.5mmol) and the mixture was refluxed for a further 18 hours.

Then, pyridine was distilled off in vacuo, the residue was recovered in dichloromethane (100ml) and the mixture was filtered through celite. The filtrate was washed with water and the aqueous phase was extracted twice with dichloromethane. The combined dichloromethane phases were dried (sodium sulfate) and concentrated in vacuo. The residue is chromatographed on silica gel, eluting with toluene: ethyl acetate (10: 1).

Yield: 4.63g (60% of theory)

M.p.：156℃

R_f＝0.12(VI)

MS(DCI，NH₃)：m/e＝237(M+H)

Example 60A

6-amino-2- (naphthyl-1-oxy) -pyridines

6-amino-2-chloropyridine (6.60g, 51.3mmol) and 1-naphthol (11.1g, 77.0mmol) were reacted by a similar method to example 59.

Yield: 4.04g (33% of theory)

R_f＝0.59(IV)

MS(ESI)：m/e＝237(M+H)

Examples 61A and 62A

4-amino-2-chloro-6- (naphthyl-1-oxy) pyridine (example 61A)

4-amino-2, 6- [ bis (naphthyl) -1-oxy ] pyridine (example 62A)

4-amino-2, 6-dichloropyridine (4.96g, 30.4mmol) and 1-naphthol (6.58g, 45.6mmol) were reacted in a similar manner to example 59A.

Yield: (example 61A): 0.14g (1.8% of theory)

M.p.：174℃

R_f＝0.37(IV)

MS(DCI/NH₃)：m/e＝271(M+H)

Yield: (example 62A): 3.59g (44% of theory)

M.p.：169℃

R_f＝0.48(IV)

MS(DCI/NH₃)：m/e＝379(M+H)

Example 63A

3- (naphthyl-1-oxy) phenol

Preparation was carried out in analogy to the preparation of example 56A, starting from the product of example 45A (9.40 g; 40.0 mmol).

Yield: 3.08g (33% of theory)

R_fNot 0.41 (dichloromethane)

MS(DCI/NH₃)：m/e＝237(M+H)

Example 64A

3-bromo-5- (naphthyl-1-oxy) pyridine

Initially, 3, 5-dibromopyridine (24.9g, 105mmol), 1-naphthol (15.1g, 105mmol) and potassium carbonate (21.8g, 158mmol) were introduced into pyridine (200ml) under an argon atmosphere. The reaction mixture was heated to reflux, treated with copper (II) oxide (0.8g, 10mmol) after 15 minutes and then heated to reflux for a further 10 hours.

After cooling to room temperature, the reaction mixture was filtered and the residue was washed with dichloromethane. The filtrate was concentrated in vacuo. The residue is recovered in dichloromethane and the dichloromethane solution is washed with water immediately after filtration. The aqueous phase was extracted with dichloromethane and the combined dichloromethane phases were dried (magnesium sulfate) and concentrated in vacuo. The residue is chromatographed on silica gel, eluting with toluene: ethyl acetate (10: 1). The product obtained is recrystallized from diethyl ether/petroleum ether.

Yield: 2.9g (10% of theory)

M.p.：59-61℃

R_f＝0.54(IV)

MS(DCI/NH₃)：m/e＝300，302(M+H)

Example 65

3-amino-5- (naphthyl-1-oxy) pyridine

A solution of the product from example 64A (1.98g, 6.6mmol) in THF (15ml) was added dropwise to potassium amide [26.4mmol, prepared from potassium (1.03g) and catalytic amounts of ferric chloride in liquid ammonia (50ml) ] at-33 ℃.

After 10 minutes, ammonium chloride (2.0g) was added and the ammonia gas was allowed to evaporate. The residue was treated with concentrated aqueous ammonium chloride (25ml) and water (25ml) and extracted with dichloromethane (5X 25 ml). The combined organic phases were washed with water (1X 25ml), dried and concentrated in vacuo.

Yield: 1.40g (90% of theory)

M.p.：91-92℃

R_f＝0.22(VII)

MS(ESI)：m/e＝237(M+H)

The compounds shown in table IV were prepared in analogy to example 1A:

example 81A

4-fluoro-2-nitrobenzoic acid methyl ester

Sulfinyl chloride (31.5ml, 0.432mol) was slowly added dropwise to a solution of 4-fluoro-2-nitrobenzoic acid (16.0g, 86.4mmol) in methanol (240ml) at 0 ℃. After warming to room temperature, stirring overnight and boiling under reflux for 4 hours, the reaction solution was concentrated in vacuo and partitioned between ethyl acetate and potassium bicarbonate solution. The organic phase was dried and concentrated to give a yellow oil.

Yield: 15.7g (85% of theory)

R_f＝0.53(XXIX)

MS(EI)：m/e＝199(M)

The compounds shown in table V were prepared in analogy to the methods of examples 29A (method a) and 30A (method B):

example 97A

4- (2-ethoxycarbonyl-1, 2-indanyl-4-oxy) -1-nitrobenzene

Prepared in analogy to example 1A, starting from 4-fluoro-1-nitrobenzene (3.76g, 26.7mmol) and ethyl 4-hydroxy-1, 2-indane-2-carboxylate (5.50g, 26.7 mmol; EP 425946).

Yield: 0.7g (7.5% of theory)

R_f＝0.37(X)

MS(DCI，NH₃)：m/e＝345(M+NH₄)

Example 98A

4- (2-ethoxycarbonyl-1, 2-indan-4-yloxy) -phenylamine

Preparation was carried out in analogy to the preparation of example 30A, starting from the product of example 97 (0.70 g; 2.14 mmol).

Yield: 0.616g (94% of theory)

R_f＝0.12(XXXI)

MS(DCI，NH₃)：m/e＝315(M+NH₄)

Example 99A

3-fluoro-5- (naphthyl-1-oxy) -1-nitrobenzene

Preparation was carried out in analogy to the preparation of example 13A, starting from 1-naphthol (13.59 g; 94.3mmol) and 3, 5-difluoronitrobenzene (15.00 g; 94.3 mmol).

Yield: 17.9g (67% of theory)

R_f＝0.32(III)

MS(DCI，NH₃)：m/e＝425(M+NH₄)

Examples 100A and 101A

3-fluoro-5- (naphthyl-1-oxy) -phenylamine (example 100A)

N- [ 3-fluoro-5- (naphthyl-1-oxy) -phenyl ] hydroxylamine (example 101A)

Example 100A example 101A

A solution of the product from example 99A in methanol (200ml) and THF (15ml) was treated with 10% palladium on activated carbon (0.2g) and hydrogenated at 1 atmosphere until 1.8 l of hydrogen were absorbed. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue is chromatographed on silica gel, eluting with toluene: ethyl acetate (10: 1).

Yield (example 100A): 3.92g (44% of theory)

R_f＝0.55(IV)

MS(DCI，NH₃)：m/e＝254(M+H)

Yield (example 101A): 5.2g (47% of theory)

R_f＝0.33(IV)

MS(DCI，NH₃)：m/e＝270(M+H)

The examples shown in Table VI were carried out in analogy to the procedure of example 1A:

TABLE VI

a) Starting from 2-acetyl-1, 2, 3, 4H-tetrahydroisoquinolin-5-ol

b) Starting from N-methyl-1, 2, 3, 4H-tetrahydroisoquinolin-5-ol, this compound was prepared from isoquinolin-5-ol according to Bull. Soc. Chim. Fr.1961, 270

c) Starting from N-allyl-1, 2, 3, 4H-tetrahydroisoquinolin-5-ol, the compound is prepared from isoquinolin-5-ol according to DOS [ German patent ]3329098

Example 106A

1- (2-acetyl-1, 2, 3, 4H-tetrahydroisoquinoline-5-oxy) -4-nitrobenzene

A solution of the product from example 105A (12g, 45mmol), acetic anhydride (4.3ml, 45mmol) and pyridine (3.6ml, 45mmol) in dichloromethane was boiled under reflux for 4 h. After cooling to room temperature, the reaction mixture was added to ice, the organic phase was washed 4 times with water and concentrated. The residue was recrystallized from dichloromethane/petroleum ether.

Yield: 11.1g (79% of theory)

M.p.：137℃

MS(ESI)：m/e＝313(M+H)

The examples shown in table VII were carried out in analogy to the methods of example 29A (method a) and example 30 (method B):

TABLE VII

^a)Starting from example 104A

Example 111A

2-fluoro-6-nitrobenzoic acid

Example 111A was prepared in analogy to Kaminski et al, j.med.chem.1987, 30, 2047.

Yield: 70% of theory

M.p.：149-151℃

R_f＝0.35(XXXIX)

MS 185 (M) (A)

Example 112A

2-fluoro-6-nitrobenzoic acid methyl ester

Example 112A was prepared in analogy to example 81A.

Yield: 93% of theory

M.p.：60-61℃

R_f＝0.83(XXVII)

MS 199 (M) (A)

The examples in table VIII were prepared in analogy to example 1A:

TABLE VIII

a) After preparation of the hydrochloride salt by treatment of the free amine with 1N HCl/ether; starting from N-methyl-1, 2, 3, 4H-tetrahydroquinolin-8-ol, the compound is prepared from quinolin-8-ol according to DOS [ German patent ] 750339.

The examples shown in table IX were prepared in analogy to the procedure of example 30A:

TABLE IX

Example 117A

2-propyl-5- (4-hydroxyphenoxy) - [1, 2, 3, 4H ] -tetrahydroisoquinoline

Example 117A was prepared in analogy to example 56A and precipitated with 1N HCl/diethyl ether.

Yield: 47% of theory

M.p.：239-240℃

R_f＝0.58(XL)

MS 284 (M+H) (C)

The examples shown in Table X were prepared in analogy to the procedure of example 1A:

example 131A

4- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-5-yl-oxy) -phenol hemisulfate salt

At 3-4 deg.C, adding NaNO at concentration of 5% within 60 min₂An aqueous solution (30ml, 21.7mmol) was added dropwise to a suspension of the compound from example 108A (5g, 19.7mmol) in 20% sulfuric acid (200 g). Excess nitrite was destroyed by adding 200mg of amino sulfuric acid and the reaction was heated at 100 ℃ for 4 hours. The reaction mixture was cooled to 3 ℃ and the precipitate was filtered off and washed with isopropanol.

Yield: 4.1g (68% of theory)

R_f＝0.28(XXXIII)

M.p.：207℃

MS (DCI, isobutane): 256M/e (M + H)

Example 132A

5-hydroxy-naphthalene-2-carboxylic acid methyl ester

5-methoxy-2-naphthoic acid (49.7g, 0.246 mol; J.Med.chem.1993, 36, 2485) in glacial acetic acid (450ml) and 48% strength aqueous hydrobromic acid (450ml) was heated at reflux for 15 h. After cooling, the reaction mixture was concentrated in vacuo and extracted with dichloromethane after addition to water. The organic phase is washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in methanol (1.6 l). The solution was saturated with hydrogen chloride (about 1 hour) and the reaction mixture was heated to reflux temperature. The solvent was then distilled off in vacuo, the residue was taken up in ethyl acetate and the mixture was washed with saturated sodium chloride solution, dried (magnesium sulfate) and concentrated in vacuo. The residue is chromatographed on silica gel, eluting with dichloromethane: ethyl acetate (20: 1). The product obtained is stirred with dichloromethane/petroleum ether, filtered off with suction and dried in vacuo.

Yield: 31.5g (63% of theory)

M.p.：116-117℃

R_f＝0.33(IV)

MS(ESI)：m/e＝220(M+NH₄)

Example 133A

6-hydroxymethyl-1-naphthol

A solution of lithium aluminum hydride in 1N THF (112.5ml, 112.5mmol) was added dropwise to a solution of the product from example 132A (18.2g, 90mmol) in THF (500ml) at 20-25 ℃. After 3 hours, the mixture was treated with concentrated aqueous ammonium chloride (250ml) and extracted with ethyl acetate (3 ×). The organic phase was washed with concentrated aqueous ammonium chloride (2 ×), dried (magnesium sulfate) and concentrated in vacuo. The residue was recrystallized from ethyl acetate.

Yield: 11.7g (75% of theory)

M.p.：169-170℃

R_f0.22 (dichloromethane: ethyl acetate 10: 1)

MS(DCI)：m/e＝192(M+NH₄)

Example 134A

1-bromo-6-hydroxymethylnaphthalene

Preparation was carried out in analogy to the preparation of example 133A, starting from methyl 5-bromo-naphthalene-2-carboxylate (104.7g, 395 mmol; Aust.J.chem.1965, 18, 1351).

Yield: 78.7g (84% of theory)

R_f＝0.52(VII)

MS(DCI/NH₃)：m/e＝254(M+NH₄)

Example 135A

4-hydroxy-2-hydroxymethyl-1, 2-indane

Preparation was carried out in analogy to the preparation of example 133A, starting from 4-hydroxy-1, 2-indane-2-carboxylic acid ethyl ester (10.0g, 48.5 mmol; EP 425946).

Yield: 7.0g (84% of theory)

M.p.：101℃

R_f＝0.33(VII)

MS(DCI/NH₃)：m/e＝224(M+NH₄)

Example 136A

4- (1-naphthyloxy) -pyridines

A suspension of 1-naphthol (24.00g, 166.5mmol), 4-chloropyridine hydrochloride (24.97g, 166.5mmol) and potassium carbonate (46.02g, 332.9mmol) in pyridine (200ml) was deoxygenated with argon. Copper (II) oxide (26.48g, 332.9mmol) was then added and the reaction mixture was stirred under argon at reflux overnight. The solvent is then distilled off in vacuo and the residue is recovered with dichloromethane, washed with water, dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel, eluting with ethyl acetate: EA (10: 1). The resulting product was stirred in ether, filtered and dried in vacuo.

Yield: 6.80g (18% of theory)

M.p.：85-86℃

R_f＝0.29(VII)

MS(DCI/NH₃)：m/e＝222(M+H)

Example 137A

4- (1-naphthoxy) -pyridine-N-oxide

A solution of the product from example 136A (6.62g, 29.9mmol) in dichloromethane (40ml) was treated with 80% strength m-chloroperbenzoic acid (7.10g, 32.9mmol), stirred at room temperature for 24 h and then heated at reflux for a further 2 h. The reaction mixture was washed 2 times with saturated aqueous sodium bicarbonate. The combined aqueous phases were extracted with dichloromethane and the dichloromethane phase was dried (sodium sulphate) and concentrated in vacuo. The residue is crystallized from dichloromethane/petroleum ether.

Yield: 3.85g (54% of theory)

M.p.：128℃

MS(ESI)：m/e＝260(M+Na)

Example 138A

2-chloro-4- (1-naphthoxy) -pyridine

A suspension of the product from example 137A (4.50g, 19.0mmol) in phosphorus oxychloride (50ml) was heated to reflux temperature over 1.5 h and stirred at this temperature overnight. The phosphorus oxychloride was evaporated in vacuo, the residue was treated with ice water and the mixture was extracted with dichloromethane. The organic phase was washed with saturated aqueous sodium bicarbonate, dried (sodium sulfate) and concentrated in vacuo. The residue is chromatographed on silica gel, eluting with toluene: EA (5: 1).

Yield: 2.99g (60% of theory)

R_f＝0.58(IV)

MS(ESI)：m/e＝256(M+H)

Example 139A

2-amino-4- (1-naphthoxy) -pyridines

Preparation was carried out in analogy to the preparation of example 65A, starting from the product of example 138A (2.08 g; 8.13 mmol).

Yield: 1.32g (69% of theory)

M.p.：97-99℃

R_f＝0.23(VII)

MS(ESI)：m/e＝237(M+H)

Example 140A

1- (6-hydroxymethyl-naphthyl-2-oxy) -3-nitrobenzene

A solution of the product from example 133A (9.40g, 54.0mmol) in DMF (200ml) was treated with potassium carbonate (7.50g, 54.0mmol) and stirred at room temperature for 1 h. After addition of 3-fluoro-1-nitrobenzene (7.60g, 54.0mmol), the reaction mixture was stirred under argon at 155 deg.C overnight. DMF was evaporated in vacuo and the residue was taken up in water and ethyl acetate (1: 1) and filtered. After phase separation, the aqueous phase was extracted 3 more times with ethyl acetate. The combined organic phases were washed 2 times with saturated aqueous sodium chloride solution, dried (magnesium sulfate) and concentrated in vacuo on a rotary evaporator. The residue is chromatographed on silica gel, eluting with dichloromethane: EA (20: 1).

Yield: 1.75g (11% of theory)

R_f0.56 (dichloromethane: EA 20: 3)

MS(DCI/NH₃)：m/e 313(M+NH₄)

Example 141A

3- (6-methyl-naphthyl-1-oxy) -aniline

A suspension of the product from example 140A (1.94g, 6.60mmol) and 10% palladium on activated carbon (0.6g) in THF: MeOH (1: 1, 50ml) was hydrogenated under a hydrogen pressure of 3 bar for 3 h. The reaction mixture was filtered through silica gel. The filtrate is concentrated in vacuo and the residue is chromatographed on silica gel, eluting with dichloromethane.

Yield: 1.05g (64% of theory)

R_fNot 0.60 (dichloromethane)

MS(ESI)：m/e＝250(M+H)

Example 142A

2- (6-hydroxymethyl-naphthyl-1-oxy) -5-nitropyridine

Preparation was carried out in analogy to the preparation of example 12A, starting from the product of example 133A (10.0 g; 57.4 mmol).

Yield: 15.2g (88% of theory)

M.p.：94℃

R_f＝0.12(IV)

MS(ESI)：m/e＝297(M+H)

Example 143A

5-amino-2- (6-hydroxymethyl-naphthyl-1-oxy) -pyridine

A suspension of the product from example 142A (10.3g, 34.8mmol) and 10% platinum on activated carbon (1.0g) in THF (80ml) is hydrogenated at room temperature and 1 bar of hydrogen for 4 hours. The reaction mixture was filtered through celite and concentrated in vacuo.

Yield: 9.2g (89% of theory)

M.p.：163℃

R_f＝0.09(VII)

MS(ESI)：m/e＝267(M+H)

Example 144A

3- (6-methoxymethyl-naphthyl-1-oxy) -aniline

Methyl iodide (0.853g, 6.01mmol) was added to a 60% liquid paraffin solution of sodium hydride (0.152g, 3.80mmol) in THF (5ml) at 50 deg.C, then a solution of the product from example 140A (0.901g, 3.05mmol) in THF (10ml) was added dropwise over 15 minutes and the mixture was stirred at 50 deg.C for a further 10 minutes. After addition of water, extraction was performed with ethyl acetate. The organic phase was washed twice with saturated aqueous sodium chloride solution, dried (magnesium sulfate) and concentrated in vacuo. The residue is chromatographed on silica gel eluting with dichloromethane. Without further purification, the resulting 1- (6-methoxymethylnaphthyl-1-oxy) -3-nitrobenzene (0.43g) was hydrogenated at room temperature and 1 bar hydrogen pressure with 10% platinum on activated carbon (0.1g) in THF (15ml) for 3 h. The reaction mixture was filtered through celite and concentrated in vacuo. The residue is chromatographed on silica gel, eluting with dichloromethane: EA (20: 1).

Yield: 0.070g (7% of theory)

R_f0.50 (dichloromethane: EA 10: 1)

MS(EI)：m/e＝279(M)

Example 145A

(R, S) -1- (2-hydroxymethyl-1, 2-indanyl-4-yloxy) -3-nitrobenzene

Prepared in analogy to example 140A, starting from the product of example 135A (60.0g, 365.4 mmol).

Yield: 34.4g (32% of theory)

M.p.：77-79℃

R_f＝0.24(VI)

MS(ESI)：m/e＝286(M+H)

Example 146A

(R, S) -3- (2-hydroxymethyl-1, 2-indanyl-4-yloxy) -phenylamine

Prepared in analogy to example 30A, starting from the product of example 145A (4.45g, 15.60 mmol).

Yield: 3.93g (97% of theory)

R_f＝0.42(VII)

MS(ESI)：m/e＝256(M+H)

Example 147A

(R, S) -3- (2-hydroxymethyl-1, 2-indanyl-4-yloxy) -phenol

Prepared in analogy to example 56A, starting from product of example 146A (3.07g, 12.0 mmol).

Yield: 1.17g (38% of theory)

R_f＝0.49(VII)

MS(DCI，NH₃)：m/e＝274(M+NH₄)

Example 148A

3- (6-hydroxymethyl-naphthyl-1-oxy) -phenol

The product from example 134A (88.9g, 375mmol) and 3-methoxyphenol (88.3g, 651mmol) were treated with potassium carbonate (89.9g, 651mmol) in pyridine (1000ml), deoxygenated with argon and heated to reflux under argon. After addition of copper (II) oxide (38.8g, 488mmol), the reaction mixture was heated to reflux overnight. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue is recovered with ethyl acetate, filtered again and the filtrate is washed 3 times with water, dried (magnesium sulfate) and concentrated in vacuo using a rotary evaporator. The residue is chromatographed on silica gel, eluting with dichloromethane: EA (5: 2). To obtain 3- (6-hydroxymethyl-naphthyl-1-oxy) -anisole (R)_f0.56(VII)), example 134A (R)_f0.51(VII)) and 3-methoxyphenol (R)_f0.60(VII)) in a ratio of 49% to 32% to 5% (HPLC), this mixture was introduced into N-methylpyrrolidone (470ml), treated with anhydrous sodium sulfide (111.2g, 1.42mol) and stirred at 140 ℃ for 3 hours. The reaction mixture was then introduced into 2N HCl (1000ml) and the pH adjusted to 2-3 with 20% hydrochloric acid. The mixture was extracted 3 times with ethyl acetate and the combined organic phases were washed 2 times with water, dried over magnesium sulfate and concentrated in vacuo.

The residue is chromatographed on silica gel, eluting with toluene: EA (10: 3).

Yield: 8.7g (9% of theory)

R_f0.54 (toluene: EA 5.4)

MS(DCI/NH₃)：m/e＝284(M+NH₄)

Example 149A

3- (2, 3-dimethylphenoxy) -anisole

First, 2, 3-dimethyl-1-bromobenzene (80.0g, 0.432mol), 3-methoxyphenol (107.3g, 0.865mol) and potassium carbonate (119.5g, 0.865mol) were introduced into pyridine (350ml) under an argon atmosphere and heated to 100 ℃. After addition of copper (II) oxide (51.6g, 0.648mol), the reaction was stirred at 140 ℃. After 15 hours and 40 hours, 2, 3-dimethyl-1-bromobenzene (80.0g, 0.432mol after 15 hours; 66.0g, 0.357mol after 40 hours) was added. After 64 hours, the reaction mixture was concentrated in vacuo, the residue was recovered with ethyl acetate, and the pH of the mixture was adjusted to 2-3 with semi-concentrated HCl. After phase separation, the organic phase is washed with saturated aqueous sodium chloride solution, dried (sodium sulfate) and concentrated in vacuo in a rotary evaporator. The residue is chromatographed on silica gel with toluene: EA 5: 1.

Yield: 94.9g (36% of theory)

R_fNot rated as 0.76 (toluene)

MS(DCI，NH₃)：m/e＝264(M+NH₄)

Example 150A

3- (2, 3-dimethylphenoxy) -phenol

First, the product from example 149A (109.6g, 480mmol) was introduced into 48% aqueous hydrogen bromide (900ml) and acetic acid (1500ml) and the mixture was stirred at reflux overnight. The reaction was then concentrated in vacuo, the residue was recovered with water and extracted 3 times with ethyl acetate. The combined organic phases were washed 2 times with water, dried (magnesium sulfate) and concentrated in vacuo. The residue is chromatographed on silica gel, eluting with toluene: EA (10: 1).

Yield: 86.5g (83% of theory)

R_fNot rated as 0.15 (toluene)

MS(ESI)：m/e＝215(M+H)

Example 151A

4, 4, 4-trifluorobutyl thiocyanate

To a stirred solution of 4, 4, 4-trifluorobutanol (35g, 0.027mol) and triethylamine (28.3g, 0.280mol) in 200ml of dichloromethane was added dropwise a solution of methanesulfonyl chloride (32.1g, 0.280mol) in 100ml of dichloromethane at 0 ℃. After the addition, the mixture was stirred for a further 30 minutes, then poured onto ice and the phases were subsequently separated. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. 55g of crude 4, 4, 4-trifluorobutyl methanesulfonate were obtained as an orange-yellow oil.

The mesylate (55g) was boiled with sodium thiocyanate (30.6g, 0.30mol) in acetone (300ml) at reflux for 6 hours. After cooling to room temperature, the mixture was poured onto ice, the phases were separated and the organic phase was dried over magnesium sulfate. After filtration and concentration under reduced pressure, 41g (89% of theory) of 4, 4, 4-trifluorobutyl thiocyanate were obtained as an oil.

¹⁹F-NMR(376MHz，CDCl₃；CFCl₃)δ[ppm]：-66.3

¹H-NMR(400MHz，CDCl₃，TMS)δ[ppm]：2.15(m，2H)；2.3(m，2H)；3.05(t，J＝7.1Hz，2H)

The compounds shown in table XII were prepared according to a similar method to that of example 151A.

TABLE XII

R⁵¹-CF₂-CR⁴⁹R⁵⁰-U-CH₂-CH₂-SCN

Example numbering	U	R	R	R	Yield [% ]]
Example numbering	U	R	R	R	Yield [% ]]	152A	O	H	H	F	91.5
153A	O	CF	H	F	94	152A	O	H	H	F	91.5
153A	O	CF	H	F	94	154A	CH	F	F	F	93
155A	-	Cl	F	Cl	55	154A	CH	F	F	F	93

Example 156A

4, 4, 4-trifluorobutanesulfonyl chloride

F₃C-CH₂-CH₂-CH₂-SO₂Cl

Chlorine was passed into an aqueous solution of the product of example 151A (40g, 0.236mol) in acetic acid (150ml acetic acid and 70ml water) at 20 to 40 ℃ and the progress of the reaction was controlled by gas chromatography. When the chlorination is complete, the excess chlorine is removed by passing a stream of nitrogen, 200ml of water are added and the reaction mixture is extracted several times with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. 44g (89% of theory) of 4, 4, 4-trifluorobutanesulfonyl chloride are obtained as a yellow oil.

¹⁹F-NMR(376MHz，CDCl₃；CFCl₃)δ[ppm]：-66.65(t，J＝10Hz)

¹H-NMR(400MHz，CDCl₃，TMS)δ[ppm]：3.8(m，2H)；2.35(m，4H)

The compounds shown in table XIII were prepared in analogy to example 156A.

TABLE XIII

R⁵¹-CF₂-CR⁴⁹R⁵⁰-U-CH₂-CH₂-SO₂-Cl

Example numbering	U	R	R	R	NMR-data (CDCl))F：CFCl/H：TMS：δ[ppm]	Yield [% ]]
Example numbering	U	R	R	R	NMR-data (CDCl))F：CFCl/H：TMS：δ[ppm]	Yield [% ]]	157A	O	H	H	F	-74.5(t，8Hz)/4.2(m，2H)；3.95(m，4H)	87
158A	O	CF	H	F	-74.2/4.45(m，2H)；4.2(m，1H)；3.95(m，2H)	75	157A	O	H	H	F	-74.5(t，8Hz)/4.2(m，2H)；3.95(m，4H)	87
158A	O	CF	H	F	-74.2/4.45(m，2H)；4.2(m，1H)；3.95(m，2H)	75	159A	CH	F	F	F	-74.2(CF)；-118(CF)/3.8(m，2H)；2.4(m，4H)	91
160A	-	Cl	F	Cl	-68.5(2F)；-120(1F)	60	159A	CH	F	F	F	-74.2(CF)；-118(CF)/3.8(m，2H)；2.4(m，4H)	91

Preparation examples

Example 1 (method A)

1-N- (1-butylsulfonyl) amino-4- (naphthyl-1-oxy) benzene

A solution of n-butylsulfonyl chloride (9.5ml, 72.0mmol) in dichloromethane (100ml) was added dropwise to a solution of the product from example 51A (17.0g, 72.3mmol) in dichloromethane (300ml) at room temperature under argon and the mixture was stirred at room temperature for 1 hour. After addition of pyridine (11.7ml, 140mmol), the mixture was stirred at room temperature overnight. The reaction mixture was washed with water, 1N hydrochloric acid (2 ×), water (2 ×), dried (sodium sulfate) and concentrated in vacuo. The residue was recrystallized from hot ethanol and redissolved in dichloromethane. After addition of activated carbon, filtration, concentration in vacuo and recrystallization from methanol.

Yield: 12.7g (49% of theory)

M.p.：108-109℃

R_f＝0.32(IV)

MS(DCI，NH₃)：m/e＝373(M+NH₄)

Example 2 and example 3 (method B)

3- (naphthyl-1-oxy) -1-N- (1-propylsulfonyl) -aminobenzene (example 2)

3- (naphthyl-1-oxy) -1-bis-N- (1-propylsulfonyl) -aminobenzene (example 3)

1-Propylsulfonyl chloride (224mg, 1.57mmol) and triethylamine (304mg, 3.00mmol) were added dropwise to a solution of example 45A (353mg, 1.50mmol) in dichloromethane (10ml) at room temperature under an argon atmosphere, and the solution was stirred at room temperature overnight. After addition of dichloromethane (40ml), the mixture was washed with water (50ml), 2N hydrochloric acid (2X 50ml), 5% sulfuric acid (70ml) and water (50 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel, eluting with dichloromethane: formic acid (200: 1).

Yield (example 2): 259mg (51% of theory)

R_f＝0.40(XV)

MS(DCI，NH₃)：m/e＝359(M+NH₄)

Yield (example 3): 111mg (16% of theory)

M.p.：112℃

R_f＝0.48(XV)

MS(DCI，NH₃)：m/e＝465(M+NH₄)

Following a similar procedure to that for example 1 (method a) and examples 2 and 3 (method B), the examples shown in table 1 were prepared:

examples 71 and 73

1-N- [ (1-methyl) butylsulfonyl ] amino-4- (naphthyl-1-oxy) benzene (example 72)

1-N- [1- (1, 1-dimethyl) butylsulfonyl ] amino-4- (naphthyl-1-oxy) benzene (example 73)

N-butyllithium (1.6N in hexane, 1.84ml, 2.94mmol) was added dropwise to a solution of example 1(500mg, 1.40mmol) in THF (15ml) under argon at-70 ℃ to-78 ℃ and the mixture was stirred at-20 ℃ to-30 ℃ for 2 h. The reaction mixture was cooled to-70 ℃ to-78 ℃ and a solution of methyl iodide (199mg, 1.40mmol) in THF (5ml) was added dropwise at this temperature. The mixture was stirred at-70 ℃ to-78 ℃ for 1 hour, and the reaction was allowed to warm to room temperature. After addition of 1N hydrochloric acid (10ml), the mixture was diluted with ethyl acetate (30ml) and shaken. After phase separation, the aqueous phase was extracted with ethyl acetate (2X 20 ml). The combined organic phases were washed with 5% aqueous sodium thiosulfate (2X 20ml) and water (3X 40ml), dried (magnesium sulfate) and concentrated in vacuo. This residue (442mg) was dissolved in THF (10ml), and after addition of example 1(60.0mg, 0.17mol), N-butyllithium (1.6N in hexane, 1.8ml, 2.94mmol) was added dropwise at-70 ℃ to-78 ℃ under an argon atmosphere. The reaction mixture was then stirred at 0 ℃ for 2 hours, cooled to-70 ℃ to-78 ℃ and a solution of methyl iodide (199mg, 1.40mmol) in THF (5ml) was added dropwise. After stirring for 1 hour at-70 ℃ to-78 ℃, the reaction was warmed to room temperature and worked up as described above. The crude product (523mg) was a mixture of examples 72, 73 and 1 in a ratio of 66: 18: 16. Compounds 72 and 73 were isolated from this mixture by preparative HPLC (column: 250X 20mm packed with Kromasil 100, C-18, 5 μm; flow rate: 15 ml/min; eluent: 25% water, 75% methanol; T ═ 40 ℃).

Yield (example 72): 222mg (38% of theory)

Retention time (HPLC): 7.07 minutes

MS(DCI，NH₃)：m/e＝387(M+NH₄)

Yield (example 73): 59mg (10% of theory)

M.p.：97-98℃

Retention time (HPLC): 8.45 minutes

MS(DCI，NH₃)：m/e＝401(M+NH₄)

Example 74

5- [4- (n-butylsulfonyl) aminophenyl-1-oxy ] -naphthalene-1-carboxylic acid

A solution of potassium hydroxide (1.51g, 27.0mmol) in water (10ml) was added dropwise to a solution of example 16(4.10g, 9.0mmol) in dioxane (20ml) at room temperature and the mixture was stirred at room temperature overnight. After water (100ml) was added, the mixture was extracted with ethyl acetate (100 ml). The organic phase was discarded and the pH of the aqueous phase was adjusted to 3 with 2N hydrochloric acid. The precipitated product was filtered off, washed with water (50ml) and dried in vacuo.

Yield: 3.16g (88% of theory)

M.p.：193℃

R_f＝0.24(XXII)

MS(DCI，NH₃)：m/e＝417(M+NH₄)

Example 75

5- [ N- (N-butylsulfonyl) amino ] -2- (naphthyl-1-oxy) benzoic acid

The title compound was prepared by a similar method to that of example 74, starting from example 43(3.74g, 9.4 mmol).

M.p.：162℃

R_f＝0.22(XXII)

MS(DCI，NH₃)：m/e＝417(M+NH₄)

Example 76

1- [ N- (N-butylsulfonyl) amino ] -2-methoxy-4- (naphthyl-1-oxy) benzene

A solution of example 15(463mg, 1.25mmol) in acetone (10ml) was treated with potassium carbonate (345mg, 2.50mmol) at room temperature and after 10 minutes with methyl iodide (177mg, 1.25 mmol). The reaction mixture was stirred at room temperature for 48 hours and the solvent was distilled off in vacuo. The residue was recovered in water (50ml) and extracted with ethyl acetate (3X 50 ml). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product is chromatographed on silica gel, eluting with toluene: ethyl acetate (10: 1).

Yield: 180mg (49% of theory)

M.p.：119℃

R_f＝0.35(IV)

MS(ESI)：424(M+K)

Example 77

1- [ N- (nonafluorobutylsulfonyl) amino ] -4- (naphthyl-1-oxy) benzene

N-butyllithium (1.6N in hexane, 3.50ml, 5.61mmol) was added dropwise to a solution of example 51A (1.20g, 5.10mmol) in THF (20ml) under argon at-70 ℃ to-75 ℃ and the mixture was stirred for 30 minutes. The resulting reaction mixture was added dropwise to a solution of perfluorobutyl-1-sulfonyl fluoride (1.54g, 5.10mmol) in THF (20ml) at-70 ℃ to-75 ℃. The reaction was warmed to room temperature, the solvent was evaporated in vacuo and the residue was recovered in dichloromethane (40 ml). The solution was washed with 1N hydrochloric acid (2X 40ml), filtered through celite, washed with water (40ml) and dried over sodium sulphate and the solvent evaporated in vacuo. The residue is chromatographed on silica gel, eluting with toluene: ethyl acetate (20: 1).

Yield: 665mg (25% of theory)

M.p.：75℃

R_f＝0.38(X)

MS(FAB)：m/e＝517(M)

Example 78

4- (naphthyl-1-oxy) -1- [ N- (2-phenethylsulfonyl) amino ] benzene

A solution of example 22(630mg, 1.57mmol) in ethanol (30ml) and THF (20ml) was treated with 5% palladium on activated carbon (100mg) and hydrogenated under 3 bar of hydrogen pressure for 43 hours. After suction filtration through kieselguhr, the solvent is evaporated off in vacuo and the residue is chromatographed on silica gel eluting with petroleum ether/diethyl ether (5: 1). A mixture of examples 22 and 78 was obtained in a ratio of 1.3: 1 (R)_f0.74(II)), in ethanol (2)0ml) and hydrogenated again after addition of 5% palladium on activated carbon (100mg) at 40 ℃ and 3 bar hydrogen pressure. The reaction mixture is filtered off with suction through celite, the solvent is distilled off in vacuo and the residue is recrystallized from methanol.

Yield: 260mg (41% of theory)

M.p.：109.5℃

R_f＝0.74(II)

MS(DCI，NH₃)：m/e＝421(M+NH₄)

Example 79

5- [4- (n-Butylsulfonyl) aminophenyl-1-oxy ] -naphthalene-1-carboxylic acid methyl ester

Methanol (0.64ml, 15.8mmol), 4-N, N-dimethylaminopyridine (38mg, 0.32mmol) and N' - (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (0.66g, 3.46mmol) were added successively to a suspension of the compound from example 74 (1.25g, 3.15mmol) in dichloromethane (14ml) at-10 ℃ and the reaction was allowed to warm to room temperature and stirred overnight. After addition of dichloromethane, the mixture was washed with water (50ml), saturated aqueous sodium bicarbonate (2X 50ml) and water (50ml), dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel, eluting with toluene: ethyl acetate (10: 1).

Yield: 0.94g (72% of theory)

M.p.：98℃

R_f＝0.23(IV)

MS(DCI，NH₃)：m/e＝431(M+NH₄)

The examples shown in table 2 were prepared analogously to example 79:

TABLE 2

Example 84

5- [ N- (N-butylsulfonyl) amino ] -2- (naphthyl-1-oxy) benzamide

Isobutyl chloroformate (0.40ml, 3.00ml) was added dropwise to a solution of example 75(799mg, 2.00mmol) and N-methylmorpholine (0.33ml, 3.00mmol) in ethyl acetate (10ml) at-15 ℃ under argon and the mixture was stirred for 1 hour at-15 ℃. Then 25% aqueous ammonia (0.47ml, 6.3mmol) was added dropwise and the reaction was allowed to warm to room temperature. After addition of ethyl acetate (80ml) and THF (20ml), the reaction mixture was washed with 50% aqueous sodium carbonate (50ml) and saturated aqueous sodium chloride (50ml), dried over sodium sulfate and the solvent was distilled off in vacuo. The residue was stirred with ethyl acetate/diethyl ether (2: 1, 6 ml). The precipitated product is filtered off, washed with diethyl ether and dried in vacuo.

Yield: 630mg (79% of theory)

M.p.：214℃

R_f＝0.11(XXII)

MS(DCI，NH₃)：m/e＝416(M+NH₄)

The compounds shown in table 3 were prepared in analogy to example 84:

TABLE 3

Example numbering	R	R	Yield (% of theory)	M.p.(℃)	R	MS m/e
Example numbering	R	R	Yield (% of theory)	M.p.(℃)	R	MS m/e	85	CONH	H	32	206	0,45(XXII)	416(M+NH)(B)
86	H	CONHCH	82	204	0,11(XXII)	430(M+NH)(B)	85	CONH	H	32	206	0,45(XXII)	416(M+NH)(B)

The compounds shown in Table 4 were prepared in analogy to the procedure of example 29A:

TABLE 4

Example numbering	Starting materials example numbering	X	Y	Yield (% of theory)	M.P.(℃)	R	MS m/e
Example numbering	Starting materials example numbering	X	Y	Yield (% of theory)	M.P.(℃)	R	MS m/e	87	36	NH	H	57	103,5	0,50(VII)	405(M+H)(B)
88	41	H	NH	70	182	-	405(M+H)(C)	87	36	NH	H	57	103,5	0,50(VII)	405(M+H)(B)

Example 89

1- [ N- (2-Acetylaminophenylmethylsulfonyl) amino ] -4- (naphthyl-1-oxy) benzene

Acetyl chloride (49mg, 0.62mmol) was added dropwise to a solution of the compound from example 87 (250mg, 0.62mmol) and triethylamine (125mg, 1.24mmol) in dichloromethane (5ml) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by washing with water (5ml), 2N hydrochloric acid (2X 5ml) andwater (5ml) was washed, dried (sodium sulfate) and concentrated in vacuo. The residue was taken up in THF (8ml) and LiOH XH was added dropwise at 0 DEG C₂O (52mg, 1.24mmol) and stirred at room temperature overnight. THF was evaporated in vacuo and the pH was adjusted to 2 by addition of 1N hydrochloric acid. The product was extracted with ethyl acetate. The ethyl acetate phase was dried over sodium sulphate and concentrated in vacuo.

Yield: 209mg (75% of theory)

M.p.：173.5℃

R_f＝0.38(VII)

MS(DCI，NH₃)：m/e＝464(M+NH₄)

Example 90

1- [ N- (3-Acetylaminophenylmethylsulfonyl) amino ] -4- (naphthyl-1-oxy) benzene

Preparation was carried out in analogy to the preparation of example 89, starting from example 88(500mg, 1.23 mmol).

Yield: 232mg (42% of theory)

M.p.：169℃

MS(DCI，NH₃)：m/e＝464(M+NH₄)

Example 91

1- [ N- (butylsulfonyl) amino ] -3-hydroxymethyl-4- (naphthyl-1-oxy) benzene

Example 43(750mg, 1.81mmol) was reacted under argon at room temperatureThe solution in THF (6ml) was added dropwise to a 1N THF solution of lithium aluminum hydride (2ml, 2.0mmol) and THF (5ml) and stirred at room temperature overnight. Adding saturated NH₄After addition of an aqueous solution of Cl (30ml), the mixture was extracted with ethyl acetate (3X 30 ml). The separated organic phase is treated with Na₂SO₄Drying and vacuum concentrating.

Yield: 698mg (100%)

R_f＝0.61(VII)

MS(DCI，NH₃)：m/e＝403(M+NH₄)。

The compounds shown in table 5 were prepared in analogy to example 91:

table 5:

example numbering	R	R	Yield (% of theory)	M.p.(℃)	R	MS m/e
example numbering	R	R	Yield (% of theory)	M.p.(℃)	R	MS m/e	92	CHOH	H	51	200	0,06(IV)	403(M+NH)(B)
93	H	CHOH	91	-	0,13(VI)	403(M+NH)(B)	92	CHOH	H	51	200	0,06(IV)	403(M+NH)(B)

Example 94

1-naphthyl-4- [ N- (N-butylsulfonyl) amino ] phenylsulfoxide

A solution of example 44(500mg, 1.34mmol) in dichloromethane (15ml) was treated with m-chlorobenzoic acid (290mg, 1.34mmol) at a concentration of 80% and stirred at room temperature overnight. The reaction mixture was washed with water (2 × 20ml), dried (sodium sulfate) and concentrated in vacuo. The residue was recrystallized from ether.

Yield: 402mg (78% of theory)

M.p.：161℃

R_f＝0.40(VII)

MS(ESI)：m/e＝426(M+K)

Example 95

1-naphthyl-4- [ N- (N-butylsulfonyl) amino ] phenylsulfone

A solution of example 44(500mg, 1.34mmol) in dichloromethane (15ml) was treated with m-chlorobenzoic acid (580mg, 2.68mmol) at a concentration of 80% and stirred at room temperature overnight. After filtration, the filtrate was washed with water (2 × 15ml), dried (sodium sulfate) and evaporated in vacuo. The residue is stirred in ether and chromatographed on silica gel eluting with toluene/ethyl acetate (8: 1).

Yield: 218mg (40% of theory)

M.p.：180℃

R_f＝0.67(VII)

MS(ESI)：m/e＝442(M+K)

Example 96

1- [ N- (N-butylsulfinyl) amino ] -4- (naphthyl-1-oxy) benzene

N-butylsulfinyl chloride (2.20g, 15.8 mmol; prepared according to JOC, 1968, 33, 2104) was added to a solution of example 51A (3.50g, 15.0mmol) and pyridine (2.40g, 30.0mmol) in dichloromethane and the mixture was stirred at room temperature overnight. The reaction mixture was introduced into methylene chloride (70ml) and water (30ml) and stirred. The precipitated product is filtered off, washed with water and dried.

Yield: 440mg (9% of theory)

M.p.：138-139℃

R_f＝0.06(VI)

MS(ESI)：m/e＝362(M+Na)

Example 97

1- (n-butylsulfonyloxy) -4- (naphthyl-1-oxy) benzene

Triethylamine (0.35ml, 2.54mmol) and 1-dropwise sulfuryl chloride (0.18ml, 1.33mmol) were added to a solution of example 56A (300mg, 1.27mmol) in dichloromethane (10ml) at room temperature, and the mixture was stirred at room temperature overnight. After addition of dichloromethane (50ml), washing was carried out with water (50ml), 1N hydrochloric acid (2X 50ml) and water (50ml), drying over sodium sulfate and evaporation of the solvent in vacuo. The residue is chromatographed on silica gel eluting with toluene.

Yield: 384mg (85% of theory)

R_fNot rated as 0.44 (toluene)

MS(DCI，NH₃)：m/e＝374(M+NH₄)

The compounds shown in table 6 were prepared in analogy to example 97:

table 6:

example 103

1- [ N- (1-propoxysulfonyl) amino ] -4- (naphthyl-1-oxy) benzene

First, the compound from example 58A (3.20g, 10.0mmol) was introduced into toluene (80 ml). After addition of phosphorus pentachloride (2.08g, 10.0mmol), the reaction mixture is slowly heated to reflux temperature over 1 hour and stirred under reflux for a further 1.5 hours. Then, it was cooled to room temperature, the solution was decanted from the poorly soluble, viscous component, and concentrated in vacuo. 1.73g (about 5mmol) of the resulting aminosulfonyl chloride (about 3.4g) was recovered in dichloromethane (40ml) and treated sequentially with sodium carbonate (3.0g), benzyltriethylammonium chloride (228mg, 1.0mmol) and 1-propanol (301mg, 5.0 mmol). The reaction was heated to reflux overnight, filtered and concentrated in vacuo. The residue is chromatographed on silica gel using toluene/ethyl acetate (12: 1).

Yield: 700mg (39% of theory)

M.p.：95℃

R_f＝0.40(IV)

MS(DCI，NH₃)：m/e＝375(M+NH₄)

Example 104

1- [ N- (1-Propylaminosulfonyl) amino ] -4- (naphthyl-1-oxy) benzene

Prepared according to a synthesis analogous to that of example 103, replacing n-propanol with n-propylamine.

Yield: 280mg (16% of theory)

M.p.：113-115℃

R_f＝0.38(IV)

MS(DCI，NH₃)：m/e＝374(M+NH₄)

Example 105

1- (N-1-butylsulfonyl-N-methyl) amino-4- (naphthyl-1-oxy) benzene

Methyl iodide (0.18ml, 2.8mmol) was added to a mixture of 51A (500mg, 1.41mmol) and potassium carbonate (389mg, 2.81mmol) in DMF (10 ml). After stirring at room temperature for 30 minutes, the reaction solution was added to water and extracted twice with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate and concentrated to give 190mg of resin, which gradually solidified.

Yield: 190mg (37% of theory)

R_f＝0.67(XVI)

MS(DCI，NH₃)：m/e＝387(M+NH₄)

Example 106 and example 107

1-N- (4-azido-1-propylsulfonyl) amino-4- (naphthyl-1-oxy) benzene (example 106)

N- (4-naphthyl-1-oxy) phenyl-1, 3-propanesultam (example 107)

A solution of example 65(15.51g, 41.3mmol) in DMSO (100ml) was treated with sodium azide (2.95g, 45.4mmol) and heated at 80 ℃ for 15 h. After addition of water (300ml), extraction was carried out with diethyl ether (3X 200 ml). The combined organic phases were washed with saturated aqueous sodium chloride (200ml), dried (sodium sulphate) and concentrated in vacuo. The residue is chromatographed on silica gel, eluting with toluene: diethyl ether (10: 1).

Yield (example 106): 9.8g (62% of theory)

M.p.：77.5℃

R_f＝0.29(IV)

MS(DCI，NH₃)：m/e＝400(M+NH₄)

Yield (example 107): 1.61g (12% of theory)

M.p.：150℃

R_f＝0.21(IV)

MS(DCI，NH₃)：m/e＝357(M+NH₄)

Example 108

1-N- (4-amino-1-phenylsulfonyl) amino-4- (naphthyl-1-oxy) benzene

A solution of example 106(4.76g, 12.4mmol) in methanol (100ml) was treated with 10% palladium on activated carbon (0.5g) and hydrogenated at 3 bar and room temperature for 3.5 h. The reaction mixture was filtered through celite and concentrated in vacuo.

Yield: 3.67g (83% of theory)

M.p.：159℃

R_f＝0.08(XXIII)

MS(DCI，NH₃)：m/e＝357(M+H)

The examples shown in Table 7 were prepared in analogy to the preparation of examples 1 to 71 (methods A and B):

example 126

1- (benzylsulfonyloxy) -3- (naphthyl-1-oxy) benzene

Preparation was carried out in analogy to the preparation of example 97, starting from example 63A (0.709 g; 3.00 mmol).

Yield: 0.680 (58% of theory)

R_fNot rated as 0.50 (toluene)

MS(DCI，NH₃)：m/e＝408(M+NH₄)

Example 127

3- (naphthyl-1-oxy) -1- (pentylsulfonyloxy) benzene

Yield: 0.800 (72% of theory)

R_fNot equal to 0.52 (toluene)

MS(DCI，NH₃)：m/e＝388(M+NH₄)

Example 128

2- (naphthyl-1-oxy) -4- (pentylsulfonylamino) pyridine sodium salt

A solution of example 110(0.227 g; 0.61mmol) in tetrahydrofuran (2ml) is treated at room temperature, under argon, with sodium methoxide (0.033 g; 0.61mmol) in methanol (1.56 ml). The reaction mixture was stirred for a further 15 minutes and the solvent was distilled off in vacuo.

The residue was stirred in ether, filtered and dried in vacuo.

Yield: 0.240g (99% of theory)

M.p. ═ 168 ℃ (decomposition)

The compounds shown in Table 8 were prepared in analogy to the procedure of example 128.

TABLE 8

Example 136

1- (naphthyl-1-oxy) -4- (3-pyridylmethylsulfonylamino) benzene

A solution of example 48(2.1g, 5.0mmol) in THF (40ml) and methanol (100ml) was treated with 10% palladium on activated carbon (0.5g) and hydrogenated at 3 bar pressure for 15 h. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo.

The residue is chromatographed on silica gel, eluting with toluene: ethyl acetate (2: 1).

Yield: 0.668g (34% of theory)

M.p.：174-176℃

R_f＝0.13(XXVII)

MS(ESI)：m/e＝391(M+H)

Example 137

1- (naphthyl-1-oxy) -3- (3-pyridylmethylsulfonylamino) benzene

Preparation was carried out in analogy to the preparation of example 136, starting from example 118(1.83 g; 4.2 mmol).

Yield: 1.43g (85% of theory)

R_f＝0.09(XVI)

MS(ESI)：m/e＝391(M+H)

Example 138

4- (N-butylsulfonylamino) -2- (N, N-dimethylamino) methyl-1- (naphthyl-1-oxy) benzene

A solution of example 83(0.200g, 0.469mmol) in THF (5ml) is treated at room temperature under argon with a solution of lithium aluminum hydride in 1N THF (0.94ml, 0.94mmol) and heated at reflux for 18 h. After addition of water (20ml), the reaction mixture was extracted with ethyl acetate (3X 20 ml). The combined organic phases were dried over sodium sulfate and concentrated in vacuo.

Yield: 0.190g (98% of theory)

R_f＝0.77(XXVI)

MS(DCI，NH₃)：m/e＝413(M+H)

The examples shown in Table 9 were prepared in analogy to the preparation of example 138.

TABLE 9

a) It is subsequently converted into the hydrochloride salt with a saturated solution of hydrogen chloride in ether

Example 141

1- [3- (N, N-dimethylamino) propylsulfonyl ] amino-4- (naphthalenyl-1-oxy) benzene

A solution of example 108(0.505g, 1.40mmol), zinc (II) chloride (0.772g, 5.70mmol) and paraformaldehyde (0.170g, 5.70mmol) in dichloromethane (25ml) was stirred at room temperature under argon for 1 h, then treated with sodium borohydride (0.214g, 5.70mmol) and stirred at room temperature overnight.

After addition of 2.6N aqueous ammonia (8.6ml), the mixture was diluted with water (50ml) and extracted twice with dichloromethane (50 ml). The combined organic phases were dried (sodium sulfate) and concentrated in vacuo. The residue is chromatographed on silica gel, eluting with dichloromethane: ethanol (5: 1).

Yield: 0.107g (20% of theory)

R_f＝0.60(XXVI)

MS(DCI，NH₃)：m/e＝385(M+H)

Example 142

3- [ (4- (naphthyl-1-oxy) -phenyl) aminosulfonyl ] propyl-N, N, N-triethylammonium iodide

A solution of example 108(1.07 g; 3.00mmol) in THF (50ml) is treated at room temperature with iodomethane (0.43 g; 3.00mmol) and stirred at room temperature for 72 h. The precipitated product was filtered off and dried in vacuo.

Yield: 0.341 (22% of theory)

M.p.：＞210℃

MS(DCI，NH₃)：m/e＝399(M+H)

The examples shown in Table 10 were prepared in analogy to the methods of example 1 (method A) and example 2 (method B).

Examples 172 and 173

2-N- (N-Butylsulfonyl) amino-4- (naphthyl-1-oxy) benzoic acid (example 172)

N-propyl 2-N- (N-butylsulfonyl) amino-4- (naphthyl-1-oxy) benzoate (example 173)

A solution of example 172(0.500g, 1.21mmol) in N-propanol (6ml) was treated with 1N sodium hydroxide solution (2.50ml) and stirred at 85 ℃ overnight. The reaction mixture was poured onto water, extracted three times with ethyl acetate, made acidic and extracted again with ethyl acetate. All ethyl acetate phases were combined, concentrated in vacuo and chromatographed on silica gel.

Example 172: yield: 0.213g (42% of theory)

M.p.：145-146℃

R_f＝0.35(XXV)

MS(ESI)：m/e＝400(N+H)

Example 173: yield: 0.195g (36.5% of theory)

Yellow oil

R_f＝0.63(IV)

MS(ESI)：m/e＝364(M+Na)

Example 174

Sodium salt of 4-N- (N-butylsulfonyl) amino-2- (naphthyl-1-oxy) pyrimidine

Example 167(0.310g, 0.84mmol) was dissolved in THF (2ml) and treated with 1N sodium hydroxide (0.84 ml). The THF was evaporated in vacuo and the resulting solution was lyophilized.

Yield: 0.317g of white powder (100% of theory)

R_f＝0.47(VII)

Example 175

Sodium salt of methyl 2-N- (benzylsulfonyl) amino-4- (naphthyl-1-oxy) benzoate

In analogy to the preparation of example 1, methyl 2-N- (benzylsulfonyl) amino-4- (naphthyl-1-oxy) benzoate was prepared from example 82A (0.590g, 2.01 mmol). The chromatographed product (0.274g) was dissolved in THF (3ml) and treated with sodium methoxide (0.033g, 0.61 mmol). The suspension was dissolved thoroughly by adding methanol (5ml), the solution was concentrated, and the solid residue was digested with a small amount of methanol and filtered.

Yield: 0.186g of a white solid (20% of theory)

R_f＝0.67(IV)

MS (corresponding acid, DCI/NH)₃)：m/e＝465(M+Na)

Example 176

1- (naphthyl-1-oxy) -4-N- (N-pentanoyl) aminobenzene

Pyridine (1.0ml, 3mmol) was added to a solution of example 51A (2.0g, 8.5mmol) and pentanoyl chloride (1.0ml, 8.5mmol) in dichloromethane (20ml) and the mixture was stirred at room temperature overnight. The reaction solution was poured into water and extracted with dichloromethane (2 ×). The organic phase was washed with water (2 ×), dried over sodium sulfate and concentrated. The resulting solid was stirred with diethyl ether and dried.

Yield: 2.37g (87% of theory)

M.p.：80℃

R_f＝0.57(XVI)

MS(DCI/NH₃)：m/e＝320(M+H)

The examples shown in Table 11 were prepared in analogy to the procedure of example 176.

TABLE 11

Example 180

1- (naphthyl-1-oxy) -4-N- (phenylsulfonyl) aminobenzene

Example 180 was prepared in analogy to the preparation of example 1, starting from example 51A (2.0 g; 8.5 mmol).

Yield: 2.35g (74% of theory)

M.p.：143-144℃

R_f＝0.25(IV)

MS(DCI/NH₃)：m/e＝393(M+NH₄)

Example 181

1-N- (1-Butylsulfonyl) amino-4- (naphthyl-1-oxy) benzene sodium salt

Preparation was carried out in analogy to the preparation of example 128, starting from example 1(0.500 g; 1.41 mmol).

Yield: 0.479g (91% of theory)

M.p.：＞210℃

R_fNot 0.32(IV, corresponding acid)

MS (corresponding acid DCI, NH)₃)：m/e＝373(M+NH₄)

Example 182

5- (n-butylsulfonyl) amino-2- (1-naphthyl-1-oxy) pyridine hydrochloride

A solution of example 32(0.500g, 1.40mmol) is treated with a 2.6N solution of hydrochloric acid in ether (0.77ml, 2.0mmol), stirred for 10 minutes and concentrated in vacuo until the product starts to precipitate. After addition of diethyl ether, the product is filtered off and dried in vacuo.

Yield: 0.550g (100% of theory)

M.p.：136-138℃

Example 183

N- (4- (naphthyl-1-oxy) phenyl) amide methyl N-butane phosphate

A solution of methanol (0.365g, 11.4mmol) in toluene (10ml) is added dropwise to a solution of n-butane phosphorus oxychloride (2.00g, 11.9mmol) and triethylamine (2.30g, 22.8mmol) in toluene (40ml) at 0 to 5 ℃ under argon and the mixture is stirred at this temperature for 2 hours. The reaction mixture was filtered under argon and the filtrate was treated successively at room temperature with triethylamine (2.30g, 22.8mmol) and a solution of the compound from example 51A (2.35g, 10.0mmol) in toluene (10 ml). The reaction mixture was stirred at room temperature overnight, ethyl acetate (100ml) was added and extracted with water (3X 50 ml). The organic phase was dried (magnesium sulfate) and concentrated in vacuo. The residue is chromatographed on silica gel, eluting with toluene/ethyl acetate (1: 1). The product thus obtained was stirred in diethyl ether, filtered and dried in vacuo.

Yield: 2.60g (70% of theory)

M.p.：119-120℃

R_f＝0.14(VII)

MS(DCI，NH₃)：m/e＝387(M+NH₄)

Example 184

4- (naphthyl-1-oxy) -benzenesulfonic acid N-benzylamide

First, 1-naphthol (10.7g, 74mmol) and potassium carbonate (20.5g, 148mmol) were added to DMF (200ml) and the mixture was stirred at room temperature for 1.5 hours. After addition of 4-fluorobenzenesulfonic acid N-benzylamide (19.6g, 74 mmol; Bull Soc. Chim. Fr.1961, 488), the reaction mixture was stirred at 80 ℃ overnight and at 120 ℃ for 5 h. The DMF is then evaporated off in vacuo, the residue is treated with water and the mixture is extracted four times with ethyl acetate. The combined organic phases were washed twice with water, dried (magnesium sulfate) and concentrated in vacuo. The residue is chromatographed on silica gel, eluting with toluene: ethyl acetate (10: 1). The product thus obtained was stirred in diethyl ether, filtered and dried in vacuo.

Yield: 3.45g (12% of theory)

M.p.：144-146℃

R_f＝0.39(IV)

MS(ESI)：m/e＝390(M+H)

Example 185

1-N- (N-pentylsulfonyl) amino-4- (2-ethoxycarbonyl-1, 2-indan-4-yloxy) benzene

Preparation was carried out in analogy to the preparation of example 1, starting from example 98A (0.546 g; 1.84mmol) and 1-pentylsulfonyl chloride (0.313 g; 1.84 mmol).

Yield: 0.432g (70% of theory)

R_f＝0.45(VII)

MS(ESI)：m/e＝432(M+H)

Example 186

1-N- (N-pentylsulfonyl) amino-4- (2-hydroxy-1, 2-indan-4-yloxy) benzene

Preparation was carried out in analogy to the preparation of example 91, starting from example 185(0.260 g; 0.60 mmol).

Yield: 0.209g (87% of theory)

R_f＝0.56(VII)

MS(ESI)：m/e＝412(M+Na)

Example 187

N- (3-fluoro- (5-naphthyl-1-oxy) -phenyl) -N-hydroxy-1-pentylsulfonyl chloride

Preparation was carried out in analogy to the preparation of example 1, starting from example 101A (1.29 g; 5.10mmol) and 1-pentylsulfonyl chloride (0.91 g; 5.36 mmol).

Yield: 0.24g (12% of theory)

R_f＝0.27(X)

MS(FAB)：m/e＝404(M+H)

Example 188

1- [ (4, 4, 4-trifluoro-1-butyl) sulfonyloxy ] -3- (naphthyl-1-oxy) benzene

Yield: 1.10g (89% of theory)

R_f＝0.50(XXX)

MS(DCI，NH₃)：m/e＝428(M+NH₄)

Example 189

1- [ (4, 4, 4-trifluoro-1-butyl) sulfonylamino ] -2- (naphthyl-1-oxy) pyridine

Preparation was carried out in analogy to the preparation of example 1, starting from example 43A (0.945 g; 4.00 mmol).

Yield: 1.20g (75% of theory)

M.p.：136-137℃

R_f＝0.69(VII)

MS(DCI，NH₃)：m/e＝411(M+H)

The examples shown in Table 12 were prepared analogously to the preparation of example 1:

the compounds shown in Table 13 were prepared in analogy to the procedure of example 2.

Watch 13

Example 201

2- (n-butylsulfonylamino) -4- (1-naphthoxy) -benzoic acid morpholinamide

Triethylamine (1.8ml, 13mmol) and 20% propylphosphoric anhydride/ethyl acetate (1.04ml, 1.58mmol) were added to a solution of example 172(0.420g, 1.05mmol) and morpholine (90. mu.l, 11mmol) in DMF (5ml) and the mixture was stirred at room temperature overnight. After addition of equal amounts of morpholine, triethylamine and propylphosphoric anhydride solution and stirring overnight, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated, and the residue is chromatographed on silica gel (dichloromethane: methanol ═ 30: 1). Recrystallization from methanol gave white crystals.

Yield: 33mg (6.29% of theory)

M.p.：105-108℃

R_f＝0.55(XXV)

MS：469(M+H)(B)

The compounds shown in table 14 were prepared in analogy to the procedure of example 201.

TABLE 14

a) Example 202 was treated with 1N HCl/diethyl ether

The compounds shown in Table 15 were prepared in analogy to the procedure of example 91.

Watch 15

Examples	R	Yield (%)	M.p.(℃)	R	MS(m/e)
Examples	R	Yield (%)	M.p.(℃)	R	MS(m/e)	206	nBu	81	0.45(XXVII)	403(M+NH)(B)
207	Bzl	82	Oil	0.45(XXX)	437(M+NH)(B)	206	nBu	81	0.45(XXVII)	403(M+NH)(B)

The compounds shown in Table 16 were prepared in analogy to the procedure of example 1.

TABLE 16

^a)Preparation of the corresponding amine by treatment with 1N HCl/diethyl ether

The compounds shown in Table 17 were prepared in analogy to the procedure of example 97.

TABLE 17

a) Preparation of the corresponding amine by treatment with 1N HCl/diethyl ether

The compounds shown in Table 18 were prepared in analogy to the procedure of example 1.

Example 237

1-bis-N- (1-pentylsulfonyl) amino-4- (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-5-yl-oxy) -benzene

According to a preparation analogous to the compound of example 3, the compound of example 108A (3.5g, 13.8mmol) is reacted at 35-40 ℃ with 1-pentylsulfonyl chloride (5.17g, 30.3mmol) and triethylamine (9.6ml, 70mmol) in dichloromethane (30 ml). After the reaction was complete, the reaction was extracted with water, sodium bicarbonate solution and water. The organic phase was dried over sodium sulfate and concentrated in vacuo. The crude product is purified by column chromatography on silica gel (dichloromethane/methanol, 98: 2).

Yield: 1.7g (24% of theory)

R_f＝0.58(XLV)

MS (DCI, isobutane): m/e 523(M + H)

Example 238

1-bis-N- (1-pentylsulfonyl) amino-4- (1, 2, 3, 4-tetrahydroisoquinolin-5-yl-oxy) -benzene hydrochloride

α -chloroethyl chloroformate was added to a solution of the compound from example 237 (1g, 1.92mmol) in anhydrous 1, 2-dichloroethane at 0 ℃. The mixture was then heated to reflux for 16 hours. The reaction was concentrated in vacuo, treated with methanol (20ml) and heated at reflux for 1 hour. After completion of the reaction, the mixture was concentrated in vacuo and the residue was recrystallized from pure ethanol (13 ml).

Yield: 625mg (64.0% of theory)

R_f＝0.22(XXXIII)

M.p.：162℃

MS (DCI, isobutane): m/e 509(M + H)

Example 239

1-bis-N- (1-pentylsulfonyl) amino-4- (2-isopropyl-1, 2, 3, 4-tetrahydroisoquinolin-5-yl-oxy) -benzene

Acetone (1.0g, 17.2mmol), molecular sieves (20 particles, 3. ANG.) and sodium cyanoborohydride (240mg, 2.81mmol) were added to a solution of the compound from example 238 (300mg, 0.55mmol) in pure methanol (15ml) at room temperature. The pH of the reaction was adjusted to 5 to 6 with several drops of acetic acid. The mixture was stirred at room temperature for 20 hours. Then, it is basified with sodium hydroxide, extracted with dichloromethane, and the organic phase is dried over sodium sulfate and concentrated in vacuo.

Yield: 300mg of crude product was reacted directly to give example 240.

R_f＝0.37(XXXIII)

MS (DCI, isobutane): m/e 551(M + H)

Example 240

N- (1-pentylsulfonyl) amino-4- (2-isopropyl-1, 2, 3, 4-tetrahydroisoquinolin-5-yl-oxy) -benzene hydrochloride

A solution of the compound from example 239 (370mg, 0.672mmol) in tetrahydrofuran (10ml) and 1N sodium hydroxide solution (1.35ml, 1.35mmol) was stirred at room temperature for 8 h. The reaction was then acidified to pH 1 with 1N hydrochloric acid and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated in vacuo. The product is purified by column chromatography on silica gel (eluent: dichloromethane/methanol, 98: 2). After dissolving the product in ethanol, it is converted to the hydrochloride salt by treatment with 1N hydrochloric acid and subsequently concentrated in vacuo.

Yield: 239mg (79% of theory)

R_f＝0.39(XXXIII)

M.p.: amorphous form

MS (DCI, isobutane): m/e 417(M + H)

Example 241

1-bis-N- (1-pentylsulfonyl) amino-4- (2-butyl-1, 2, 3, 4-tetrahydroisoquinolin-5-yl-oxy) -benzene

The product was prepared in analogy to example 239 using example 238(215mg, 0.394mmol) and butyraldehyde (889mg, 12.3 mmol).

Yield: 260mg of crude product, which was reacted directly to give example 242.

R_f＝0.7(XXXIII)

MS (DCI, isobutane): 565(M + H)

N- (1-pentylsulfonyl) amino-4- (2-butyl-1, 2, 3, 4-tetrahydroisoquinolin-5-yl-oxy) -benzene

This product was prepared in analogy to example 240, using example 241(255mg, 0.451 mmol).

Yield: 236mg (64% of theory)

R_f＝0.25(XXXIII)

M.p.：187℃

MS (DCI, isobutane): 431(M + H) with M/e ═ 431

The examples shown in Table 19 were prepared in analogy to the preparation of example 97:

watch 19

The compounds in table 19 were converted to the corresponding hydrochloride salts by dissolving them in methanol or ethanol, treating with 1N hydrochloric acid and then concentrating in vacuo.

Watch 20

Example 249

4- (1, 2, 3, 4-tetrahydroisoquinolin-5-yl-oxy) -1- (1-pentylsulfonyl) oxy-benzene

This product was prepared in analogy to example 238, using example 243(2g, 5.14 mmol).

Yield: 1.60g (75% of theory)

R_f＝0.23(XXXIII)

M.p.：143℃

MS (DCI, isobutane): m/e 376(M + H)

The examples shown in Table 21 were prepared in analogy to the preparation of example 97. The amine is converted to the hydrochloride salt by dissolving it in methanol or ethanol, treating with 1N hydrochloric acid and then concentrating in vacuo.

TABLE 21

Examples	R	Yield (% of theory)	M.p.(℃)	R	MS(m/e)
Examples	R	Yield (% of theory)	M.p.(℃)	R	MS(m/e)	250	Ethyl radical	22	-	0.48(XXXIII)	-
251	Isopropyl group	85	185	0.56(XXXIII)	418(M+H)(E)	250	Ethyl radical	22	-	0.48(XXXIII)	-
251	Isopropyl group	85	185	0.56(XXXIII)	418(M+H)(E)	252	N-butyl	55	151	0.69(XXXIII)	432(M+H)(E)

Example 253

1- (4-aminonaphthalen-1-yl-oxy) ═ 4 (benzylsulfonylamino) -benzene hydrochloride

The compound from example 190 (374mg, 0.839mmol) was dissolved in warm ethanol (200 ml). Hydrochloric acid (200ml) diluted once was added, and the mixture was heated under reflux for 1.5 hours, and then concentrated in vacuo.

Yield: 370mg (100% of theory)

R_f＝0.46(XLI)

M.p.：252℃

MS(FAB)：m/e＝405(M+H)

Example 254

4- (Benzylsulfonylamino) -1- (4-ethoxycarbonylamino-naphthalen-1-yl-oxy) benzene

A mixture composed of the compound (52mg, 0.12mmol) obtained in example 253, anhydrous dichloromethane (40ml), anhydrous tetrahydrofuran (30ml), triethylamine (24mg, 0.24mmol) and propionyl chloride (18mg, 0.18mmol) was stirred at room temperature for 16 hours. The reaction was concentrated in vacuo and the crude product was recrystallized from ethanol.

Yield: 42mg (% of theory)

R_f＝0.35(XLI)

M.p.：180℃

MS (DCI, isobutane): m/e 461(M + H)

The examples shown in Table 22 were prepared in analogy to the preparation of example 254:

TABLE 22

Examples	R	Yield (% of theory)	M.p.(℃)	R	MS(m/e)
Examples	R	Yield (% of theory)	M.p.(℃)	R	MS(m/e)	255	Cyclopropyl carbonyl group	66	177	0.54(XLI)	473(M+H)(E)
256	Benzoyl radical	46	197	0.56(XLI)	509(M+H)(E)	255	Cyclopropyl carbonyl group	66	177	0.54(XLI)	473(M+H)(E)
256	Benzoyl radical	46	197	0.56(XLI)	509(M+H)(E)	257	Mesyl radical	22	205	0.3(XLVI)	483(M+H)(E)

Example 258

2- (6-hydroxymethyl-naphthyl-1-oxy) -5- (N-1-pentylsulfonyl) amino-pyridine

Preparation was carried out in analogy to the preparation of example 1, starting from example 143A (7.30 g; 27.4 mmol).

Yield: 2.98g (27% of theory)

R_f＝0.42(VII)

MS(ESI)：m/e＝401(M+H)

Example 259

2- (6-hydroxymethyl-naphthyl-1-oxy) -5- (4, 4, 4-trifluoro-1-butylsulfonyl) aminopyridine

Preparation was carried out in analogy to the preparation of example 1, starting from example 143A (1.01 g; 3.78 mmol).

Yield: 0.62g (36% of theory)

M.p.：60℃

R_f＝0.36(VII)

MS(DCI/NH₃)：m/e＝441(M+H)

Example 260

3- (6-methyl-naphthyl-1-oxy) -1- (4, 4, 4-trifluoro-1-butylsulfonyl) amino-benzene

Preparation was carried out as in example 1, starting from example 141A (0.90 g; 3.61 mmol).

Yield: 1.09g (71% of theory)

M.p.：75-77℃

R_fNot 0.38 (dichloromethane)

MS(ESI)：m/e＝424(M+H)

Example 261

5- (1-Butylsulfonyl) amino-2- (naphthyl-1-oxy) -benzoic acid N-morpholinamide

Preparation was carried out in analogy to the preparation of example 79, starting from example 75(0.509 g; 1.27 mmol).

Yield: 0.425% (71% of theory)

R_f0.29 (dichloromethane: methanol 40: 1)

MS(DCI，NH₃)：m/e＝486(M+H)

Example 262

4- (naphthalen-1-yl-oxy) -2- (1-N-pentylsulfonyl) aminopyridine

Preparation was carried out in analogy to the preparation of example 2, starting from example 139A (0.300 g; 1.27 mmol).

Yield: 0.164g (35% of theory)

R_f＝0.66(VII)

MS(ESI)：m/e＝371(M+H)

Example 263

2- (N-benzylsulfonyl) amino-4- (naphthyl-1-oxy) -pyridine

Yield: 0.289g (58% of theory)

R_f＝0.55(VII)

MS(ESI)：m/e＝391(M+H)

Example 264

3-fluoro-5- (naphthyl-1-oxy) -1- (N-1-pentylsulfonyl) amino-benzene

Preparation was carried out in analogy to the preparation of example 1, starting from example 100A (1.00 g; 3.95 mmol).

Yield: 1.49g (96% of theory)

M.p.：72℃

R_f＝0.50(IV)

MS(ESI)：m/e＝410(M+Na)

Example 265

1- (N-benzylsulfonyl) amino-3-fluoro-5- (naphthyl-1-oxy) -benzene

Yield: 1.29 (77% of theory)

M.p.：122

R_f＝0.54(IV)

MS(DCI，NH₃)：m/e＝425(M+NH₄)

Example 266

3-fluoro-5- (naphthyl-1-oxy) -1- (4, 4, 4-trifluoro-1-butylsulfonyl) amino-benzene

Yield: 1.18g (69% of theory)

R_f＝0.49(IV)

MS(DCI，NH₃)：m/e＝445(M+NH₄)

Examples 267 and 268

(R) -and (S) -1-N- (N-pentylsulfonyl) amino-4- (2-hydroxymethyl-1, 2-indanyl-4-yloxy) -benzene

Enantiomer A (example 267) and enantiomer B (example 268)

The mixture of example 186(0.100g, 0.257mmol) was separated into the two enantiomers a (example 267) and B (example 268) by preparative HPLC (Chiralpak AD, 250mm × 20mm) eluting with 82% petroleum ether/18% isopropanol, T50 ℃ and flow rate 0.2 ml/min.

Example 267:

yield: 3.43mg (68% of theory)

Retention time: 10.6 minutes

Example 268:

yield: 13.3mg (26% of theory)

Retention time: 11.4 minutes

Example 269

3- (naphthyl-1-oxy) -1- [2- (bis-trifluoromethyl-methoxy) ethanesulfonyl ] aminobenzene

Preparation was carried out in analogy to the preparation of example 1, starting from example 45A (0.518 g; 2.20 mmol).

Yield: 0.315g (28% of theory)

R_fNot 0.56 (dichloromethane)

MS(DCI，NH₃)：m/e＝511(M+NH₄)

Example 270

3- (naphthyl-1-oxy) -1- (4, 4, 5, 5, 5-pentafluoro-1-pentylsulfonyl) amino-benzene

Yield: 0.665g (63% of theory)

R_fNot 0.54 (dichloromethane)

MS(DCI，NH₃)：m/e＝477(M+NH₄)

Example 271

3- (naphthyl-1-oxy) -1- (4, 4, 5, 5, 5-pentafluoro-1-pentylsulfonyl) oxy-benzene

Preparation was carried out in analogy to the preparation of example 97, starting from example 63A (0.210 g; 0.89 mmol).

Yield: 0.346g (85% of theory)

R_fNot 0.38 (dichloromethane)

MS(ESI)：m/e＝461(M+H)

Example 272

3- (6-methoxymethyl-naphthyl-1-oxy) -1- (N-1-pentylsulfonyl) amino-benzene

Preparation was carried out in analogy to the preparation of example 1, starting from example 144A (59.0mg, 0.21 mmol).

Yield: 64g (74% of theory)

R_f0.77 (dichloromethane: EA 10: 1)

MS(OCI，NH₃)：m/e＝431(M+NH₄)

Example 273

(R, S) -1-N- (4, 4, 4-trifluoro-1-butylsulfonyl) amino-3- (2-hydroxymethyl-1, 2-indanyl-4-yloxy) -benzene

Preparation was carried out in analogy to the preparation of example 1, starting from example 146A (0.800 g; 3.13 mmol).

Yield: 0.832g (64% of theory)

R_f＝0.50(VII)

MS(DCI，NH₃)：m/e＝447(M+NH₄)

Example 274 and example 275

(R) and (S) -1-N- (4, 4, 4-trifluoro-1-butylsulfonyl) amino-3- (2-hydroxymethyl-1, 2-indanyl-4-yloxy) -benzene

Enantiomer A (example 274) and enantiomer B (example 275)

The compound of example 273 (0.560g, 1.30mmol) was separated by preparative HPLC (Chiralpak AD 10 μm, 250 × 20mm, eluent: 88% petroleum ether 40 ℃ -70 ℃/12% ethanol, T ═ 15 ℃) into enantiomer a (example 274) and enantiomer B (example 275).

Example 274:

yield: 85mg (15% of theory)

Retention time: 13.3 minutes

Example 275:

yield: 80mg (14% of theory)

Retention time: 15.6 minutes

Example 276

(R, S) -1- (4, 4, 4-trifluoro-1-butylsulfonyl) oxy-3- (2-hydroxymethyl-1, 2-indanyl-4-oxy) -benzene

A solution of example 147A (1.228 g; 4.79mmol) in THF (10ml) is treated at room temperature under argon with potassium tert-butoxide (0.538 g; 4.79mmol) and stirred at room temperature for 30 minutes. Then, 4, 4, 4-trifluorobutyl-1-sulfonyl chloride (1.009g, 4.79mmol) was added dropwise and the reaction mixture was stirred for 16 hours. After addition of ethyl acetate (50ml), the mixture was washed with water (50ml) and saturated aqueous sodium chloride (50ml) and dried (sodium sulfate), and the solvent was evaporated in vacuo. The residue is chromatographed on silica gel, eluting with toluene: EA (3: 1).

Yield: 0.894g (41% of theory)

R_f0.39 (toluene: EA: 3: 1)

MS(DCI，NH₃)：m/e＝448(M+NH₄)

Example 277 and example 278

(R) and (S) -1- (4, 4, 4-trifluoro-1-butylsulfonyl) oxy-3- (2-hydroxymethyl-1, 2-dihydroindenyl-4-oxy) -benzene

(+) -enantiomer A (example 277) and (-) -enantiomer B (example 278)

The compound of example 276 (490mg, 1.14mmol) was separated by preparative HPLC (chiralel OD 10 μm, 250 × 20mm, flow rate 10 ml/min, eluent: 80% petroleum ether 40 ℃ -70 ℃/20% isopropanol, T ═ 10 ℃) into enantiomer a (example 277) and enantiomer B (example 278).

Example 277:

yield: 111mg (23% of theory)

M.p.：60-61℃

Retention time: 12.5 minutes

[α]_D ²⁰(c-1, methanol) +10.70

Example 278:

yield: 105mg (21% of theory)

Retention time: 15.4 minutes

[α]_D ²⁰(c-1, methanol) -10.35

Example 279

5- [ (4, 4, 4-trifluoro-1-butyl) sulfonylamino ] -2- (naphthyl-1-oxy) -pyridine sodium salt

Preparation was carried out in analogy to the preparation of example 128, starting from example 189(452mg, 1.10 mmol).

Yield: 315mg (66% of theory)

M.p.: 170 deg.C (decomposition)

The examples shown in table 23 were prepared in analogy to example 279.

TABLE 23

Example 285

5-fluoro-1- [ (4, 4, 4-trifluoro-1-butyl) sulfonyl ] amino-3- (naphthalenyl-1-oxy) -benzenepotassium salt

Preparation was carried out in analogy to the preparation of example 128, starting from example 266(400mg, 0.94mmol) and using potassium tert-butoxide (105mg, 0.94mmol) instead of sodium methoxide.

Yield: 433mg (99% of theory)

M.p.：46-50℃

Example 286

(R, S) -1- [ (4, 4, 4-trifluoro-1-butyl) sulfonyl ] amino-3- (2-methanesulfonyloxymethyl-1, 2-indanyl-4-yloxy) -benzene

Methanesulfonyl chloride (195mg, 1.70mmol) was added dropwise to a solution of example 276(665mg, 1.55mmol) and triethylamine (235mg, 2.32mmol) in dichloromethane (10ml) at-10 ℃ under argon and the reaction was stirred at-10 ℃ for a further 30 minutes and allowed to warm to room temperature. The reaction mixture was diluted with dichloromethane (10ml) and washed with water (20ml), 1N hydrochloric acid (10ml), saturated aqueous sodium bicarbonate (20ml) and water (20ml), dried over sodium sulphate and concentrated in vacuo.

Yield: 706mg (88% of theory)

R_f＝0.74(VII)

MS(ESI)：m/e＝509(M+H)

Example 287

(R, S) -3- (2-azidomethyl-1, 2-indanyl-4-oxy) -1- [ (4, 4, 4-trifluoro-1-butyl) sulfonyl ] amino-benzene

A solution of example 286(637mg, 1.25mmol) in DMSO (5ml) was treated with sodium azide (407mg, 6.26mmol) and stirred at 80 ℃ for 1 h under argon. After addition of water (50ml), the mixture was extracted with diethyl ether (2X 50 ml). The combined organic phases were washed with water (30ml), dried over sodium sulphate and concentrated in vacuo.

Yield: 507mg (87% of theory)

R_f＝0.78(IV)

MS(EI)：m/e＝427(M-N₂)

Example 288

(R, S) -3- (2-aminoethyl-1, 2-indanyl-4-yloxy) -1- [ (4, 4, 4-trifluoro-1-butyl) sulfonyl ] amino-benzene hydrochloride

Example 287(457mg, 1.00mmol) was dissolved in methanol (10ml), treated with 10% palladium on activated carbon (50mg) and hydrogenated under 1 bar of hydrogen for 1.5 h. The reaction was filtered through silica gel and concentrated in vacuo. The residue was taken up in diethyl ether (5ml) and methanol (4ml) and treated with a saturated solution of hydrogen chloride in diethyl ether (2 ml). The solvent was then evaporated in vacuo and the residue was stirred in ether, filtered and dried in vacuo.

Yield: 321mg (69% of theory)

M.p.：192℃

R_f0.10 (dichloromethane: methanol 20: 1)

MS(DCI，NH₃)：m/e＝430(M+H)

Example 289

(R, S) -3- (2-dimethylaminomethyl-1, 2-dihydroindenyl-4-oxy) -1- [ (4, 4, 4-trifluoro-1-butyl) sulfonyl ] amino-benzene hydrochloride

Example 288(140mg, 0.30mmol) was dissolved in dichloromethane and washed with aqueous ammonia solution. The aqueous phase was washed with dichloromethane (2X 20 ml). The combined organic phases were dried (sodium sulfate) and concentrated in vacuo. The residue was dissolved in acetonitrile (5.0ml) and treated with 37% aqueous formaldehyde (246mg, 3.0mmol) and sodium cyanoborohydride (191mg, 3.0mmol) at room temperature. The mixture was stirred at room temperature for 30 minutes, the pH was adjusted to 3 with acetic acid, the mixture was stirred for 5 minutes and 20ml of 1N sodium hydroxide was added. The reaction mixture was washed with dichloromethane (2X 20 ml). The combined organic phases were dried (sodium sulfate) and concentrated in vacuo on a rotary evaporator. The residue was dissolved in methanol (5ml) and treated with a saturated solution of hydrogen chloride in diethyl ether (0.1 ml). The solution was then concentrated in vacuo.

Yield: 134mg (90% of theory)

R_f＝0.33(XXV)

MS(DCI，NH₃)：m/e＝458(M+H)

Example 290

1- [ (4, 4, 4-trifluoro-1-butyl) sulfonyl ] amino-3- (6-hydroxymethyl-naphthalen-1-oxy) benzene

Preparation was carried out in analogy to the preparation of example 276, starting from example 148A (1.01 g; 3.80 mmol).

Yield: 0.72g (43% of theory)

R_f0.60 (toluene: EA: 5: 4)

MS(DCI，NH₃)：m/e＝458(M+NH₄)

Example 291

3- (6-hydroxymethyl-naphthyl-1-oxy) -1- (1-pentylsulfonyl) oxy-benzene

Preparation was carried out in analogy to the preparation of example 276, starting from example 148(5.33 g; 20.0 mmol).

Yield: 4.0g (49% of theory)

R_f＝0.67(VI)

MS(DCI，NH₃)：m/e＝418(M+NH₄)

Example 292

3- (6-Methanesulfonyloxymethyl-naphthyl-1-oxy) -1- (1-pentylsulfonyl) oxy-benzene

Preparation was carried out in analogy to the preparation of example 286, starting from example 291(3.73 g; 9.00 mmol).

Yield: 3.19g (74% of theory)

R_f0.64 (toluene: EA: 5: 2)

MS(DCI，NH₃)：m/e＝496(M+NH₄)

Example 293

3- (6-azidomethyl-naphthyl-1-oxy) -1- (1-pentylsulfonyl) oxy-benzene

Preparation was carried out in analogy to the preparation of example 287, starting from example 292(3.60 g; 7.52 mmol).

Yield: 2.68g (84% of theory)

R_f0.88 (toluene: EA: 5: 2)

MS(DCI，NH₃)：m/e＝443(M+NH₄)

Example 294

3- (6-aminomethyl-naphthyl-1-oxy) -1- (1-pentylsulfonyl) oxy-benzene hydrochloride

Preparation was carried out in analogy to the preparation of example 288, starting from example 293(2.40 g; 5.64 mmol).

Yield: 2.23g (90% of theory)

M.p.: > 150 ℃ (decomposition)

R_f＝0.41(XXV)

MS(DCI，NH₃)：m/e＝400(M+H)

Example 295

3- (6-N, N-dimethylaminomethyl-naphthyl-1-oxy) -1- (1-pentylsulfonyl) oxy-benzene hydrochloride

Preparation was carried out in analogy to the preparation of example 289, starting from example 294(1.09 g; 2.50 mmol).

Yield: 0.220g (19% of theory)

R_f＝0.49(XXV)

MS(DCI，NH₃)：m/e＝428(M+H)

Example 296

1- (1-pentylsulfonyl) amino-4- (2, 3-dimethyl-phenyl-1-oxy) -benzene

Preparation was carried out in analogy to the preparation of example 1, starting from example 29A (7.25 g; 34.0 mmol).

Yield: 10.9g (93% of theory)

R_f＝0.43(IV)

MS(ESI)：m/e＝348(M+H)

Example 297

1- [ N, N-bis- (1-pentylsulfonyl) amino ] -4- (2, 3-dimethyl-phenyl-1-oxy) benzene

Potassium tert-butoxide (1.18g, 10.5mmol) was added to a solution of example 296(3.48g, 10.0mmol) in THF (40ml) with cooling in an ice bath, the mixture was stirred for 20 minutes and 1-pentylsulfonyl chloride (2.04g, 12.0mmol) was added dropwise at 0 ℃. The mixture was stirred at room temperature overnight and after addition of water was extracted three times with ethyl acetate, dried (magnesium sulfate) and concentrated in vacuo. The residue is chromatographed on silica gel eluting with toluene.

Yield: 3.71g (77% of theory)

M.p.：91℃

R_f0.64 (PE: ether: 10: 3)

MS(ESI)：m/e＝482(M+H)

Example 298

1- [ N, N-bis- (1-pentylsulfonyl) amino ] -4- [2, 3- (bis-bromomethyl) -phenyl-1-oxy ] benzene

N-bromosuccinimide (10.2g, 57.4mmol) was added dropwise to a solution of example 297(13.0g, 27.0mmol) in carbon tetrachloride (250ml) and the reaction was heated under reflux for 4 hours while irradiating with a 300W lamp. After cooling, the reaction was filtered and the filtrate was concentrated in vacuo. The residue is chromatographed on silica gel, eluting with cyclohexane/diethyl ether (10: 1). The resulting product was crystallized from cyclohexane.

Yield: 13.4g (78% of theory)

M.p.：68-75℃

R_f0.90 (PE: ether: 10: 3)

MS(ESI)：m/e＝662(M+Na)

Example 299

4- (1-n-butyl-isoindolinyl-3-oxy) -1- (1-pentylsulfonyl) amino-benzene hydrochloride

A solution of example 298(0.750 g; 1.17mmol) and n-butylamine (0.858 g; 11.7mmol) in THF (150ml) is stirred at room temperature overnight. The reaction was treated with 1N sodium hydroxide (5.0ml) and stirred at 50 ℃ for 24 h. The solvent was evaporated in vacuo and the residue was taken up in ethyl acetate (50ml) and washed with water (50 ml). The aqueous phase was extracted with ethyl acetate (25ml) and the combined organic phases were dried (sodium sulphate) and concentrated in vacuo. The residue is chromatographed on silica gel, eluting with toluene/ethyl acetate (1: 1). The resulting amine was dissolved in diethyl ether (5ml) and treated with a saturated solution of hydrogen chloride in diethyl ether (1 ml). The solvent was evaporated in vacuo and the product was dried in vacuo.

Yield: 0.255g (47% of theory)

M.p.: 70-73 deg.C (decomposition)

R_f＝0.37(VII)

MS(DCI，NH₃)：m/e＝417(M+H)

The examples shown in Table 24 were prepared in analogy to the procedure of example 299.

Watch 24

Examples	R	Yield (% of theory)	R	MS
Examples	R	Yield (% of theory)	R	MS	300	Me	63	0.50(XXV)	375(M+H)，B
301	nPr	50	0.58(XXV)	403(M+H)，B	300	Me	63	0.50(XXV)	375(M+H)，B

Example 302

4- [2, 2-bis- (ethoxycarbonyl) -1, 2-indanyl-4-oxy ] -1- [ N, N-bis (1-pentylsulfonyl) amino ] -benzene

A solution of example 298(2.00g, 3.13mmol) and diethyl malonate (0.50g, 3.13mmol) in 2-butanone (30ml) was treated with potassium carbonate (1.88g, 13.6mmol) and stirred at reflux for 18 h. Cooled to room temperature and filtered, and the filtrate concentrated in vacuo. The residue is chromatographed on silica gel, eluting with toluene: EA (30: 1).

Yield: 0.480g (24% of theory)

R_f＝0.53(X)

MS(ESI)：m/e＝638(M+H)

Example 303

4- [2, 2-bis- (hydroxymethyl) -1, 2-indanyl-4-oxy ] -1- [ 1-n-pentylsulfonyl ] amino-benzene

A1N THF solution of lithium aluminum hydride (1.42ml, 1.42mmol) was added dropwise to a solution of example 302(452mg, 0.71mmol) in THF (5.0ml) under argon at room temperature, and the mixture was stirred at room temperature for 18 hours. After addition of a saturated aqueous ammonium chloride solution (20ml), extraction was carried out with ethyl acetate (1X 50ml, 2X 25 ml). The combined organic phases were washed with saturated aqueous sodium chloride (25ml), dried (sodium sulphate) and concentrated in vacuo. The residue is chromatographed on silica gel with toluene: EA 1: 1.

Yield: 149mg (49% of theory)

M.p.：135-137℃

R_f＝0.25(VII)

MS(ESI)：m/e＝442(M+Na)

Example 304

3- (2, 3-dimethyl-phenyl-1-oxy) -1- (4, 4, 4-trifluoro-1-butylsulfonyl) oxy-benzene

Preparation was carried out in analogy to the preparation of example 97, starting from example 150A (4.54 g; 21.2 mmol).

Yield: 7.80g (95% of theory)

R_fNot rated as 0.51 (toluene)

MS(DCI，NH₃)：m/e＝406(M+NH₄)

Example 305

3- (2, 3-bis-bromomethyl-phenyl-oxy) -1- (4, 4, 4-trifluoro-1-butylsulfonyl) oxy-benzene

Preparation was carried out in analogy to the preparation of example 298, starting from example 304(6.76 g; 17.4 mmol).

Yield: 7.98g (84% of theory)

R_f＝0.71(IV)

MS(DCI，NH₃)：m/e＝564(M+NH₄)

Example 306

1- (4, 4, 4-trifluoro-1-butylsulfonyl) oxy-3- [2, 2-bis- (methoxycarbonyl) -1, 2-indanyl-4-oxy ] benzene

Preparation was carried out in analogy to the preparation of example 302, starting from example 305(6.00 g; 10.2 mmol).

Yield: 1.95g (37% of theory)

R_f＝0.45(X)

MS(DCI，NH₃)：m/e＝534(M+NH₄)

Example 307

1- (4, 4, 4-trifluoro-1-butylsulfonyl) oxy-3- (1-n-propylisoindolinyl-3-oxy) -benzene

A solution of example 305(2.00g, 3.66mmol) and n-propylamine (2.16g, 36.6mmol) in THF (200ml) was stirred at room temperature for 5 hours. The THF is distilled off in vacuo, the residue is recovered in water and the mixture is extracted with ethyl acetate. The organic phase was extracted with 5% aqueous potassium carbonate and the organic phase was extracted twice with water, dried (magnesium sulfate) and concentrated in vacuo. The residue is chromatographed on silica gel, eluting with dichloromethane: methanol 20: 1. The resulting amine was dissolved in diethyl ether (5ml) and treated with a saturated solution of hydrogen chloride in diethyl ether (1.5 ml). The solvent was removed in vacuo and the residue triturated with ether, filtered and dried in vacuo.

Yield: 0.775g (44% of theory)

R_f＝0.29(XXXII)

MS(ESI)：m/e＝444(M+H)

Example 308

3- (1-hexyl) oxy-3- (naphthyl-1-oxy) benzene

A solution of example 63A (300mg, 1.27mmol) in acetone (5.0ml) was treated with potassium carbonate (193mg, 1.40mmol) and 1-iodohexane (296mg, 1.40mmol) and stirred at reflux for 18 h. The solvent was then removed in vacuo, the residue taken up in water (30ml) and the mixture extracted with diethyl ether (3X 30 ml). The combined organic phases were dried (sodium sulfate) and concentrated in vacuo. The residue is chromatographed on silica gel, eluting with cyclohexane: dichloromethane (4: 1).

Yield: 285mg (69% of theory)

R_f0.50 (PE: dichloromethane 4: 1)

MS(DCI，NH₃)：m/e＝321(M+H)

Example 309

N-1-hexyl-3- (naphthyl-1-oxy) anilines

A solution of example 45A (1.176g, 5.00mmol) and 1-iodohexane (0.509g, 2.40mmol) in petroleum ether (10ml) was heated at reflux overnight. After addition of 1-iodohexane (0.170g, 0.80mmol) and THF (4ml), the mixture was stirred at reflux for a further 3 hours. After addition of diethyl ether (50ml), it was washed with dilute aqueous ammonia (50ml) and water (2X 50ml) and dried (sodium sulphate) and the solvent removed in vacuo. The residue is chromatographed on silica gel, eluting with cyclohexane: dichloromethane (3: 1).

Yield: 0.211g (28% of theory)

R_f＝0.86(IV)

MS(DCI，NH₃)：m/e＝320(M+H)

Claims

1. A compound of the general formula (I):

R¹-A-D-E-G-L-R² (I)

wherein

R¹Represents optionally substituted by (C)₁-C₆) -alkyl-substituted naphthalen-1-yl, wherein alkyl is substituted by hydroxy, (C)₁-C₆) -amido, amino or (C)₁-C₆) -alkoxy substitution; or by hydroxy (C)₁-C₆) Alkyl-substituted-1, 2-indan-4-yl;

or R¹To representA group of the formula:

wherein R is³Is (C)₁-C₆) -an alkyl group,

e and A represent a chemical bond,

d represents an oxygen atom, and D represents an oxygen atom,

l represents formula-NH-SO₂-or-O-SO₂-, and

R²is represented by (C)₁-C₆) -alkyl optionally substituted by chloro, trifluoromethyl, of formula-O-CH₂-CF₃Substituted by radicals, phenyl or pyridyl, the phenyl and pyridyl radicals being optionally substituted by bromine or ammonia atoms

2. A compound of the formula:

racemic or enantiomeric forms

Racemic or enantiomeric forms

3. Process for the preparation of a compound according to claim 1 or 2, characterised in that

[A] A compound of the general formula (II)

R¹-A-D-E-G-M-H (II)

Wherein R is¹A, D, E and G are as defined in claim 1, and

m represents an oxygen atom or-N (R)³²)-，

R³²Is a hydrogen atom or (C)₁-C₄) -an alkyl group,

with a compound of the general formula (III) in an inert solvent, optionally in the presence of a base,

R³³-Q-R² (III)

wherein R is²As defined in claim 1, wherein the first and second substrates are,

R³³represents a halogen, and is characterized in that,

q represents a group-SO₂-、-SO-、-CO-、-P(O)(OR²⁷) -or a single bond,

wherein R is²⁷Represents a hydrogen atom or (C)₁-C₄) -an alkyl group,

to give compounds of the general formula (Ia)

R¹-A-D-E-G-M-Q-R² (Ia)

Wherein R is¹A, D, E, G, M, Q and R²As defined above;

alternatively, the first and second electrodes may be,

[B] the compound of the general formula (II) is firstly reacted with trialkylsilyl chlorosulfonate, treated with acid and then reacted with a chlorinating agent to obtain a compound of the general formula (IV),

R¹-A-D-E-G-M-SO₂-Cl (IV)

wherein R is¹A, D, E, G and M are as defined above,

then reacting with a compound of the general formula (V),

H-T-R² (V)

and T represents an oxygen atom or a nitrogen atom,

the reaction is carried out in an inert solvent, optionally Bzl-NEt₃ ⁺Cl^-And in the presence of a base to give a compound of the formula (Ib)

R¹-A-D-E-G-M-SO₂-T-R² (Ib)

Wherein R is¹A, D, E, G, M, T and R²As defined above;

alternatively, the first and second electrodes may be,

[C] a compound of the general formula (VI)

R¹-A-D′-H (VI)

Wherein R is¹And A is as defined above, and,

d' represents an oxygen atom, a sulfur atom or-N (R)⁹) -, and

with a compound of the general formula (VII),

R³⁴-E-G-SO₂-NH-R² (VII)

wherein E, G and R²Is as defined above, and

R³⁴represents a leaving group, and represents a leaving group,

to give a compound of the formula (Ic)

R¹-A-D′-E-G-SO₂-NH-R² (Ic)

Wherein R is¹A, D', E, G and R²As defined above;

alternatively, the first and second electrodes may be,

[D] a compound of the formula (Id)

R³⁷-A-D-E-G-L-R² (Id)

Wherein A, D, E, G, L and R²Is as defined above, and

R³⁷represents a group of the formula

Wherein R is³As defined in claim 1, wherein the first and second substrates are,

with chloroformates or methyl chloroformates, followed by reaction with alcohols, optionally in the presence of a base, to give a compound of the formula (Ie)

R³⁸-A-D-E-G-L-R² (Ie)

Wherein A, D, E, G, L and R²Is as defined above, and

R³⁸represents a group of the formula

Alternatively, the first and second electrodes may be,

[E] a compound of the formula (Ie)

And (C)₁-C₆) -ketone or (C)₁-C₆) -an aldehyde reaction, carried out in the presence of a reducing agent, optionally in the presence of an acid, to give a compound of general formula (If)

R³⁹-A-D-E-G-L-R² (If)

Wherein A, D, E, G, L and R²The definition is as above-mentioned,

alternatively, the first and second electrodes may be,

[F] reacting a compound of formula (Ie) with a compound of formula (VIII),

R³⁵-R³ (VIII)

R³⁵represents a leaving group, and represents a leaving group,

the reaction is carried out in an inert solvent, optionally in the presence of a base, to give a compound of the general formula (Ig)

R⁴⁰-A-D-E-G-L-R² (Ig)

Wherein A, D, E, G, L and R²The definition is as above-mentioned,

and R is⁴⁰Represents a group of the formula

Wherein R is³The definition is as above-mentioned,

alternatively, the first and second electrodes may be,

[G] a compound of the formula (Ih)

Wherein A, D, E, G, L and R²The definition is as above-mentioned,

by free radical bromination in an inert solvent, to the compounds of formula (Ii)

Wherein A, D, E, G, L and R²The definition is as above-mentioned,

then reacting it with a compound of the general formula (IX) or (X),

CH₂(CO₂R⁴²)₂ (IX)

H₂N-R³ (X)

wherein R is⁴²Is represented by (C)₁-C₆) -an alkyl group,

and R is³The definition is as above-mentioned,

the reaction is carried out in an inert solvent, optionally in the presence of a base, to give a compound of the general formula (Ij)

R⁴³-A-D-E-G-L-R² (Ij)

Wherein A, D, E, G, L and R²The definition is as above-mentioned,

and R is⁴³To represent

Wherein R is⁴²And R³The definition is as above-mentioned,

and, optionally introducing and derivatizing the above substituents according to a conventional method,

and if D is-SO-or-SO₂The oxidation is carried out in a conventional manner starting from the corresponding thioether, i.e. D ═ S,

4. The method of claim 3, wherein:

step [ A ]]In, R³³Represents chlorine or iodine, and represents chlorine or iodine,

in the step (B), the trialkylsilyl chlorosulfonate is trimethylsilyl chlorosulfonate, or the chlorinating agent is phosphorus pentachloride,

step [ C]In, R³⁴Represents a halogen, and is characterized in that,

in the step [ D ], the chloroformate is 1- (1-chloro) ethyl chloroformate, or the alcohol is methanol,

in the step [ E ], the reducing agent is sodium cyanoborohydride,

in the step [ F ], the leaving group is halogen,

in the step [ G ], the bromination reaction is carried out by reacting with N-bromosuccinimide.

5. The method of claim 4, wherein:

step [ C]In, R³⁴Represents fluorine, chlorine or bromine.

6. A pharmaceutical composition comprising as active ingredient at least one compound according to claim 1 or 2 in admixture with at least one pharmaceutically tolerable, substantially non-toxic carrier or excipient.

7. Use of a compound according to claim 1 or 2 for the preparation of a medicament for the prevention and/or treatment of cerebral ischemia and craniocerebral trauma.