WO1997021678A1 - Carbamic acid derivatives as leukotriene antagonists - Google Patents

Carbamic acid derivatives as leukotriene antagonists Download PDF

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Publication number
WO1997021678A1
WO1997021678A1 PCT/EP1996/005248 EP9605248W WO9721678A1 WO 1997021678 A1 WO1997021678 A1 WO 1997021678A1 EP 9605248 W EP9605248 W EP 9605248W WO 9721678 A1 WO9721678 A1 WO 9721678A1
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Prior art keywords
phenyl
formula
carbon atoms
straight
chain
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PCT/EP1996/005248
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French (fr)
Inventor
Mazen Es-Sayed
Masaru Yamamoto
Klaus Frobel
Chris Poll
Suzanna Grix
Stephen Tudhope
Original Assignee
Bayer Aktiengesellschaft
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Priority to AU10941/97A priority Critical patent/AU1094197A/en
Publication of WO1997021678A1 publication Critical patent/WO1997021678A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates

Definitions

  • the invention relates to carbamic acid derivatives, process for their preparation and their use in medicaments
  • Leukotrienes are arachidonic acid metabolites produced by the 5-l ⁇ poxygenase pathway in activated phagocytes and are important mediators of bronchial asthma and acute inflammation The pathophysiological importance of leukotrienes suggests that selective inhibitors of leukotriene synthesis may be useful anti- allergic and anti-inflammatory therapeutic agents
  • the invention relates to carbamic acid derivatives of the general formula (I)
  • R 1 represents a 6 membered aromatic heterocycle having up to 2 nitrogen atoms and to which a phenyl ring can be fused and wherein the rings optionally are monosubstituted or disubstituted by identical or different substituents from the series comprising halogen, carboxyl, nitro or a straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms or by a group of the formula -(CO) -NRY 4
  • a denotes a number 0 or 1 ,
  • R 1 and R 4 are identical or different and denote hydrogen, biphenyl, phenyl, adamantyl or straight-chain or branched alkyl oi ac ⁇ l each having up to 6 carbon atoms, which optionally are monosubstituted or disubstituted by phenyl and/or hydroxyl,
  • R ⁇ represents adamantyl, cycloalkyl having 3 to 6 carbon atoms, pyridyl, phenyl or benzyl, which optionally are substituted by halogen, carboxyl or straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, or represents a group of the formula
  • A represents adamantyl, dicyclohexylmethyl, cyclododecyl, cis-decahydro-1 - naphthyl, 4-tert.butylphenyl, 2-naphthyl, 2,6-diphenylphenyl, dibenzo- suberolyl, 2-methylbenzyl, ⁇ -cyclopropyl-benzyl, 9-hydroxy-phenanthrenyl, 4-tritylphenyl, or represents a residue of the formula and then salts
  • the compound of the general formula (I) can also be present in the form of their salts in general, salts with organic or inorganic bases or acids may be mentioned here
  • Physiologically acceptable salts are preferred Physiologically acceptable salts of the carbamic acid derivatives can be metal or ammonium salts of the substances according to the invention, which contain a free carboxylic group Those which are particularly preferred are, for example, sodium, potassium, magnesium or cal ⁇ cium salts, and also ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanol ⁇ amine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylene ⁇ diamine
  • Physiologically acceptable salts can also be salts of the compounds according to the invention with inorganic or organic acids
  • Preferred salts here are those with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, or salts with organic carboxylic or sulphonic acids such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid
  • the compounds according to the invention can exist in stereoisome ⁇ c forms which either behave as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers)
  • the invention relates both to the anti ⁇ podes and to the racemate forms, as well as the mixture of diastereomers
  • the racemate forms, like the diastereomers, can be separated into the stereoisome ⁇ - cally uniform constituents in a known manner
  • Preferred compounds of the general formula (I) are those
  • R 1 represents isoquinolyl, pyrazinyl, pyridyl or pyrimidyl, which optionally are monosubstituted or disubstituted by identical or different substituents from the series comprising fluorine, chlorine, bromine, iodine, carboxyl, nitro or a straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms or by a group of the formula -(CO) a -NR 3 R 4 ,
  • a denotes a number 0 or 1
  • R 3 and R 4 are identical or different and denote hydrogen, biphenyl, phenyl, adamantyl or straight-chain or branched alkyl or acyl each having up to 5 carbon atoms, which optionally are monosubstituted or di ⁇ substituted by phenyl and/or hydroxyl,
  • R 2 represents cyclopentyl, cyclohexyl, pyridyl, phenyl or benzyl, which optionally are substituted by fluorine, chlorine, bromine, carboxyl, straight- chain or branched alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, or represents the group of the formula
  • R 1 and R 2 including the nitrogen atom together form a residue of a formula
  • A represents adamantyl, dicyclohexylmethyl, cyclododecanyl, cis-decahydro-
  • Particularly preferred compounds are those of the general formula (I),
  • R represents pyridyl or pyrimidyl, which optionally are monosubstituted or disubstituted by identical or different substituents from the series comprising fluorine, chlorine, bromine, carboxyl, nitro or a straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms or by a group of the formula -(CO) r NR 3 R 4 ,
  • R denotes a number 0 or R s and R are identical or different and denote hydrogen, biphenyl, phenyl, adamantyl, straight-chain or branched alkyl or acyl each having up to 3 carbon atoms, which are optionally monosubstituted or disub ⁇ stituted by phenyl and/or hydroxyl,
  • R 2 represents cyclopentyl, cyclohexyl, pyridyl or phenyl, which optionally are substituted by fluorine, chlorine, bromine, carboxyl, straight-chain or branched alkoxy or alkoxycarbonyl each having up to 3 carbon atoms, or represents the group of the formula
  • T represents halogen, preferably chlorine
  • Suitable solvents are generally customary organic solvents which do not change under the reaction conditions
  • T hese include ethers such as diethyl ether, dioxane or tetrahydrofuran, acetone, dimethylsulfoxide, dimethylformamide or alcohols such as methanol, ethanol, propanol or halogenohydrocarbons such as dichlor- methane, t ⁇ chloromethane or tetrachloromethane Tetrahydrofuran is preferred
  • Suitable bases are generally inorganic or organic bases These preferably include alkali metal hydroxides such as, for example, sodium hydroxide, sodium hydrogen- carbonate or potassium hydroxide, alkaline earth metal hydroxides such as, for example, barium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, or alkaline metal or organic amines (trialkyl(C ] -C 6 )amines) such as triethylamine, or heterocycles such as l,4-d ⁇ azab ⁇ cyclo[2 2 2]octane (DABCO), 1,8-d ⁇ azab ⁇ cyclo- [5 4 0]undec-7-ene (DBU), or amides such as sodium amides, lithium butyl amide or butyllithium, pyridine or methylpipe ⁇ dine It is also possible to employ alkali metals, such as sodium or its hydrides such as sodium hydride, as bases
  • the process is in general carried out in a temperature range from 0°C to +100°C, preferably from room temperature to +60°C
  • the process is generally carried out at normal pressure However, it is also possible to carry out it at elevated pressure or at reduced pressure (for example in a range from 0 5 to 5 bar)
  • the base is employed in an amount from 1 mol to 10 mol, preferably from 1 0 mol to 4 mol, relative to 1 mol of the compounds of the general formula (III)
  • the compounds of the general formula (III) are known or can be prepared by customary methods
  • the carbamic acid derivatives of the general formula (I) can be employed as active compounds in medicaments.
  • the substances can act as inhibitors of enzy ⁇ matic reactions in the context of arachidonic acid metabolism.
  • the compounds of the general formula (I) surprisingly show a high activity as inhibitors of leukotriene synthesis, specifically inhabit the production of leuko ⁇ triene B 4 in polymorphonuclear leucocytes (PMNL).
  • the new active compounds can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, nontoxic, pharmaceuti- cally suitable excipients or solvents
  • the therapeutically active compound should in each case be present in a concentration of about 0 5 to 90% by weight of the total mixture, l e in amounts which are sufficient in order to achieve the dosage range indicated
  • the formulations are prepared, for example, by extending the active compounds with solvents and/or excipients, if appropriate using emulsifiers and/or dispersants, where, for example, in the case of the use of water as a diluent, organic solvents can be used as auxiliary solvents if appropriate
  • Administration is carried out in a customary manner, preferably orally or paren ⁇ terally, in particular perhngually or intravenously
  • solutions of the active compound can be employed using suitable liquid vehicles
  • intravenous administration amounts from about 10 to 100 mg/kg, preferably about 10 to 50 mg/kg of body weight to achieve effective results, and on oral administration the dosage is about 10 to 100 mg/kg, preferably 10 to 50 mg/kg of body weight

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Carbamic acid derivatives are prepared by reacting amines with appropriately substituted halo-formates. The compounds act as inhibitors of the leukotrienes synthesis and therefore can be used as active ingredients in medicaments.

Description

CARBAMIC ACID DERIVATIVES AS LEUKOTRIENE ANTAGONISTS
The invention relates to carbamic acid derivatives, process for their preparation and their use in medicaments
Leukotrienes are arachidonic acid metabolites produced by the 5-lιpoxygenase pathway in activated phagocytes and are important mediators of bronchial asthma and acute inflammation The pathophysiological importance of leukotrienes suggests that selective inhibitors of leukotriene synthesis may be useful anti- allergic and anti-inflammatory therapeutic agents
Carbamic acid, phenyI-2-pyπdιnyl-4-phenyl and benzyl esters are described as 5- poxygenase and cyclooxygenase inhibitors or antitumor medicaments in the publications EP 472 053 A2, EP 347 698 Al, J Pharm, Sci (1976), 65 (10), 1505- 10, J Prakt Chem 328, (1986), 3, 393-400
The invention relates to carbamic acid derivatives of the general formula (I)
R1
, N W
R C02-A v -
in which
R1 represents a 6 membered aromatic heterocycle having up to 2 nitrogen atoms and to which a phenyl ring can be fused and wherein the rings optionally are monosubstituted or disubstituted by identical or different substituents from the series comprising halogen, carboxyl, nitro or a straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms or by a group of the formula -(CO) -NRY4
in which
a denotes a number 0 or 1 ,
R1 and R4 are identical or different and denote hydrogen, biphenyl, phenyl, adamantyl or straight-chain or branched alkyl oi ac\ l each having up to 6 carbon atoms, which optionally are monosubstituted or disubstituted by phenyl and/or hydroxyl,
. 1
R~ represents adamantyl, cycloalkyl having 3 to 6 carbon atoms, pyridyl, phenyl or benzyl, which optionally are substituted by halogen, carboxyl or straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, or represents a group of the formula
Figure imgf000004_0001
or
R1 and R2 including the nitrogen atom together form a residue of the formula
Figure imgf000004_0002
A represents adamantyl, dicyclohexylmethyl, cyclododecyl, cis-decahydro-1 - naphthyl, 4-tert.butylphenyl, 2-naphthyl, 2,6-diphenylphenyl, dibenzo- suberolyl, 2-methylbenzyl, α-cyclopropyl-benzyl, 9-hydroxy-phenanthrenyl, 4-tritylphenyl, or represents a residue of the formula
Figure imgf000005_0001
and then salts
The compound of the general formula (I) can also be present in the form of their salts in general, salts with organic or inorganic bases or acids may be mentioned here
Physiologically acceptable salts are preferred Physiologically acceptable salts of the carbamic acid derivatives can be metal or ammonium salts of the substances according to the invention, which contain a free carboxylic group Those which are particularly preferred are, for example, sodium, potassium, magnesium or cal¬ cium salts, and also ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanol¬ amine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylene¬ diamine
Physiologically acceptable salts can also be salts of the compounds according to the invention with inorganic or organic acids Preferred salts here are those with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, or salts with organic carboxylic or sulphonic acids such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid
The compounds according to the invention can exist in stereoisomeπc forms which either behave as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers) The invention relates both to the anti¬ podes and to the racemate forms, as well as the mixture of diastereomers The racemate forms, like the diastereomers, can be separated into the stereoisomeπ- cally uniform constituents in a known manner Preferred compounds of the general formula (I) are those
in which
R1 represents isoquinolyl, pyrazinyl, pyridyl or pyrimidyl, which optionally are monosubstituted or disubstituted by identical or different substituents from the series comprising fluorine, chlorine, bromine, iodine, carboxyl, nitro or a straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms or by a group of the formula -(CO)a-NR3R4,
in which
a denotes a number 0 or 1,
R3 and R4 are identical or different and denote hydrogen, biphenyl, phenyl, adamantyl or straight-chain or branched alkyl or acyl each having up to 5 carbon atoms, which optionally are monosubstituted or di¬ substituted by phenyl and/or hydroxyl,
R2 represents cyclopentyl, cyclohexyl, pyridyl, phenyl or benzyl, which optionally are substituted by fluorine, chlorine, bromine, carboxyl, straight- chain or branched alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, or represents the group of the formula
Figure imgf000006_0001
or
R1 and R2 including the nitrogen atom together form a residue of a formula
Figure imgf000007_0001
A represents adamantyl, dicyclohexylmethyl, cyclododecanyl, cis-decahydro-
1-naphthyl, 4-tert butylphenyl, 2-naphthyl, 2,6-dιphenylphenyl, dibenzo- suberolyl, 2-methylbenzyl, α-cyclopropyl-benzyl, 9-hydroxy-phenanthrenyl, 4-tπtylphenyl, or represents a residue of the formula
Figure imgf000007_0002
and their salts
Particularly preferred compounds are those of the general formula (I),
in which
R represents pyridyl or pyrimidyl, which optionally are monosubstituted or disubstituted by identical or different substituents from the series comprising fluorine, chlorine, bromine, carboxyl, nitro or a straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms or by a group of the formula -(CO) rNR3R4,
in which
denotes a number 0 or Rs and R are identical or different and denote hydrogen, biphenyl, phenyl, adamantyl, straight-chain or branched alkyl or acyl each having up to 3 carbon atoms, which are optionally monosubstituted or disub¬ stituted by phenyl and/or hydroxyl,
R2 represents cyclopentyl, cyclohexyl, pyridyl or phenyl, which optionally are substituted by fluorine, chlorine, bromine, carboxyl, straight-chain or branched alkoxy or alkoxycarbonyl each having up to 3 carbon atoms, or represents the group of the formula
Figure imgf000008_0001
represents adamantyl, dtcyclohexylmethyl, cyclododecanyl, cis-decahydro-
1-naphthyl, 4-tert butylphenyl, 2-naphthyl, 2,6-diphenylphenyl, dibenzo- suberolyl, 2-methylbenzyl, -cyclopropyl-benzyl, 9-hydroxy-phenanthrenyl,
4-tπtylphenyl, or a residue of the formula
Figure imgf000008_0002
and their salts
Additionally a process for the preparation of the compounds of the general formula (I) according to the invention has been found, characterized in that
compounds of the general formula (II)
R'
I . NH (II)
FT in which
R and R~ have the abovementioned meaning
are reacted with compounds of the general formula (III)
T-CO,-A (III)
which
A has the abovementioned meaning
and
T represents halogen, preferably chlorine,
in solvents, if appropriate in the presence of a base and or in the presence of an auxiliary
The process according to the invention can be illustrated by way of example by the following equation
Figure imgf000009_0001
Suitable solvents are generally customary organic solvents which do not change under the reaction conditions T hese include ethers such as diethyl ether, dioxane or tetrahydrofuran, acetone, dimethylsulfoxide, dimethylformamide or alcohols such as methanol, ethanol, propanol or halogenohydrocarbons such as dichlor- methane, tπchloromethane or tetrachloromethane Tetrahydrofuran is preferred
Suitable bases are generally inorganic or organic bases These preferably include alkali metal hydroxides such as, for example, sodium hydroxide, sodium hydrogen- carbonate or potassium hydroxide, alkaline earth metal hydroxides such as, for example, barium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, or alkaline metal or organic amines (trialkyl(C]-C6)amines) such as triethylamine, or heterocycles such as l,4-dιazabιcyclo[2 2 2]octane (DABCO), 1,8-dιazabιcyclo- [5 4 0]undec-7-ene (DBU), or amides such as sodium amides, lithium butyl amide or butyllithium, pyridine or methylpipeπdine It is also possible to employ alkali metals, such as sodium or its hydrides such as sodium hydride, as bases
Potassium carbonate, triethylamine, sodium hydrogencarbonate and sodium- hydroxide are preferred
The process is in general carried out in a temperature range from 0°C to +100°C, preferably from room temperature to +60°C
The process is generally carried out at normal pressure However, it is also possible to carry out it at elevated pressure or at reduced pressure (for example in a range from 0 5 to 5 bar)
The base is employed in an amount from 1 mol to 10 mol, preferably from 1 0 mol to 4 mol, relative to 1 mol of the compounds of the general formula (III)
The compounds of the general formula (II) are known or can be prepared by customary methods
The compounds of the general formula (III) are known or can be prepared by customary methods The carbamic acid derivatives of the general formula (I) can be employed as active compounds in medicaments. The substances can act as inhibitors of enzy¬ matic reactions in the context of arachidonic acid metabolism.
The compounds of the general formula (I) surprisingly show a high activity as inhibitors of leukotriene synthesis, specifically inhabit the production of leuko¬ triene B4 in polymorphonuclear leucocytes (PMNL).
They are therefore preferably suitable for the treatment and prevention of diseases of the respiratory passages, such as allergies/asthma, bronchitis, emphysema, shock lung, pulmonary hypertension, inflammations/rheumatism and oedemas, thrombo- ses and thromboembolism, ischaemis (disturbances in peripheral, cardiac and cere¬ bral circulation), cardiac and cerebral infarctions, disturbances in cardiac rhythm, angina pectoris and arteriosclerosis, in the event of tissue, transplants, dermatoses, such as psoriasis, inflammatory dermatoses, for example eczema, dermatophyte infection, infections of the skin by bacteria, metastases and for cytoprotection in the gastrointestinal tract.
lest description
1 Preparation of human PMNL
Blood was taken from healthy subjects by venous puncture and neutrophils were purified by dextran sedimentation and resuspended in the buffered medium
2 Inhibition of thaspsigargin-induced leuktoπene B4 generation Neutrophils (4 x 105 cells/ml) were placed in a 96 well microtitre plate and prewarmed to 37°C Compounds according to the invention were added in dimethyl sulphoxide (DMSO) Compound concentration ranged from 0 3 to 30 μfvl, the DMSO concentration was < 0 3% v/v The plate was incubated for 5 min at 37°C Neutrophils were then stimulated by addition of 1 μM thapsigargin followed by 1 3 M Ca' 1 The reaction was stopped after 5 minutes and supernatants assayed for the presence of leukotriene (LT) B4 using an LTB4-specιfic radioimmunoassay kit supplied by Amersham Internationl pic Percentage inhibition was determined by comparison with vehicle-containing controls
The new active compounds can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, nontoxic, pharmaceuti- cally suitable excipients or solvents In this connection, the therapeutically active compound should in each case be present in a concentration of about 0 5 to 90% by weight of the total mixture, l e in amounts which are sufficient in order to achieve the dosage range indicated
The formulations are prepared, for example, by extending the active compounds with solvents and/or excipients, if appropriate using emulsifiers and/or dispersants, where, for example, in the case of the use of water as a diluent, organic solvents can be used as auxiliary solvents if appropriate
Administration is carried out in a customary manner, preferably orally or paren¬ terally, in particular perhngually or intravenously
In the case of parenteral administration, solutions of the active compound can be employed using suitable liquid vehicles In general, it has proved advantageous on intravenous administration to administer amounts from about 10 to 100 mg/kg, preferably about 10 to 50 mg/kg of body weight to achieve effective results, and on oral administration the dosage is about 10 to 100 mg/kg, preferably 10 to 50 mg/kg of body weight
In spite of this, it may be necessary to depart from the amounts mentioned, in par¬ ticular depending on the body weight or the type of application route, on indivi¬ dual behaviour towards the medicament, the manner of its formulation and the time or interval at which administration takes place Thus, in some cases it may be sufficient to manage with less than the abovementioned minimum amount, while in other cases the upper limit mentioned must be exceeded In the case of admini¬ stration of relatively large amounts, it is advisable to divide these into several individual doses over the course of the day
Preparation example
Example 1
Menthyloxycarbonyl-2-anιlιnopyridine
Figure imgf000014_0001
To a suspension of 500 mg (2 9 mmol) 2-anilino-pyπdine in saturated aqueous
NaHCO were added 0 94 ml (1 5 eq) (-)-menthyl chloroformate in 1 ml THF After 45 min the aqueous phase was extracted with ethyl acetate, the organic phase dried over MgSO4 and concentrated under reduced pressure The crude product was recrystalized from ether / PE, yielding 287 mg (27 6%) The mother liquor was carefully concentrated and the precipitate filtered off, yielding another
286 mg (27 5%)
Η-NMR (300 MHz, CDC13) δ = 0 77 (d, 3H), 0 81 (d, 3H), 0 89 (d, 3H), 0 72 - 1.22 (m, 4H), 1.41 - 1 54 (m, IH), 1.57 - 1 65 (m, 2H), 1 76 - 1 86 (dddd, IH), 2 12 -2 19 (m, IH), 4 62 - 4 71 (dt, IH), 7 04 - 7 08 (dddd, IH), 7 19 - 7 27 (m, 3H), 7 33 - 7 38 (m, 2H), 7 57 (d, IH), 7 69 (dt, IH), 8 36 (m, IH)
MS (70 eV) e/m [%] = 352 [M ]
The compounds shown in table 1 are prepared in analogy to the procedure of example 1
Table 1:
Figure imgf000015_0001
Figure imgf000015_0002

Claims

Patent Claims:
1. Carbamic acid derivatives of the general formula (1)
R '
2 / . (I)
R C02-A
in which
R represents a 6 membered aromatic heterocycle having up to 2 nitrogen atoms and to which a phenyl ring can be fused and wherein the rings optionally are monosubstituted or disubstituted by identical or different substituents from the series comprising halo¬ gen, carboxyl, nitro, a straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms or by a group or the formula
-(CO) -NR3R4,
in which
a denotes a number 0 or 1 ,
R3 and R4 are identical or different and denote hydrogen, biphenyl, phenyl, adamantyl or straight-chain or branched alkyl or acyl each having up to 6 carbon atoms, which optionally are monosubstituted or disubstituted by phenyl and/or hydroxyl,
R" represents adamantyl, cycloalkyl having 3 to 6 carbon atoms, pyridyl, phenyl or benzyl, which optionally are substituted by halogen, carboxyl or straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, or
represents a group of the formula
Figure imgf000017_0001
or
R and R~ including the nitrogen atom together form a residue of a formula
Figure imgf000017_0002
represents adamantyl, dicyclohexylmethyl, cyclododecanyl, cis-deca- hydro-1 -naphthyl, 4-tert butylphenyl, 2-naphthyl, 2,6-diphenyl- phenyl, dibenzosuberolyl, 2-methylbenzyl, α-cyclopropyl -benzyl, 9- hydroxy-phenanthrenyl, 4-tπtylphenyl or
represents a residue of the formula
Figure imgf000017_0003
and their salts
Carbamic acid derivatives of the formula according to Claim 1,
wherein R represents isoquinolyl, pyrazinyl, pyridyl or pyrimidyl, which optionally are monosubstituted or disubstituted by identical or different substituents from the series comprising fluorine, chlorine, bromine, iodine, carboxyl, nitro, a straight-chain or branched alk- oxycarbonyl having up to 5 carbon atoms or by a group of the formula -(CO) ,-NR3R4,
in which
a denotes a number 0 or 1,
R3 and R4 are identical or different and denote hydrogen, biphenyl, phenyl, adamantyl or straight-chain or branched alkyl or acyl each having up to 5 carbon atoms, which optionally are monosubstituted or disubstituted by phenyl and/or hydroxyl,
R2 represents cyclopentyl, cyclohexyl, pyridyl, phenyl or benzyl, which optionally are substituted by fluorine, chlorine, bromine, carboxyl or straight-chain or branched alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, or represents a group of the formula
Figure imgf000018_0001
or
R and R~ including the nitrogen atom together form a residue of a formula
represents adamantyl, dicyclohexylmethyl, cvclododecanyl, cis-deca- hydro- 1-naphthyl, 4-tert butylphenyl, 2-naphthyl, 2,6-dιphenyl- phenyl, dibenzosuberolyl, 2-methyl benzyl, -cyclopropyl-benzyl, 9- hydroxy-phenanthrenyl, 4-tπtylphenyl, or a residue of the formula
Figure imgf000019_0001
and their salts
Carbamic acid derivatives of the formula according to Claim 1,
wherein
R! represents pyridyl or pyrimidyl, which optionally are monosub¬ stituted or disubstituted by identical or different substituents from the series comprising fluorine, chlorine, bromine, carboxyl, nitro, a straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms or by a group of the formula -(CO) L-NR R4,
in which
denotes a number 0 or 1,
W and R are identical or different and denote hydrogen, biphenyl, phenyl or adamantyl, straight-chain or branched alkyl or acyl each having up to 3 carbon atoms, which optionally are monosubstituted or disubstituted by phenyl and/or hydroxyl,
R2 represents cyclopentyl, cyclohexyl, pyridyl or phenyl, which are optionally substituted by fluorine, chlorine, bromine, carboxvl or straight-chain or branched alkoxy oi alkoxycarbonyl each having up to 3 carbon atoms, or represents a group of the formula
Figure imgf000020_0001
represents adamantyl, dicyclohexylmethyl, cyclododecanyl, cis- decahydro-1 -naphthyl, 4-tert butylphenyl, 2-naphthyl, 2,6-dιphenyl- phenyl, dibenzosuberolyl, 2-methylbenzyl, α-cyclopropyl-benzyl, 9- hydroxy-phenanthrenyl, 4-trityl phenyl, or a residue of the formula
Figure imgf000020_0002
and their salts
Carbamic acid derivatives according to Claim 1 to 3, for therapeutic use
Process for the preparation of carbamic acid derivatives according to Claims 1 to 3, characterized in that
compounds of the general formula (II)
R'
I (II)
. NH
R^
in which
R1 and R have the abovementioned meaning are reacted with compounds of the general formula (III)
T-CO -A (III)
in which
A has the abovementioned meaning
and
T represents halogen, preferably chlorine,
in solvents, if appropriate in the presence of a base and/or in the presence of an auxiliary
Medicaments consisting of at least one carbamic acid derivative according to Claims 1 to 3 and a pharmacologically acceptable diluent
A medicament according to Claim 6 as inhibitor of the leukotrienes synthesis
Process for the preparation of a medicament according to Claims 6 and 7, characterized in that the carbamic acid derivative is brought into a suitable administration form if appropriate with the aid of customary auxiliaries and excipients
Use of the carbamic acid derivatives according to Claim 1 to 3 for the production of medicaments
Use according to Claim 1 for the production of inhibitors of the leuko- tπenes synthesis
PCT/EP1996/005248 1995-12-11 1996-11-28 Carbamic acid derivatives as leukotriene antagonists WO1997021678A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU10941/97A AU1094197A (en) 1995-12-11 1996-11-28 Carbamic acid derivatives as leukotriene antagonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9525261.5 1995-12-11
GBGB9525261.5A GB9525261D0 (en) 1995-12-11 1995-12-11 Carbamic acid derivatives

Publications (1)

Publication Number Publication Date
WO1997021678A1 true WO1997021678A1 (en) 1997-06-19

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Country Status (3)

Country Link
AU (1) AU1094197A (en)
GB (1) GB9525261D0 (en)
WO (1) WO1997021678A1 (en)

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US6780861B2 (en) 2000-05-05 2004-08-24 Novartis Ag Azabicyclic carbamates and their use as α-7 nicotinic acetylcholine receptor agonists
WO2006019874A1 (en) * 2004-07-14 2006-02-23 Inflammation Research Center Company Ltd. Method for inhibiting tumor metastasis
WO2010097480A3 (en) * 2010-05-25 2011-04-14 Symrise Ag Menthyl carbamate compounds as skin and/or hair lightening actives
WO2010097479A3 (en) * 2010-05-25 2011-04-14 Symrise Ag Cyclohexyl carbamate compounds as active anti-cellulite ingredients
WO2010089421A3 (en) * 2010-05-25 2011-04-14 Symrise Ag Menthyl carbamate compounds as active anti-cellulite ingredients
WO2010122178A3 (en) * 2010-05-25 2011-04-14 Symrise Ag Cyclohexyl carbamate compounds as skin and/or hair lightening actives
EP2389922A1 (en) * 2010-05-25 2011-11-30 Symrise AG Cyclohexyl carbamate compounds as anti-ageing actives
KR20200128028A (en) * 2018-02-26 2020-11-11 닛뽄 가야쿠 가부시키가이샤 Base-reactive resin composition containing base proliferating agent and said base proliferating agent

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EP0518818A2 (en) * 1991-06-11 1992-12-16 Ciba-Geigy Ag Arylethers, their manufacture and use as medicament

Patent Citations (1)

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EP0518818A2 (en) * 1991-06-11 1992-12-16 Ciba-Geigy Ag Arylethers, their manufacture and use as medicament

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KR101213926B1 (en) 2004-07-14 2012-12-18 인플러메이션 리서치 센터 컴퍼니 엘티디. Method and pharmaceutical composition for inhibiting tumor metastasis
WO2006019874A1 (en) * 2004-07-14 2006-02-23 Inflammation Research Center Company Ltd. Method for inhibiting tumor metastasis
EP1997491A1 (en) * 2004-07-14 2008-12-03 Inflammation Research Center Company Ltd. Method for inhibiting tumor metastasis
CN103025311A (en) * 2010-05-25 2013-04-03 西姆莱斯有限公司 Menthyl carbamate compounds as skin and/or hair lightening actives
JP2013533218A (en) * 2010-05-25 2013-08-22 シムライズ アーゲー Cyclohexyl carbamate compounds as anti-cellulite active ingredients
WO2010122178A3 (en) * 2010-05-25 2011-04-14 Symrise Ag Cyclohexyl carbamate compounds as skin and/or hair lightening actives
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WO2010097479A3 (en) * 2010-05-25 2011-04-14 Symrise Ag Cyclohexyl carbamate compounds as active anti-cellulite ingredients
CN103002868A (en) * 2010-05-25 2013-03-27 西姆莱斯有限公司 Cyclohexyl carbamate compounds as active anti-cellulite ingredients
WO2010097480A3 (en) * 2010-05-25 2011-04-14 Symrise Ag Menthyl carbamate compounds as skin and/or hair lightening actives
JP2013526592A (en) * 2010-05-25 2013-06-24 シムライズ アーゲー Cyclohexyl carbamate compounds as lightening actives for skin and / or hair
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US9072676B2 (en) 2010-05-25 2015-07-07 Symrise Ag Cyclohexyl carbamate compounds as skin and/or hair lightening actives
CN103025311B (en) * 2010-05-25 2016-03-16 西姆莱斯有限公司 As the carbamic acid menthyl ester compound of skin and/or hair whitening active thing
KR20200128028A (en) * 2018-02-26 2020-11-11 닛뽄 가야쿠 가부시키가이샤 Base-reactive resin composition containing base proliferating agent and said base proliferating agent
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US11905361B2 (en) 2018-02-26 2024-02-20 Nippon Kayaku Kabushiki Kaisha Base proliferating agent, and base-reactive resin composition containing said base proliferating agent

Also Published As

Publication number Publication date
GB9525261D0 (en) 1996-02-07
AU1094197A (en) 1997-07-03

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