WO1998056756A1 - Catechol amino acid derivatives and pharmaceutical compositions containing them - Google Patents

Catechol amino acid derivatives and pharmaceutical compositions containing them Download PDF

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Publication number
WO1998056756A1
WO1998056756A1 PCT/KR1997/000156 KR9700156W WO9856756A1 WO 1998056756 A1 WO1998056756 A1 WO 1998056756A1 KR 9700156 W KR9700156 W KR 9700156W WO 9856756 A1 WO9856756 A1 WO 9856756A1
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alkyl
nitro
halogen
compound
phenyl
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PCT/KR1997/000156
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French (fr)
Inventor
Chung Keun Rhee
Myung Xik Xiang
Byoung Chool Suh
Kwang Hyuk Lee
Youn Ha Lee
Won Young Bhang
Young Gi Kim
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Cheil Jedang Corporation
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Priority to AU39531/97A priority Critical patent/AU3953197A/en
Publication of WO1998056756A1 publication Critical patent/WO1998056756A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/52—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to novel cathecol amino acid derivatives which inhibit the enzymatic activity of phosphodiesterase IV or tumor necrosis factor. These compounds may be useful in prevention or treatment of bronchial asthma, arthritis, bronchitis, chronic atretic airway, psoriasis, allergic rhinitis, dermatitis, AIDS, Crohn's disease, septicemia, septic shock, other inflammatory diseases such as cachexia, TNF related diseases, etc. Also, the present invention relates to a method for producing the said compounds and a pharmaceutical composition containing the said compounds.
  • Phosphodiesterase IV is an enzyme that specifically hydrolyzes cAMP (adenosine 3',5'-cyclic monophosphate) into inactive adenosine 3',5'-mono- phosphate.
  • cAMP adenosine 3',5'-cyclic monophosphate
  • the cAMP has been shown to be a second messenger mediating the cellular responses to external stimuli and to act as relaxing or contradicting bronchial muscles.
  • TNF tumor necrosis factor
  • the present invention provides a compound of the general formula I:
  • Rl represents methyl, ethyl, difluoromethyl or trifluoromethyl
  • R3 represents hydrogen, hydroxy, Ci-C ⁇ alkyl or phenyl substituted with C ⁇ -C alkyl, C ⁇ -C alkoxy, nitro or halogen
  • R4 represents hydrogen, trifluoromethyl, d-C 6 alkyl, -(CH 2 ) n CO 2 H, -(CH 2 ) usuallyCONH 2 , -(CH) n phenyl, -(CH) classroom phenylalcohol, -(CH 2 ) n indole, -(CH 2 ) classroomimidazole, -(CH 2 ) x OH, -(CH 2 ) X SH,
  • C ⁇ -C 8 alkyl C 3 -C ⁇ cycloalkyl substituted with halogen, nitro, hydroxy, C ⁇ -C alkyl or C ⁇ -C 4 alkoxy or phenyl substituted with halogen, nitro, hydroxy, C ⁇ -C alkyl or C ⁇ -C 4 alkoxy; and W represents oxygen or sulfur.
  • the present invention provides a process for producing the above compound of the general formula I.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising pharmaceutically effective amount of the present compound of the general formula I or pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.
  • the preferred compounds of the present invention are those wherein
  • Rl is methyl; R2 is cyclopentyl or norbonyl; R3 is hydrogen; R4 is hydrogen, C ⁇ -C alkyl or CH 3 SH; or R3 and R4 are together taken with C 4 to form a ring; R5 is NR6R7, -OR8 or -OCH(R8)OCO 2 R9 in which R6 and R7 are each independently hydrogen or C ⁇ -C 4 alkyl and R8 and R9 are each independently C ⁇ -C alkyl; and W is oxygen.
  • the process for producing the compound of the general formula I according to the present invention comprises reacting a compound of the general formula II:
  • the compounds of the present invention are usually administered as a standard pharmaceutical composition. Therefore, the present invention provides in a further aspect pharmaceutical compositions comprising a novel compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the compounds of foraiula I may be administered by any convenient method, for example by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.
  • the compounds of formula I and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or physiologically acceptable salt in a suitable liquid carrier, for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
  • a suitable liquid carrier for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
  • the formulation may also contain a suspending agent, preservative, flavouring or colouring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical carrier(s) include magnesium stearate, starch, lactose, sucrose and cellulose.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • Typical parenteral compositions consist of a solution or suspension of the compound or physiologically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilized and then reconstituted with a suitable solvent prior to administration.
  • compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders.
  • Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device.
  • the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted.
  • the dosage form comprises an aerosol dispenser
  • a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon.
  • the aerosol dosage forms can also take the form of a pump-atomiser.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
  • a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
  • compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
  • compositions suitable for transdermal administration include ointments, gels and patches.
  • composition is in unit dose form such as a tablet, capsule or ampoule.
  • Phosphodiesterase IV partially purified from human U937 cells, test compound and 1.0 ⁇ M cAMP including 0.01 ⁇ M [ 3 H] cAMP were incubated at 30°C for 20 minutes.
  • the PDE reaction to convert cAMP into AMP was completed by boiling the reaction solution for 2 minutes.
  • AMP was converted into adenosine by adding snake venom nucleotidase and incubating the reaction solution at 30 °C for 10 minutes. While unhydrolyzed cAMPs were bonded to AG1-X2 resin, the [ H] adenosine in the aqueous solution was quantified by scintillation counting. The results are shown in Table II below, in which the values indicate inhibition(%) of the PDE IV by each test compound. Table I

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

A phosphodiesterase IV inhibiting catechol derivative of general formula (I) or a pharmaceutically acceptable salt thereof in which R1, R2, R3, R4, R5 and W are as defined herein. In addition, a process for producing the compound of general formula (I) and a pharmaceutical composition containing pharmaceutically effective amount of the compound of general formula (I) are disclosed.

Description

CATECHOL AMINO ACID DERIVAΗVES AND PHARMACEUΗCAL COMPOSITIONS CONTAINING THEM
FIELD OF THE INVENTION
The present invention relates to novel cathecol amino acid derivatives which inhibit the enzymatic activity of phosphodiesterase IV or tumor necrosis factor. These compounds may be useful in prevention or treatment of bronchial asthma, arthritis, bronchitis, chronic atretic airway, psoriasis, allergic rhinitis, dermatitis, AIDS, Crohn's disease, septicemia, septic shock, other inflammatory diseases such as cachexia, TNF related diseases, etc. Also, the present invention relates to a method for producing the said compounds and a pharmaceutical composition containing the said compounds.
BACKGROUND OF THE INVENTION
Phosphodiesterase IV is an enzyme that specifically hydrolyzes cAMP (adenosine 3',5'-cyclic monophosphate) into inactive adenosine 3',5'-mono- phosphate. The cAMP has been shown to be a second messenger mediating the cellular responses to external stimuli and to act as relaxing or contradicting bronchial muscles.
The inhibition of phosphodiesterase IV leads to the prevention of broncospasm by maintaining the concentration of cAMP and also induces an anti-inflammation. Therefore, compounds that inhibit phosphodiesterase IV should be effective in treating asthma and the like diseases.
It is known that tumor necrosis factor (TNF) is implicated in infectious disease such as cachexia and autoimmune disease. Also TNF appears to act as a primary mediator for inflammatory reaction such as septicemia and septic shock.
Therefore, it is expected that compounds with the inhibitory activity against phosphodiesterase IV or TNF will be pharmaceutically valuable and there is always a need to develop new compounds which inhibit phosphodiesterase IV and TNF.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a compound of the general formula I:
Figure imgf000004_0001
Formula I
or a pharmaceutically acceptable salt or solvate thereof in which
Rl represents methyl, ethyl, difluoromethyl or trifluoromethyl; R2 represents
Cι-C7 alkyl optionally substituted with nitro or halogen, C3-C7 cycloalkane optionally substituted with nitro or halogen, phenyl optionally substituted with nitro or halogen, C2-C5 heteroaryl including N, O or S optionally substituted with nitro or halogen; R3 represents hydrogen, hydroxy, Ci-Cβ alkyl or phenyl substituted with Cι-C alkyl, Cι-C alkoxy, nitro or halogen; R4 represents hydrogen, trifluoromethyl, d-C6 alkyl, -(CH2)nCO2H, -(CH2)„CONH2, -(CH)n phenyl, -(CH)„ phenylalcohol, -(CH2)n indole, -(CH2)„imidazole, -(CH2)xOH, -(CH2)XSH, -(CH)XS Ci-Cβ alkyl, -(CH2),NHC(NH)NH2 or -(CH2)XNH in which x is 1 to 5 and n is 0 to 5; or R3 and R4 are together taken with Cι-C4 to form a ring; R5 represents NR6R7, -OR8 or -OCH(R8)OCOR9 in which R6 and R7 are each independently hydrogen, C1-C6 alkyl or phenyl substituted with Cι-C4 alkoxy, nitro or halogen and R8 and R9 are each independently
Cι-C8 alkyl, C3-Cπ cycloalkyl substituted with halogen, nitro, hydroxy, Cι-C alkyl or Cι-C4 alkoxy or phenyl substituted with halogen, nitro, hydroxy, Cι-C alkyl or Cι-C4 alkoxy; and W represents oxygen or sulfur.
In another aspect, the present invention provides a process for producing the above compound of the general formula I.
In still another aspect, the present invention provides a pharmaceutical composition comprising pharmaceutically effective amount of the present compound of the general formula I or pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.
DETAILED DESCRIPTION OF THE INVENTION
The preferred compounds of the present invention are those wherein
Rl is methyl; R2 is cyclopentyl or norbonyl; R3 is hydrogen; R4 is hydrogen, Cι-C alkyl or CH3SH; or R3 and R4 are together taken with C4 to form a ring; R5 is NR6R7, -OR8 or -OCH(R8)OCO2R9 in which R6 and R7 are each independently hydrogen or Cι-C4 alkyl and R8 and R9 are each independently Cι-C alkyl; and W is oxygen.
The more preferred compounds of the present invention are as follows:
ethyl-2-(3-cyclopentyloxy-4-methoxypheπylcarboxylamido)-3-sulfamyl-(2S)- propanoate; lN-carbamoylmethyl-3-cyclopentyloxy-4-methoxybenzylamide; and ethyl-2-(3-cyclopentyloxy-4-methoxyphenylcarboxylamido)acetate.
The process for producing the compound of the general formula I according to the present invention comprises reacting a compound of the general formula II:
R1
Figure imgf000006_0001
Formula II
in which Rl, R2 and W represent the same as defined above, with a compound of the general formula III:
Figure imgf000006_0002
R4
Formula HI
in which R3, R4 and R5 are the same as defined above, to produce the compound of the general formula I. The above compound II was obtained by known method (J. Med. Chem. 1994, 37, 1696). This method is represented by the following reaction scheme:
Figure imgf000007_0001
The above compound III is commercially available.
For use in medicine, the compounds of the present invention are usually administered as a standard pharmaceutical composition. Therefore, the present invention provides in a further aspect pharmaceutical compositions comprising a novel compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The compounds of foraiula I may be administered by any convenient method, for example by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.
The compounds of formula I and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
A liquid formulation will generally consist of a suspension or solution of the compound or physiologically acceptable salt in a suitable liquid carrier, for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring or colouring agent.
A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.
A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
Typical parenteral compositions consist of a solution or suspension of the compound or physiologically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilized and then reconstituted with a suitable solvent prior to administration.
Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomiser.
Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
Compositions suitable for transdermal administration include ointments, gels and patches.
Preferably the composition is in unit dose form such as a tablet, capsule or ampoule.
The invention will now be described with reference to the following illustrative Examples.
EXAMPLES
REFERENCE EXAMPLE 1 3-CyclopentyIoxy-4-methoxybenzylaldehyde
50 g of isovanillin was added dropwise to 300 ml of dimethylformamide and, then, 70 g of anhydrous potassium carbonate and 1.5 g of potassium iodide were added to form a supension. The suspension was stirred at 65 °C for 30 minutes. 63 g of cyclopentyl bromide was added dropwise to the suspension over 1 hour and was stirred at 65 °C for 1 day. After cooling to room temperature, the suspension was diluted by adding 1 L of toluene and, then, was washed with 1 N sodium hydroxide (2x500 ml) and distilled water (2x250 ml) in succession. The organic layer was dried over anhydrous sodium sulfate and was concentrated under reduced pressure to obtain 58 g of the title compound (yield: 80%). 1H NMR(CDC13, δ): 9.84(lH,s), 7.42(2H,m), 6.94(1 H,DJ=9Hz), 4.87(lH,m),
3.93(3H,s), 2J-1.6(8H,m)
REFERENCE EXAMPLE 2 3-CycIopentyloxy-4-methoxybenzoic acid
35 g of sulfamic acid was added dropwise to a solution of 58 g of
3-cyclopentyloxy-4-methoxybenzylaldehyde in 450 ml of 80% acetic acid.
Then, a solution of 30 g of 80% sodium chloride in 450 ml of distilled water was added dropwise to the suspension over 1 hour while maintaining the reaction temperature to 18°C-20°C. The reaction solution was stirred for 1 hour and was diluted by adding dropwise 450 ml of distilled water over 30 minutes. The solution was filtered with distilled water and was dried to obtain
56 g of white solid title compound (yield: 90%).
1H NMR(CDC13, 5): 7.73(lH,dd,J=9,lHz), 7.24(2H,d,J=lHz), 6.92(lH,dJ=9Hz), 4.84(lH,m), 3.93(3H,s), 2J-1.6(8H,m)
REFERENCE EXAMPLE 3 3-CyclopentyIoxy-4-methoxybenzoic acid chloride
54 g of 3-cyclopentyloxy-4-methoxybenzoic acid was added to 30 ml of thiochloride and was stirred for 5 hours. 50 ml of toluene was added to the reaction solution and was concentrated under reduced pressure to obtain 58 g of the dense brown title compound (yield: 98%).
1H NMR(CDC13, δ): 7.82(lH,dd,J=9JHz), 7.53(lH,dJ=lHz), 6.92(lH,dJ=9Hz), 4.9-4.8(lH,m), 3.87(3H,s), 2J-1.9(2H,m), 1.9-1.7(4H,m), 1.7-1.5(2H,m)
EXAMPLE 1
EthyI-2-(3-cycIopentyIoxy-4-methoxyphenylcarboxyIamido)-3-phenyI-(2S)- propanoate
10 ml of pyridine was added dropwise to 400 mg of L-phenylalanine to form a suspension. 500 mg of 3-cyclopentyloxy-4-methoxybenzoic acid chloride (Reference Example 3) was added dropwise to the suspension and was refluxed for 4 hours. The reaction solution was concentrated under reduced pressure, diluted with dichlorom ethane and washed with IN hydrochloric acid, saturated sodium bicarbonate and sodium chloride in succession. The organic layer was dried and concentrated under reduced pressure. The solid compound obtained therefrom was recrystallized with toluene to yield 630 mg of the solid thin yellow title compound. m.p. 105-107°C
1H NMR(DMSO-d6, δ): 7.23(lH,d), 7.20(4H,m), 7.05(2H,m), 6.72(lH,H,d), 6.40(lH,d), 4.90(lH,ddd), 4.70(lH,m), 4J2(2H,q), 3.77(3H,s), 3J2(2H,ddd), 1.76(6H,m), 1.40(2H,m), 1.12(3H,t)
EXAMPLE 2
Ethyl-2-(3-cycIopentyIoxy-4-methoxyphenyIcarboxyIamido)-3-sulfanyl-(2S)- propanoate
321 mg of L-cysteine ethylester was reacted with 400 mg of 3-cyclopentyloxy-4-methoxybenzoic acid chloride (Reference Example 3) in the same manner as described in Example 1 to yield 600 mg of the title compound, m.p. 54-56 "C
1H NMR(CDC13, δ): 7.60(lH,dd), 7.41(lH,d), 7.41(lH,d), 7.38(lH,d), 6.80(lH,d), 5.00(lH,ddd), 4.85(lH,m), 4.25(2H,q), 3.84(3H,s), 3.65(lH,ddd), 3J7(lH,ddd), 1.70(8H,m), 1.28(3H,t)
EXAMPLE 3 lN-[l-carbamoyI-2-phenyI-(lS)-ethyl-3-cyclopentyloxy-4-methoxybenzylamide
10 ml of ammonium hydroxide was added to a solution of 780 mg of ethyl-2-(3-cyclopentyloxy-4-methoxyphenylcarboxylamido)-3-phenyl-(2S)- propanoate (Example 1) in 50 ml of methanol and was refluxed for 10 hours. After cooling the reaction solution, the solids formed was filtered and recrystallized with toluene to yield 450 mg of the solid white title compound. m.p. 139-140°C
1H NMR(DMSO-d6, δ): 8.69(lH,d), 7.43(lH,d), 7.25(5H,m), 7.20(lH,dd), 6.99(lH,d), 4.80(lH,m), 4.62(lH,m), 3.79(3H,s), 3J3(2H,ddd), 1.75(8H,m)
EXAMPLE 4 lN-carbamoylmethyl-3-cyclopentyloxy-4-methoxybenzylamide
385 mg of glycineamide hydrochloride was reacted with 1.0 g of 3-cyclopentyloxy-4-methoxybenzoic acid chloride (Reference Example 3) in the same manner as described in Example 1 to yield 600 mg of the white title compound, m.p. 131-132 °C
1H NMR(CDC13, δ): 7.45(lH,d), 7.38(lH,dd), 7.2-7.0(lH,brs), 6.89(lH,d), 6.5-6.3(lH,brs), 5.7-5.5(lH,brs), 5.0-4.8(lH,m), 4J8(2H,d), 3.91(3H,s), 2J-1.8(4H,m), 1.8-1.6(2H,m)
EXAMPLE 5 Ethyl-2-(3-cyclopentyIoxy-4-methoxyphenylcarboxylamido)acetate
490 mg of glycine ethylester hydrochloride was reacted with 1.0 g of 3-cyclopentyloxy-4-methoxybenzoic acid chloride (Reference Example 3) in the same manner as described in Example 1 to yield 950 mg of the light yellow title compound, m.p. 73-74°C
1H NMR(CDC13, δ): 7.50(lH,d), 7.41(lH,dd), 6.95(lH,d), 6.7-6.6(lH,brs), 5.9-5.8(lH,m), 4J4(2H,q), 4.30(2H,d), 3.97(3H,s), 2.0-1.6(8H,m), 1.40(3H,t)
EXAMPLE 6
MethyI-2-(3-cycIopentyloxy-4-methoxyphenylcarboxylamido)-4-methyI-(2S)- pentanoate
785 mg of L-leucine ethylester hydrochloride was reacted with 1.0 g of 3-cyclopentyloxy-4-methoxybenzoic acid chloride (Reference Example 3) in the same manner as described in Example 1 to yield 900 mg of the white title compound, m.p. 123-124 °C
1H NMR(CDC13, 8): 7.43(lH,d), 7.29(lH,dd), 6.87(lH,d), 6.43(lH,d),
4.9-4.7(lH,m), 3.90(3H,s), 3.78(3H,s), 2.0-1.6(1 lH,m), 1.01(3H,d), 0.99(3H,d)
EXAMPLE 7 l-(3-cyclopentyloxy-4-methoxybenzoyI)-(2S)-perhydro-2-pyrroIecarboxyIamide
460 mg of L-prolineamide was reacted with 1.0 g of 3-cyclopentyloxy-4-methoxybenzoic acid chloride (Reference Example 3) in the same manner as described in Example 1 to yield 500 mg of the white title compound, m.p. 170-171 °C
1H NMR(CDC13, 8): 7.2-7.0(2H,m), 7.0-6.8(lH,brs), 6.89(lH,d), 5.7-5.5(1H, brs), 4.9-4.8(2H,m), 3.90(3H,s), 3.8-3.6(2H,m), 2.6-2.4(lH,m), 2.2-1.6(1 lH,m) EXAMPLE 8
Methyl-l-(3-cyclopentyl-4-methoxybenzoyl)-(2S)-perhydro-2-pyrrolecarboxyI- ester
670 mg of L-prolinemethyl ester was reacted with 1.0 g of
3-cyclopentyloxy-4-methoxybenzoic acid chloride (Reference Example 3) in the same manner as described in Example 1 to yield 500 mg of the liquid colorless title compound. 1H NMR(CDC13, δ): 7.2-7.0(2H,m), 6.78(lH,d), 4.9-4.8(lH,m), 4.7-4.6(lH,m), 3.90(3H,s), 3.78(3H,s), 3.8-3.6(2H,m), 2.2-1.6(12H,m)
EXPERIMENTAL EXAMPLE
Inhibition of phosphodiesterase IV activity
Compounds prepared by Examples 1 to 7 and Rolipram as control were tested on the inhibition of phosphodiesterase IV.
Phosphodiesterase IV partially purified from human U937 cells, test compound and 1.0 μM cAMP including 0.01 μM [3H] cAMP were incubated at 30°C for 20 minutes. The PDE reaction to convert cAMP into AMP was completed by boiling the reaction solution for 2 minutes. AMP was converted into adenosine by adding snake venom nucleotidase and incubating the reaction solution at 30 °C for 10 minutes. While unhydrolyzed cAMPs were bonded to AG1-X2 resin, the [ H] adenosine in the aqueous solution was quantified by scintillation counting. The results are shown in Table II below, in which the values indicate inhibition(%) of the PDE IV by each test compound. Table I
Test Compound — J — Rolipram 1 2 J 4 0 6 7
Inhibition(%) 74.5 38.2 72.4 36.5 ~74J 77\9 65JΪ 59J

Claims

WHAT IS CLAIMED IS:
1. A compound of the general formula I:
Figure imgf000016_0001
Formula I
or a pharmaceutically acceptable salt or solvate thereof in which
Rl represents methyl, ethyl, difluoromethyl or trifluoromethyl; R2 represents Cι-C7 alkyl optionally substituted with nitro or halogen, C3-C7 cycloalkane optionally substituted with nitro or halogen, phenyl optionally substituted with nitro or halogen, C2-Cs heteroaryl including N, O or S optionally substituted with nitro or halogen; R3 represents hydrogen, hydroxy, Ci-Cό alkyl or phenyl substituted with Cι-C alkyl, Cι-C4 alkoxy, nitro or halogen; R4 represents hydrogen, trifluoromethyl, Cι-C6 alkyl, -(CH2)„CO2H, -(CH2)„CONH2, -(CH)n phenyl, -(CH)n phenylalcohol, -(CH2)„ indole, -(CH2)nimidazole, -(CH2)xOH, -(CH2)XSH, -(CH)XS Cj-Ce alkyl, -(CH2)XNHC(NH)NH2 or -(CH2)XNH in which x is 1 to 5 and n is 0 to 5; or R3 and R4 are together taken with Cι-C to form a ring; R5 represents NR6R7, -OR8 or -OCH(R8)OCOR9 in which R6 and R7 are each independently hydrogen, Ci-Ce alkyl or phenyl substituted with Cι-C alkoxy, nitro or halogen and R8 and R9 are each independently Cι-C8 alkyl, C3-C11 cycloalkyl substituted with halogen, nitro, hydroxy, Cι-C alkyl or Cι-C alkoxy or phenyl substituted with halogen, nitro, hydroxy, Cι-C alkyl or G-C alkoxy; and W represents oxygen or sulfur.
2. The compound of claim 1 wherein Rl is methyl; R2 is cyclopentyl or norbonyl; R3 is hydrogen; R4 is hydrogen, C1-C4 alkyl or CH SH; or R3 and R4 are together taken with C4 to form a ring; R5 is NR6R7, -OR8 or -OCH(R8)OCO2R9 in which R6 and R7 are each independently hydrogen or C╬╣-C4 alkyl and R8 and R9 are each independently C1-C4 alkyl; and W is oxygen.
3. The compound of claim 1 which is in the form of optical isomer or geometrical isomer.
4. The compound of claim 1 which is ethyl-2-(3-cyclopentyloxy-4- methoxyphenylcarboxylamido)-3-phenyl-(2S)-propanoate, ethyl-2-(3-cyclopentyl- oxy-4-methoxyphenylcarboxylamido)-3-sulfanyl-(2S)-propanoate, lN-[ 1 -carbamoyl- 2-phenyl-(lS)-ethyl-3-cyclopentyloxy-4-methoxybenzylamide, lN-carbamoylmethyl -3-cyclopentyloxy-4-methoxybenzylamide, ethyl-2-(3-cyclopentyloxy-4-methoxy- phenylcarboxylamido)acetate, methyl-2-(3-cyclopentyloxy-4-methoxyphenyl- carboxylamido)-4-methyl-(2S)-pentanoate, l-(3-cyclopentyloxy-4-methoxybenzoyl)- (2S)-perhydro-2-pyrrolecarboxylamide, or methyl- 1 -(3 -cyclopentyl -4-methoxy- benzoyl)-(2S)-perhydro-2-pyrrolecarboxylester.
5. A process for producing a compound of the general formula I:
Figure imgf000017_0001
Formula I 6756
or a pharmaceutically acceptable salt or solvate thereof in which Rl represents methyl, ethyl, difluoromethyl or trifluoromethyl; R2 represents Cι-C7 alkyl optionally substituted with nitro or halogen, C3-C7 cycloalkane optionally substituted with nitro or halogen, phenyl optionally substituted with nitro or halogen, C2-Cs heteroaryl including N, O or S optionally substituted with nitro or halogen; R3 represents hydrogen, hydroxy, CJ-CG alkyl or phenyl substituted with C1-C4 alkyl, C1-C4 alkoxy, nitro or halogen; R4 represents hydrogen, trifluoromethyl, G-C6 alkyl, -(CH2)„CO2H, -(CH2)„CONH2, -(CH)„ phenyl, -(CH)„ phenylalcohol, -(CH2)n indole, -(CH2)„imidazole, -(CH2)xOH, -(CH2)XSH, -(CH)χS Cι-C6 alkyl, -(CH2)XNHC(NH)NH2 or -(CH2)XNH in which x is 1 to 5 and n is 0 to 5; or R3 and R4 are together taken with Cι-C4 to form a ring; R5 represents NR6R7, -OR8 or -OCH(R8)OCOR9 in which R6 and R7 are each independently hydrogen, G-Cό alkyl or phenyl substituted with Cι-C4 alkoxy, nitro or halogen and R8 and R9 are each independently G-C8 alkyl, C3-C11 cycloalkyl substituted with halogen, nitro, hydroxy, C1-C4 alkyl or
C╬╣-C4 alkoxy or phenyl substituted with halogen, nitro, hydroxy, C1-C4 alkyl or G-C4 alkoxy; and W represents oxygen or sulfur, which comprises reacting a compound of the general formula II:
R1
Figure imgf000018_0001
Formula II
in which Rl, R2 and W represent the same as defined above, with a compound of the general formula III: 6756
Figure imgf000019_0001
Formula III
in which R3, R4 and R5 represent the same as defined above, to produce the said compound of the general formula I.
6. A pharmaceutical composition useful in the inhibition of phosphodiesterase IV or tumor necrosis factor comprising pharmaceutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.
PCT/KR1997/000156 1997-06-12 1997-08-20 Catechol amino acid derivatives and pharmaceutical compositions containing them WO1998056756A1 (en)

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EP3492100A1 (en) 2001-06-26 2019-06-05 Amgen Inc. Antibodies to opgl
EP2087908A1 (en) 2001-06-26 2009-08-12 Amgen, Inc. Antibodies to opgl
US7695980B2 (en) 2003-07-30 2010-04-13 Roche Diagnostics Operations, Inc. Chemiluminescent compounds and their use
US7618981B2 (en) 2004-05-06 2009-11-17 Cytokinetics, Inc. Imidazopyridinyl-benzamide anti-cancer agents
WO2005107762A2 (en) 2004-05-06 2005-11-17 Cytokinetics, Inc. Certain chemical entities, compositions, and methods
US7795448B2 (en) 2004-05-06 2010-09-14 Cytokinetics, Incorporated Imidazoyl-benzamide anti-cancer agents
US8163919B2 (en) 2004-05-06 2012-04-24 Cytokinetics, Incorporated Imidazopyridinyl benzamide mitotic kinesin inhibitors
US8207340B2 (en) 2004-05-06 2012-06-26 Cytokinetics, Incorporated Imidazopyridinyl benzamide mitotic kinesin inhibitors
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US7504413B2 (en) 2004-05-06 2009-03-17 Cytokinetics, Inc. N-(4-(imidazo[1,2A]pyridin-YL)phenethyl)benzamide inhibitors of the mitotic kinesin CENP-E for treating certain cellular proliferation diseases
US7582668B2 (en) 2005-11-09 2009-09-01 Cytokinetics, Incorporated Imidazoyl-benzamide anti-cancer agents
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