WO2000075107A2 - Bradykinin receptor antagonists - Google Patents

Bradykinin receptor antagonists Download PDF

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Publication number
WO2000075107A2
WO2000075107A2 PCT/EP2000/005059 EP0005059W WO0075107A2 WO 2000075107 A2 WO2000075107 A2 WO 2000075107A2 EP 0005059 W EP0005059 W EP 0005059W WO 0075107 A2 WO0075107 A2 WO 0075107A2
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WO
WIPO (PCT)
Prior art keywords
alkyl
compound
formula
phenyl
bradykinin
Prior art date
Application number
PCT/EP2000/005059
Other languages
French (fr)
Other versions
WO2000075107A3 (en
Inventor
Christopher Thomas Brain
William Cantrell
Andrew James Culshaw
Edward Karol Dziadulewicz
Terance William Hart
Timothy John Ritchie
Liladhar Waykole
Original Assignee
Novartis Ag
Novartis-Erfindungen Verwaltungsgesellschaft Mbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to BR0011329-8A priority Critical patent/BR0011329A/en
Priority to PL00352056A priority patent/PL352056A1/en
Priority to IL14611200A priority patent/IL146112A0/en
Priority to SK1749-2001A priority patent/SK17492001A3/en
Priority to US10/009,009 priority patent/US6958331B1/en
Priority to CA2372575A priority patent/CA2372575C/en
Priority to MXPA01012473A priority patent/MXPA01012473A/en
Priority to AU55282/00A priority patent/AU765628B2/en
Application filed by Novartis Ag, Novartis-Erfindungen Verwaltungsgesellschaft Mbh filed Critical Novartis Ag
Priority to DE60022999T priority patent/DE60022999T2/en
Priority to NZ515304A priority patent/NZ515304A/en
Priority to JP2001501588A priority patent/JP3820148B2/en
Priority to AT00940304T priority patent/ATE305920T1/en
Priority to EP00940304A priority patent/EP1183233B1/en
Publication of WO2000075107A2 publication Critical patent/WO2000075107A2/en
Publication of WO2000075107A3 publication Critical patent/WO2000075107A3/en
Priority to NO20015779A priority patent/NO20015779D0/en
Priority to HK02105567.0A priority patent/HK1045834A1/en

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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
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Definitions

  • the present invention relates to novel sulfonyl amine derivatives, to processes for their production, their use as pharmaceuticals and to pharmaceutical compositions comprising them.
  • R 5A is -X A -R 6A or -N(R 7A )R 8A , wherein
  • X A is piperidinylene or piperazinylene
  • R 6A is H, d-C ⁇ lkyl, C 3 -C 4 alkenyl, C 3 -C 4 alkinyl, C C 4 (alkoxyalkyl), C C 4 (carboxyalkyl), a C 5 -C 7 heterocyclic group or phenyl-CrCalkyl;
  • R 7A is amino-C 2 -C 4 alkyl or mono- or dKC CsalkylJamino-Cz-Csalkyl, and
  • R 8A is H, C 1 -C 4 alkyl or has the meanings as given for R 7A ;
  • R n is zero or 1 ;
  • X 3 is CH or N;
  • X 4 is a direct bond
  • R 3A is H, C C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkinyl, C 7 -C 10 aralkyl or C 6 -C 9 heteroaralkyl
  • R 4A is H and m is 1 or 2 or 3; or
  • X 4 is -CH(R 12 )-, R 3A is H and R 4A and R 12 together are propylene and m is 1 , or ethylene and m is 2;
  • X ,2 is a divalent group of formula IA" wherein
  • X 3 is CH or N
  • R 11 is C ⁇ -C 4 alkyl, C 3 -C 6 cycloalkyl or -NR ⁇ R 2 , wherein
  • R 1A and R ⁇ independently are d-C 4 alkyl or, together with the N-atom to which they are attached, represent a 5 to 7 membered heterocyclic ring; and R 9 and R 10 independently are a phenyl or pyridine ring; and salts thereof.
  • substituents within their structure e.g. may bear appropriate phenyl ring or alkylene moiety substituents, e.g. phenyl and pyridine in the meaning of R 9 or R 10 may be unsubstituted or substituted by one or more halogen, and in the meaning of R 3A alkyl may be unsubstituted or substituted by halogen, C 3 -C 6 cycloalkyl or aryl; aralkyl may be unsubstituted or substituted by halogen, methoxy, nitro or C ⁇ -C alkyl which may be unsubstituted or substituted by halogen; heteroaralkyl may be unsubstituted or substituted by CrC 4 alkyl.
  • the amino moiety of the defined aminocarb- onyl or amide groupings can be any appropriate amino grouping, e.g. cyclic or aliphatic or may bear further substituent groupings.
  • the present invention provides a 2-(2,2-diphenylethylamino)- -5-(4-aminocarbonyl-piperidine-1-sulfonyl)-benzoic acid amide or -5-(aminocarbonyl- C 2 -C alkyleneaminosulfonyl)-benzoic acid amide, or salt thereof.
  • R 1 and R 2 independently are d-C 4 alkyl or, together with the N-atom to which they are attached, represent a 5 to 7 membered heterocyclic ring;
  • R 3 and R 4 together are ethylene and m is 2; or
  • R 3 is H, C 1 -C 4 alkyl, C 5 -C 7 cycloalkyl or phenyl-C C 4 alkyl, R 4 is H and m is 1 or 2 or 3; n is zero or 1 ; and
  • R 5 is -X-R 6 or -N(R 7 )R 8 , wherein X is -N N- ,
  • R 6 is C C 4 alkyl, C 3 -C 4 alkenyl, C 3 -C 4 alkinyl, d-C ⁇ alkoxyalkyl), d-C 4 (carboxyalkyl), a
  • R 7 is amino-C 2 -C 4 alkyl or mono- or di-(C ⁇ -C 5 alkyl)amino-C 2 -C 5 alkyl
  • R 8 is H, C ⁇ -C 4 alkyl or has the meanings as given for R 7 ; and salts thereof.
  • Alkyl groups and moieties in the compounds of formula IA or I may be branched or straight chain. Alkyl groups are suitably straight chain.
  • Heterocyclic groups may be saturated or unsaturated and may contain one or more additional heterocyclic atoms, e.g. oxygen or sulfur.
  • additional heterocyclic atoms e.g. oxygen or sulfur.
  • Examples include piperidin-1-yl, morpholin- 1-yl, 3,6-dihydro-2.H.pyridin-1 -yl, thiomorpholin-1-yl, pyrrolin-1-yl, morpholin-4-yl, thiomor- pholin-4-yl, 3,6-dihydro-2H-pyridin-1 -yl, 2,5-dihydropyrrol-1-yl and 4-dif luoropiperidin-1 -yl, and may be unsubstituted or substituted by one or two halogen atoms.
  • R 5A is unsubstituted piperazinyl or piperazinyl substituted by methyl, ethyl, benzyl, 2- pyridinyl, methoxyethyl, carboxymethyl or -CH 2 CHCH 2 ; or piperidine substituted by methyl;
  • R 5A is N(R 7A )R 8A wherein R 7A is aminopropyl, aminobutyl, dimethylaminopropyl, diethylaminopropyl, dibutylaminoethyl, dimethylaminobutyl, or dimethylaminopentyl; and
  • R 8A is H, methyl, aminopropyl, aminobutyl, dimethylaminopropyl or dimethylaminobutyl;
  • X 1 is -(CH 2 ) n -CH(R 4A )-(CH 2 ) 2 -N(R 3A )- wherein n is zero or 1 and R 3A and R 4A together are ethylene;
  • X 1 is -CH(R 4A )-(CH 2 ) m -CH(R 12 )-NH- wherein m is 1 or 2 and R 4A and R 12 together are propylene or ethylene;
  • X 1 is -(CH 2 ) n -CH 2 -(CH 2 ) m -N(R 3A )- wherein n is zero or 1 , m is 1 or 2 or 3 and R 3A is H, methyl, isopropyl, isobutyl, fluoroethyl, cyclopropylmethyl, cyclohexylmethyl, cyclobutylmethyl, -CH(CH 3 )C 6 H 5) cyclohexyl, propenyl, butenyl, pentenyl, propinyl, butinyl, pentinyl, benzyl, methylbenzyl, fluorobenzyl, trifluoromethylbenzyl, methoxybenzyl, nitrobenzyl, pyridinylmethyl, methylisoxazolylmethyl, methylthiazolylmethyl or thiophenmethyl;
  • X 2 is a divalent group of formula IA" wherein X 3 is CH and R 11 is methyl, cyclopentyl, cyclohexyl, N(CH 3 )CH 2 CH 3 , piperidinyl, morpholinyl, thiomorpholinyl, dihydropyridinyl, dihydropyrrolyl or difluoropiperidinyl;
  • X 2 is a divalent group of formula IA" wherein X 3 is N and R 11 is morpholinyl;
  • R 9 and R 10 are phenyl which is unsubstituted or substituted by halogen
  • R 9 is phenyl and R 10 is pyridine.
  • R 1 and R 2 are independently methyl or ethyl.
  • R 1 and R 2 together with the N-atom to which they are attached are piperidin-1-yl, morpholin-1-yl, 3,6-dihydro-2.H.pyridin-1 -yl, thiomorpholin-1-yl or pyrrolin-1 -yl.
  • R 3 is H, methyl, cyclohexyl or benzyl; R 4 is H and m is 1 or 2 or 3, especially 1.
  • R 5 is -X-R 6 , wherein R 6 is C ⁇ -C 4 alkyl (e.g. methyl, ethyl or isopropyl), 3-propenyl, methoxyethyl, carboxymethyl, 2-pyridyl, or benzyl, and X is as defined above.
  • R 6 is C ⁇ -C 4 alkyl (e.g. methyl, ethyl or isopropyl), 3-propenyl, methoxyethyl, carboxymethyl, 2-pyridyl, or benzyl, and X is as defined above.
  • R 5 is -N(R 7 )R 8 , wherein R 7 is aminopropyl, aminobutyl, dipropylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, diethylaminopropyl or dimethylaminopentyl; and R 8 is H, methyl, aminopropyl, aminobutyl, dimethylaminopropyl or dimethylaminobutyl.
  • the present invention also provides a process for the production of a compound of formula IA which process comprises reacting a compound of formula IIA (IIA) wherein X 1 , X 2 , R 9 and R 10 have the meanings given for formula IA, with an amine, e.g. of formula IIIA
  • the present invention also provides a process for the production of a 2-(2,2-diphenylethyl- amino)- -5-(4-aminocarbonyl-piperidine-1-sulfonyl)-benzoic acid amide or -5-(aminocarbon- y ⁇ alkylene aminosulfonyl)-benzoic acid amide, for example a compound of formula I as defined above, or salt thereof, which process comprises reacting a 2-(2,2-diphenylethylamino)- -5-(4-carboxy-piperidine-1 -sulfonyl)-benzoic acid amide or -5-(carboxy-C 2 . 4 alkylene aminosulfonyl)-benzoic acid amide, for example a compound of formula II
  • R 1 , R 2 , R 3 , R 4 , m and n have the meanings given for formula I, with an amine, e.g. of formula III
  • the reaction may be earned out in accordance with standard procedures, for example by a first acid chloride formation step using e.g. thionyl chloride and catalytic DMF in an inert solvent, e.g. CH 2 CI 2 , at ambient temperature, followed by the coupling step involving addition of the acid chloride to a mixture of the amine and e.g. TEA, at a temperature of, e.g. -10°C.
  • Aqueous workup followed by precipitation from, e.g. ethyl acetate gives the free base.
  • the salt forms are made by standard procedures known to the skilled artisan.
  • DMF dimethyl formamide
  • DMSO dimethyl sulfoxide
  • EDTA ethylenediamine-tetraacetic acid
  • EtOAc ethylacetate
  • IPA isopropanol
  • RT room temperature
  • TBME t-butyl methyl ether
  • TBTU (O-(benzotriazol-1 - yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate
  • TEA triethylamine
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran.
  • the solution of acid chloride is added to a mixture of isopropylpiperazine (47.60 g), TEA (98.09 g) and CH 2 CI 2 (1 I) at -10°C over 1 h.
  • the reaction is worked up by removing volatiles via rotary evapor- tion.
  • the residue is suspended in EtOAc (2.0 I) and washed with water (2 x 500 ml), brine (500 ml) and dried (Na 2 SO 4 ).
  • the volume is reduced by rotary evaporation (35°C, house vacuum) to -500 ml and stirred at ambient temperature for 17 h.
  • the suspension is filtered and dried (40°C, house vacuum) to give the title compound as free base.
  • R 1A and R ⁇ independently are d-C alkyl or, together with the N-atom to which they are attached, represent a 5 to 7 membered heterocyclic ring, may be prepared applying known techniques, e.g. in accordance with the following reaction scheme:
  • Hal is halogen, e.g. chlorine
  • R 15 is d-C 4 alkyl, e.g. ethyl
  • X 1 , X 2 , R A , R 2 *, R 9 and R 10 are as defined for formula IA.
  • step (aA) the compound of formula XIIA may conveniently be reacted with e.g. chlorosulfonic acid or with chlorosulfonic acid followed by thionyl chloride.
  • step (bA) the compound of formula XIA may be reacted with the compound of formula XA and e.g. triethyl- amine in the presence of a solvent like acetonitrile and acetone at 0°C.
  • step (cA) the compound of formula IXA may be reacted with the compound of formula VINA at room temperature in the presence of a solvent like acetonitrile, acetone or ethyl acetate, ethyl acetate being preferred.
  • a solvent like acetonitrile, acetone or ethyl acetate, ethyl acetate being preferred.
  • an excess of the compound of formula VIIIA may be used, e.g. a 10 % excess.
  • step (dA) the compound of formula VIIA may be reacted with an excess of the compound of formula VIA, e.g. a 10 % excess, in the presence of, e.g. trifluoroacetic acid and a desiccant, e.g. trimethyl orthoacetate.
  • the reduction of step (eA) may, e.g.
  • step (fA) may be accomplished via hydrogenation over 10 % palladium on carbon in the presence of a solvent, e.g. tetrahydrofuran.
  • the hydrolysis of the ester of formula IVA [step (fA)] may be accomplished in the presence of a base like NaOH, in a solvent like ethanol, methanol, acetone or tetrahydrofuran, preferably tetrahydrofuran.
  • the reac- tants may be warmed prior to reaction.
  • R 11 is d-C 4 alkyl, C 3 -C 6 cycloalkyl, may be prepared applying known techniques, e.g. in accordance with the following reaction scheme:
  • Hal is halogen, e.g. chlorine
  • R 15 is d-C alkyl, e.g. ethyl
  • y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal
  • X 1 , R 9 , R 10 and R 11 are as defined for formula IA.
  • Examples of a metal include an alkali metal, e.g. lithium (Li), sodium (Na) and potassium (K), an alkaline earth metal, e.g. magnesium (Mg), or manganese (Mn), iron (Fe), zinc (Zn) or silver (Ag).
  • an alkali metal e.g. lithium (Li), sodium (Na) and potassium (K)
  • an alkaline earth metal e.g. magnesium (Mg), or manganese (Mn), iron (Fe), zinc (Zn) or silver (Ag).
  • Hal is halogen, e.g. chlorine, R 15 ; i smartphoness r C. ⁇ - _C-. 4 a profession
  • R ,-,10 are as defined for formula IA.
  • R 11 is C ⁇ -C 4 alkyl, C 3 -C 6 cycloalkyl, may be prepared applying known techniques, e.g. in accordance with the following reaction scheme:
  • Hal is halogen, e.g. chlorine
  • R 15 is d-C 4 alkyl, e.g. ethyl
  • R , R ,R , R , m and n are as defined for formula I.
  • step (a) the compound of formula XII may conveniently be reacted with e.g. chlorosulfonic acid or with chlorosulfonic acid followed by thionyl chloride.
  • step (b) the compound of formula XI is reacted with the compound of formula X and e.g. triethylamine in the presence of a solvent like acetonitrile and acetone at 0°C.
  • step (c) the sulfonamide of formula IX is reacted with the compound of formula VIII at room temperature in the presence of a solvent like acetonitrile, acetone or ethyl acetate, ethyl acetate being preferred.
  • a solvent like acetonitrile, acetone or ethyl acetate, ethyl acetate being preferred.
  • an excess of the compound of formula VIII may be used, e.g. a 10 % excess.
  • step (d) the compound of formula VII may be reacted with an excess of the compound of formula VI, e.g. a 10 % excess, in the presence of, e.g. trifluoroacetic acid and a desiccant, e.g. tri- methyl orthoacetate.
  • step (e) may for example be accomplished via hydro- genation over 10 % palladium on carbon in the presence of a solvent, e.g. tetrahydrofuran.
  • a solvent e.g. tetrahydrofuran.
  • the hydrolysis of the ester of formula IV [step (f)] may be accomplished in the presence of a base like NaOH, in a solvent like ethanol, methanol, acetone or tetrahydrofuran, preferably tetrahydrofuran.
  • the reactants may be warmed prior to reaction.
  • Starting compounds of formula IIIA, VB, VIA, VIB, VIC, VID, VIIB, VINA, XA, XIB, XIC and XIIIB are known or may be prepared from corresponding known compounds.
  • Starting compounds III, VI, VIII, X and XII are known or may be prepared from corresponding known compounds.
  • compositions of the invention have pharmacological activity and are useful as pharmaceuticals.
  • Pharmaceutical Compounds exhibit bradykinin antagonist activity.
  • Pharmaceutical Compounds, e.g. compounds of Example 1 and 2 are active at the human Bi bradykinin receptor. Bradykinin receptor interaction of the Pharmaceutical Compounds is demonstrated by their ability to displace bradykinin at human bradykinin receptor sites, e.g. as demonstrated in accordance with the following test method.
  • Test I Bradykinin receptor binding assay
  • the human bradykinin B1 receptor is cloned from WI38 human foetal lung cell fibroblast cells by expression cloning in Xenopus laevis oocytes, which do not express bradykinin B1 receptors normally.
  • a cDNA library is prepared in bacteriophage lambda ZAP express and grown in pools of approximately 10,000 clones per pool. Bacteriophage DNA is prepared from these pools and copy RNA is synthesised with T3 RNA polymerase and after phenol extraction and precipitation, the RNA is injected into Xenopus oocytes and allowed to be expressed for 3 days.
  • the oocytes are then assayed electrophysiologically using two electrode voltage clamp, for a response in an endogenous chloride channel that can be activated by endogenous heterotrimeric GTP binding proteins of the Gq/G11 type that can couple to bradykinin receptors.
  • a positive clone is isolated from a positive pool by several stages of splitting the pool into smaller pools and assaying, until a single clone is isolated.
  • This cDNA is sequenced and subcloned into pcDNA3 (Clontech) and used to generate a cell-line which expresses the human bradykinin B1 receptor.
  • the human bradykinin B1 receptor cDNA is subcloned into the Kpn1 and Not1 sites of pcDNA3 (HB1-pcDNA3), is grown up and transfected into human embryonic kidney fibroblast cell line, HEK 293 using the Calcium phosphate method.
  • Cells are grown in Minimum Essential Medium with Earle's Salts (GIBCO) supplemented with 2 mM L-glutamine, 100 units/ml penicillin, 100 ⁇ g/ml streptomycin, 1 % nonessential amino acids and 10 % myoclone foetal calf serum (GIBCO) in a humidified atmosphere with 5 % C0 2 at 37°C.
  • GEBCO Minimum Essential Medium with Earle's Salts
  • the 293Hek cells are split 1 :2 the day prior to transfection.
  • One 175 cm 2 flask with approximately 50 % confluent cells is transfected with approximately 30 ⁇ g/ml HB1-pcDNA3 DNA using the calcium phosphate precipitate method of transfection.
  • the flask of transfected cells is split 1 :3 on day 2 post transfection to prevent overgrowth.
  • the following day the cells are split 1 :5 and selection in 700 ⁇ g/ml G418 begins.
  • the selective medium is changed every 3-4 days.
  • the cells are cloned by limiting dilution and assayed for binding of [ 3 H]desArg 10 -kallidin. The clone with the highest binding is chosen for further use. Care is taken not to allow the cells to overgrow and to maintain G418 in the growth medium.
  • HEK 293 cells expressing the human bradykinin B. receptor are used to prepare membranes.
  • Cells are homogenised in 50 mM Tris-HCI, 1 mM EDTA pH 7.4 at 10,000 rpm for 30 sec in a Polytron homogeniser. All subsequent operations are carried out at 4°C.
  • the resultant suspension is centrifuged for 30 min at 28,000 x g.
  • the pellet is washed a further two times by resuspension in Tris-HCI (50 mM, pH 7.4) and recentrifugation.
  • the final pellet is resuspended in Tris-HCI (50 mM, pH 7.4), containing 5 % glycerol and frozen rapidly on dry ice in 500 ⁇ l aliquots and stored at -80°C.
  • membranes are thawed, homogenised, and diluted with physiological binding buffer (10 mM HEPES, HBSS ⁇ 137 mM NaCI, 5.4 mM KCI, 1.3 mM CaCI 2 , 0.4 mM KH 2 PO 4 , 0.3 mM NaHPO 4 , 0.5 mM MgCI 2 , 0.4 mM MgSO 4 , 5.6 mM glucose, pH 7.4 ⁇ containing 1 mM 1 -10 phenanthroline and 0J4 g/l bacitracin.
  • physiological binding buffer 10 mM HEPES, HBSS ⁇ 137 mM NaCI, 5.4 mM KCI, 1.3 mM CaCI 2 , 0.4 mM KH 2 PO 4 , 0.3 mM NaHPO 4 , 0.5 mM MgCI 2 , 0.4 mM MgSO 4 , 5.6 mM glucose, pH 7.4 ⁇ containing 1 mM 1 -10 phenan
  • Binding assays are performed in 1.2 ml polypropylene assay tubes (incorporated into a deep well block of 96 or individual Micronics tubes) containing a final volume of 0.5 ml.
  • the assay composition is 425 ⁇ l membrane suspension (approximately 20 ⁇ g protein per tube) in physiological binding buffer, 50 ⁇ l [ 3 H]desArg 10 -kallidin (specific activity 95 Ci/mMol; 6.0 ⁇ 0.5 nM), 25 ⁇ l of either DMSO, or unlabelled desArg 10 kallidin (20 ⁇ M) or different concentrations of Pharmaceutical Compounds made up in DMSO. Specific binding to the bradykinin B.
  • the receptor is defined as the difference between that found in total bound tubes and that found in non-specific binding tubes.
  • the reaction is initiated with the addition of membranes and incubated at 4°C for 60 min.
  • the reaction is terminated by rapid filtration of the assay mixture through Canberra Packard Unifilter-96 GF/B filterplates (which have been pre-soaked in 0.6% polyethylene- imine for 2 to 3 h at RT).
  • the filters are washed 4 times with 1 ml aliquots of ice cold wash buffer.
  • Microscintillant-40 liquid scintillant is added to the filters and radioactivity bound is determined in a Canberra Packard Topcount scintillation counter.
  • Binding parameters are derived from non-linear iterative curve fitting of three or four data sets simultaneously, using a logistic model in MicrocalTM Origin.
  • Activity specifically as analgesic agents may be demonstrated in accordance with standard test methods, e.g. as described in the following test.
  • Test II Thermal antinociception in monkeys (warm water tail-withdrawal)
  • Carrageenan at a dosage of 2 mg in 100 ⁇ l saline is injected subcutaneously into the terminal 1 to 4 cm of the tail of adult rhesus monkeys (Macaca mulatta) followed by administration of Pharmaceutical Compound in 100 ⁇ l vehicle (0.5 % methylcellulose in distilled water) or vehicle to the animal.
  • the animals are seated in restraint chairs and the lower part of the shaved tail (approximately 15 cm) immersed into warm water maintained at temperatures of 42, 46, and 50°C.
  • Tail-withdrawal latencies are recorded manually by a computerized timer.
  • a maximum cutoff latency (20 sec) is recorded if the subjects fail to remove their tails by this time.
  • a single dosing procedure is used in all test sessions. Each experimental session begins with control determinations at each temperature. Subsequent tail withdrawal latencies are determined based on each experimental condition.
  • the subjects are tested 1 to 2 times at three temperatures in a varying order, with approximately 1 to 2 min interval between tests. Experimental sessions are conducted once per week.
  • bradykinin Bi receptor antagonists are accordingly useful as bradykinin Bi receptor antagonists, e.g. in the treatment of diseases and conditions in which B. receptor activation plays a role or is implicated.
  • diseases and conditions include in particular pain, e.g. bone and joint pain (osteoarthritis), cancer pain, myofascial pain (muscular injury, fibromyalgia) and perioperative pain (general surgery, gynecologic surgery).
  • Pharmaceutical Compounds are particularly useful in the treatment or prevention of chronic pain, especially inflammatory, e.g. chronic inflammatory pain, inflammatory diseases for example inflammatory airways disease, e.g. COPD, or in asthma, rhinitis, inflammatory bowel disease, cystitis, e.g. interstitial cystistis, pancreatitis, uveitis, inflammatory skin disorders and rheumatoid arthritis.
  • inflammatory for example inflammatory airways disease, e.g. COPD
  • cystitis e.g. interstitial cystistis
  • pancreatitis e.g. interstitial cystistis
  • pancreatitis e.g. interstitial cystistis
  • uveitis inflammatory skin disorders and rheumatoid arthritis.
  • Pharmaceutical Compounds are thus useful as bradykinin B ⁇ receptor antagonists, e.g.
  • bradykinin for the treatment of pain of various genesis or aetiology and as anti-inflammatory and/or anti-oedemic agents for the treatment of inflammatory reactions, diseases or conditions, as well as for the treatment of allergic responses mediated by bradykinin.
  • analgesic/anti- inflammatory profile they are useful for the treatment of inflammatory pain, for the treatment of hyperalgesia and, in particular, for the treatment of severe chronic pain. They are, for example, useful for the treatment of pain, inflammation and or oedema consequential to trauma, e.g. associated with bums, sprains, fracture or the like, subsequent to surgical intervention, e.g.
  • analgesics as post-operative analgesics, as well as for the treatment of inflammatory pain of diverse genesis, e.g. for the treatment of osteo and rheumatoid arthritis and rheumatic disease, teno-synovitis and gout. They are further suitable as analgesics for the treatment of pain associated with, e.g., angina, menstruation or cancer.
  • anti-inflammatory/anti-oedema agents they are further useful, e.g., for the treatment of inflammatory skin disorders, for example psoriasis and eczema.
  • bradykinin BK1 receptor antagonists Pharmaceutical Compounds are also useful as smooth muscle relaxants, e.g. for the treatment of spasm of the gastro-intestinal tract or uterus, e.g. in the therapy of Crohn's disease, ulcerative collitis or pancreatitis.
  • Pharmaceutical Compounds are in particular useful as agents for the therapy of airways hyperreactivity and for the treatment of inflammatory events associated with airways disease, in particular asthma.
  • Pharmaceutical Compounds may, for example, be used for the control, restriction or reversal of airways hyperreactivity in asthma.
  • Inflammatory or obstructive airways diseases to which the present invention is applicable include asthma of whatever type or genesis including both intrinsic and, especially, extrinsic asthma.
  • Pharmaceutical Compounds are useful for the treatment of allergic asthma, whether atopic (i.e. IgE-mediated) or non-atopic, as well as, for example, exercise induced asthma, occupational asthma, asthma induced following bacterial infection, other non-allergic asthmas and "whez-infant syndrome".
  • Efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g. of acute asthmatic or bronchoconstrictor attack and by reduced requirement for other, symptomatic therapy, for example anti-inflammatory (e.g. corticosteroid) or bronchodilator (e.g. ⁇ 2 adrenergic) therapy.
  • symptomatic attack e.g. of acute asthmatic or bronchoconstrictor attack
  • other, symptomatic therapy for example anti-inflammatory (e.g. corticosteroid) or bronchodilator (e.g. ⁇ 2 adrenergic) therapy.
  • anti-inflammatory e.g. corticosteroid
  • bronchodilator e.g. ⁇ 2 adrenergic
  • Inflammatory or obstructive airways diseases to which the present invention is applicable further include pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and, in particular, byssinosis.
  • pneumoconiosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by repeated inhalation of dusts
  • pneumoconiosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by repeated inhalation of dusts
  • aluminosis anthracosis
  • asbestosis chalicosis
  • ptilosis ptilosis
  • siderosis silicosis
  • tabacosis tabacosis
  • ARDS adult respiratory distress syndrome
  • COAD chronic obstructive pulmonary or airways disease
  • bronchitis bronchitis
  • Pharmaceutical Compounds may also be used for the treatment of allergic and vasomotor rhinitis.
  • Compounds are also indicated for use in the therapy of septic shock, e.g. as anti-hypovolaemic and/or anti-hypotensive agents, in the treatment of inflammatory bowel disease cerebral oedema, headache, migraine and inflammatory skin disease such as eczema and psoriasis, and inflammatory disorders of the gut, e.g. irritable bowel syndrome, Crohn's disease, ulcerative colitis, cystitis, e.g. interstitial cystitis, nephritis, uveitis.
  • septic shock e.g. as anti-hypovolaemic and/or anti-hypotensive agents
  • inflammatory disorders of the gut e.g. irritable bowel syndrome, Crohn's disease, ulcerative colitis
  • cystitis e.g. interstitial cystitis, nephritis, uveitis.
  • the appropriate dosage of Pharmaceutical Compounds will, of course, vary depending upon, for example, the host, the mode of administration and the nature and severity of the condition being treated as well as the relative potency of the particular Pharmaceutical Compound employed.
  • the amount of active agent required may be determined on the basis of known in vitro and in vivo techniques, determining how long a particular active agent concentration in the blood plasma remains at an acceptable level for a therapeutic effect.
  • satisfactory results in animals are indicated to be obtained at daily dosages of from about 0.01 to about 20.0 mg/kg p.o.
  • an indicated daily dosage is in the range of from about 0.7 to about 1400 mg/day p.o., e.g.
  • Oral dosage forms accordingly suitably comprise from about 1.75 or 2.0 to about 700 or 1400 mg
  • Pharmaceutical Compounds may alternatively be administered e.g. topically in the form of a cream, gel or the like for example for the treatment of conditions of the skin as hereinbefore described or by inhalation, e.g. in dry powder form, for example for the treatment of asthma.
  • compositions comprising Pharmaceutical Compound include, e.g. a solid dispersion, an aqueous solution, e.g. containing a solubilising agent, e.g. cyclodextrin, a microemulsion and a suspension of, e.g. a micronized hydrochloride salt of a compound of formula IA in, e.g. aqueous methyl cellulose in the range of from OJ to 1 %, e.g. 0.5 %.
  • the composition may be buffered to, e.g. a pH in the range of from 3.5 to 9.5, e.g. to pH 4.5, by a suitable buffer, e.g. malic acid.
  • the present invention also provides:
  • a pharmaceutical compound for use as a bradykinin BK, receptor antagonist for example for use in any of the particular indications hereinbefore set forth;
  • composition comprising a pharmaceutical compound as under (1) as active ingredient together with a pharmaceutically acceptable diluent or carrier therefor;
  • a pharmaceutical composition for the treatment or prevention of a disease or condition in which bradykinin Bi receptor activation plays a role or is implicated comprising a compound of formula IA and a carrier.
  • a method for treating or preventing a disease or condition in which bradykinin Bi receptor activation plays a role or is implicated comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula IA.
  • a compound of formula IA for the manufacture of a medicament for the treatment or prevention of a disease or condition in which bradykinin Bi receptor activation plays a role or is implicated;
  • the preferred Pharmaceutical Compounds for use in accordance with the invention are those of Examples 1 and 2.

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Abstract

Novel sulfonyl amine derivatives, of formula (IA) processes for their production, their use as pharmaceuticals and pharmaceutical compositions comprising them.

Description

Bradvkinin receptor antagonists
The present invention relates to novel sulfonyl amine derivatives, to processes for their production, their use as pharmaceuticals and to pharmaceutical compositions comprising them.
More particularly the present invention provides in a first aspect, a compound of formula IA
(IA)
Figure imgf000002_0001
wherein
R5A is -XA-R6A or -N(R7A)R8A, wherein
XA is piperidinylene or piperazinylene,
R6A is H, d-C^lkyl, C3-C4alkenyl, C3-C4alkinyl, C C4(alkoxyalkyl), C C4(carboxyalkyl), a C5-C7heterocyclic group or phenyl-CrCalkyl;
R7A is amino-C2-C4alkyl or mono- or dKC CsalkylJamino-Cz-Csalkyl, and
R8A is H, C1-C4alkyl or has the meanings as given for R7A;
X1 is a divalent group of formula IA' ~ <CH2>rT— ^~(CH2)π^— x_g~ wherein
R n is zero or 1 ; X3 is CH or N;
(a) X4 is a direct bond, R3A and R4A together are ethylene and m is 2; or
(b) X4 is a direct bond, R3A is H, C C4alkyl, C3-C6cycloalkyl, C3-C6alkenyl, C3-C6alkinyl, C7-C10aralkyl or C6-C9heteroaralkyl, R4A is H and m is 1 or 2 or 3; or
(c) X4 is -CH(R12)-, R3A is H and R4A and R12 together are propylene and m is 1 , or ethylene and m is 2;
X ,2 is a divalent group of formula IA" wherein
Figure imgf000002_0002
X3 is CH or N; and
R11 is Cι-C4alkyl, C3-C6cycloalkyl or -NR^R2 , wherein
R1A and R^ independently are d-C4alkyl or, together with the N-atom to which they are attached, represent a 5 to 7 membered heterocyclic ring; and R9 and R10 independently are a phenyl or pyridine ring; and salts thereof.
It will be understood that the above defined compounds may bear substituents within their structure, e.g. may bear appropriate phenyl ring or alkylene moiety substituents, e.g. phenyl and pyridine in the meaning of R9 or R10 may be unsubstituted or substituted by one or more halogen, and in the meaning of R3A alkyl may be unsubstituted or substituted by halogen, C3-C6cycloalkyl or aryl; aralkyl may be unsubstituted or substituted by halogen, methoxy, nitro or Cι-C alkyl which may be unsubstituted or substituted by halogen; heteroaralkyl may be unsubstituted or substituted by CrC4alkyl. The amino moiety of the defined aminocarb- onyl or amide groupings can be any appropriate amino grouping, e.g. cyclic or aliphatic or may bear further substituent groupings.
Even more particularly the present invention provides a 2-(2,2-diphenylethylamino)- -5-(4-aminocarbonyl-piperidine-1-sulfonyl)-benzoic acid amide or -5-(aminocarbonyl- C2-C alkyleneaminosulfonyl)-benzoic acid amide, or salt thereof.
Preferred compounds in accordance with the invention are those of formula I
Figure imgf000003_0001
wherein
R1 and R2 independently are d-C4alkyl or, together with the N-atom to which they are attached, represent a 5 to 7 membered heterocyclic ring;
(a) R3 and R4 together are ethylene and m is 2; or
(b) R3 is H, C1-C4alkyl, C5-C7cycloalkyl or phenyl-C C4alkyl, R4 is H and m is 1 or 2 or 3; n is zero or 1 ; and
R5is -X-R6 or -N(R7)R8, wherein X is -N N- ,
\ /
R6 is C C4alkyl, C3-C4alkenyl, C3-C4alkinyl, d-C^alkoxyalkyl), d-C4(carboxyalkyl), a
C5-C7heterocyclic group or phenyl-d-dalkyl; R7 is amino-C2-C4alkyl or mono- or di-(Cι-C5alkyl)amino-C2-C5alkyl, and R8 is H, Cι-C4alkyl or has the meanings as given for R7; and salts thereof.
Alkyl groups and moieties in the compounds of formula IA or I may be branched or straight chain. Alkyl groups are suitably straight chain.
Heterocyclic groups may be saturated or unsaturated and may contain one or more additional heterocyclic atoms, e.g. oxygen or sulfur. Examples include piperidin-1-yl, morpholin- 1-yl, 3,6-dihydro-2.H.pyridin-1 -yl, thiomorpholin-1-yl, pyrrolin-1-yl, morpholin-4-yl, thiomor- pholin-4-yl, 3,6-dihydro-2H-pyridin-1 -yl, 2,5-dihydropyrrol-1-yl and 4-dif luoropiperidin-1 -yl, and may be unsubstituted or substituted by one or two halogen atoms.
Compounds of the invention exist in free or salt, e.g. acid addition salt form. The invention is to be understood as including both the compounds of formula IA or I in free as well as in salt form, e.g. as trifluoroacetate or hydrochloride salt. Suitable pharmaceutically acceptable acid addition salts for pharmaceutical use in accordance with the invention include in particular the hydrochloride salt.
In formula IA the following significances are preferred independently, collectively or in any combination or sub-combination:
(a') R5A is unsubstituted piperazinyl or piperazinyl substituted by methyl, ethyl, benzyl, 2- pyridinyl, methoxyethyl, carboxymethyl or -CH2CHCH2; or piperidine substituted by methyl; (a") R5A is N(R7A)R8A wherein R7A is aminopropyl, aminobutyl, dimethylaminopropyl, diethylaminopropyl, dibutylaminoethyl, dimethylaminobutyl, or dimethylaminopentyl; and
R8A is H, methyl, aminopropyl, aminobutyl, dimethylaminopropyl or dimethylaminobutyl; (b') X1 is -(CH2)n-CH(R4A)-(CH2)2-N(R3A)- wherein n is zero or 1 and R3A and R4A together are ethylene; (b") X1 is -CH(R4A)-(CH2)m-CH(R12)-NH- wherein m is 1 or 2 and R4A and R12 together are propylene or ethylene;
(b'") X1 is -(CH2)n-CH2-(CH2)m-N(R3A)- wherein n is zero or 1 , m is 1 or 2 or 3 and R3A is H, methyl, isopropyl, isobutyl, fluoroethyl, cyclopropylmethyl, cyclohexylmethyl, cyclobutylmethyl, -CH(CH3)C6H5) cyclohexyl, propenyl, butenyl, pentenyl, propinyl, butinyl, pentinyl, benzyl, methylbenzyl, fluorobenzyl, trifluoromethylbenzyl, methoxybenzyl, nitrobenzyl, pyridinylmethyl, methylisoxazolylmethyl, methylthiazolylmethyl or thiophenmethyl;
(c') X2 is a divalent group of formula IA" wherein X3 is CH and R11 is methyl, cyclopentyl, cyclohexyl, N(CH3)CH2CH3, piperidinyl, morpholinyl, thiomorpholinyl, dihydropyridinyl, dihydropyrrolyl or difluoropiperidinyl;
(c") X2 is a divalent group of formula IA" wherein X3 is N and R11 is morpholinyl;
(d) R9 and R10 are phenyl which is unsubstituted or substituted by halogen;
(d") R9 is phenyl and R10 is pyridine.
In formula I the following significances are preferred independently, collectively or in any combination or sub-combination:
(a1) R1 and R2 are independently methyl or ethyl.
(a2) R1 and R2 together with the N-atom to which they are attached are piperidin-1-yl, morpholin-1-yl, 3,6-dihydro-2.H.pyridin-1 -yl, thiomorpholin-1-yl or pyrrolin-1 -yl.
(b1) R3 and R4 together are ethylene and m is 2.
(b2) R3 is H, methyl, cyclohexyl or benzyl; R4 is H and m is 1 or 2 or 3, especially 1.
(c) n is zero or 1.
(d1) R5 is -X-R6 , wherein R6 is Cι-C4alkyl (e.g. methyl, ethyl or isopropyl), 3-propenyl, methoxyethyl, carboxymethyl, 2-pyridyl, or benzyl, and X is as defined above.
(d2) R5 is -N(R7)R8, wherein R7 is aminopropyl, aminobutyl, dipropylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, diethylaminopropyl or dimethylaminopentyl; and R8 is H, methyl, aminopropyl, aminobutyl, dimethylaminopropyl or dimethylaminobutyl.
In addition to the foregoing the present invention also provides a process for the production of a compound of formula IA which process comprises reacting a compound of formula IIA (IIA)
Figure imgf000006_0001
wherein X1, X2, R9 and R10 have the meanings given for formula IA, with an amine, e.g. of formula IIIA
H-R5A (IIIA) wherein R5A has the meanings given for formula IA, and recovering the obtained compound, e.g. of formula IA, in free or in salt form, e.g. acid addition salt form.
The present invention also provides a process for the production of a 2-(2,2-diphenylethyl- amino)- -5-(4-aminocarbonyl-piperidine-1-sulfonyl)-benzoic acid amide or -5-(aminocarbon- y ^alkylene aminosulfonyl)-benzoic acid amide, for example a compound of formula I as defined above, or salt thereof, which process comprises reacting a 2-(2,2-diphenylethylamino)- -5-(4-carboxy-piperidine-1 -sulfonyl)-benzoic acid amide or -5-(carboxy-C2.4alkylene aminosulfonyl)-benzoic acid amide, for example a compound of formula II
(")
Figure imgf000006_0002
wherein R1, R2, R3, R4, m and n have the meanings given for formula I, with an amine, e.g. of formula III
H-R5 (III) wherein R5 has the meanings given for formula I, and recovering the obtained compound, e.g. of formula I, in free or in salt form, e.g. acid addition salt form.
The reaction may be earned out in accordance with standard procedures, for example by a first acid chloride formation step using e.g. thionyl chloride and catalytic DMF in an inert solvent, e.g. CH2CI2, at ambient temperature, followed by the coupling step involving addition of the acid chloride to a mixture of the amine and e.g. TEA, at a temperature of, e.g. -10°C. Aqueous workup followed by precipitation from, e.g. ethyl acetate gives the free base. The salt forms are made by standard procedures known to the skilled artisan.
In the examples the following abbreviations are used: DMF: dimethyl formamide; DMSO: dimethyl sulfoxide; EDTA: ethylenediamine-tetraacetic acid; EtOAc: ethylacetate; IPA: isopropanol; RT: room temperature; TBME: t-butyl methyl ether; TBTU: (O-(benzotriazol-1 - yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran.
Example 1 : Preparation of {2-(2,2-diphenyl-ethylamino)-5-[4-(4-isopropyl-piperazine-1- carbonyl)-piperidine-1-sulfonyl]-phenyl}-morpholin-4-yl-methanone (formula I: R1 + R2 + N = morpholin-4-yl, R3 + R4 = ethylene, m = 2, n = zero, R5 = 4-isopropyl-piperazin-1-yl)
(a) A 5 liter flask is charged with {2-(2,2-diphenyl-ethylamino)-5-[4-(4-carboxy)-piperidine- 1-sulfonyl]-phenyl}-morpholin-4-yl-methanone (130.2 g), CH2CI2 (1.3 I), DMF (0.82 g) and thionyl chloride (18J ml, 29.51 g). The suspension is stirred at ambient temperature (the solids dissolved after -2 h). The volatiles are removed by rotary evaporation (30°C, house vacuum) and the crude acid chloride is redissolved in CH CI2 (300 ml). The solution of acid chloride is added to a mixture of isopropylpiperazine (47.60 g), TEA (98.09 g) and CH2CI2 (1 I) at -10°C over 1 h. The reaction is worked up by removing volatiles via rotary evapor- tion. The residue is suspended in EtOAc (2.0 I) and washed with water (2 x 500 ml), brine (500 ml) and dried (Na2SO4). The volume is reduced by rotary evaporation (35°C, house vacuum) to -500 ml and stirred at ambient temperature for 17 h. The suspension is filtered and dried (40°C, house vacuum) to give the title compound as free base.
(b) A 5 liter flask is charged with the above compound (121.3 g), CH2CI2 (1.2 I), and 37 % HCI (17.38 g). After stirring for 30 min, the volatiles are removed by rotary evaporation and the residue is triturated with IPA (1 I). The suspension is filtered and dried (40°C, house vacuum) to give the crude HCI salt of the title compound.
(c) A 2 liter flask is charged with the above crude HCI salt (133.7 g), silica gel (13.0 g) and CH2CI2 (1.3 I). The mixture is stirred for 15 min at ambient temperature and then filtered. This process is repeated twice more. The solvent is removed by rotary evaporation. The residue is suspended in a mixture of IPA (1.0 I) and water (100 ml) and heated to reflux. The solution is allowed to cool to ambient temperature and stir for 17 h. The resulting sus- pension is filtered and dried. The solid is suspended in acetone (1.0 I) and refluxed for 4.5 h. The suspension is cooled to ambient temperature and stirred for 3 days. The suspension is filtered and dried (60°C, house vacuum, 2 days) to give the title compound as HCI salt.
-,3A A
In the following examples compounds of formula IA wherein R and R together are ethylene, m is 2, X3 is CH and R5A is -XA-R6A wherein XA is piperazin-1 , 4-ylene, are prepared analogously to Example 1 :
Figure imgf000008_0001
* as trifluoroacetate ln the following examples compounds of formula I wherein R3 and R4 together are ethylene, m is 2 and R5 is -N(R7)R8 are prepared analogously to Example 1 :
Figure imgf000009_0001
In the following examples compounds of formula IA wherein n is 0, m is 2, X4 is a direct bboonndd,, RR33AA aanncd R4A together are ethylene and R11 is morpholin-4-yl are prepared analogously to Example 1 :
Figure imgf000009_0002
In the following examples compounds of formula IA wherein R3A is H, R5A is 4- methylpiperazin-1 -yl, R9 and R10 are phenyl, R11 is morpholin-4-yl, n is 0, X3 and X5 are CH and X4 is -CH(R12)- are prepared analogously to Example 1 :
Figure imgf000009_0003
In the following examples compounds of formula IA wherein R1A and R2 together with the N-atom to which they are attached are morpholin-4-yl, R4A is H and R5A is -XA-R6A wherein X is piperazin-1 ,4-ylene, are prepared analogously to Example 1 :
Figure imgf000010_0001
Figure imgf000011_0002
CHARACTERISING DATA
Compounds of the above tables are found to exhibit the following HPLC retention data [min]:
Figure imgf000011_0001
Figure imgf000012_0001
HPLC conditions:
*: Hypersil 3 micron C 18 BDS column. Gradient elution 10-100% MeCN in water
(+0.1% TFA) over 10 min **: Kingsorb 50x4.6mm C18 column, 3micron particle size; flow rate 3ml/min; 90% water
(+10mM NH4OAc 0.3% HCOOH) 10% MeCN to 100% MeCN over 10min ***: Nucleosil 5 micron C18 column, 25cm x 4.6mm. Gradient elution 10-100% MeCN in water (+0.1% TFA) over 40 min ****: Waters Symmetry 3 micron C18 column; 5 x 0.46 cm. Gradient elution, 10% to 100%
MeCN in water (+ 0.1 % TFA) over 10 min *****: Kingsorb 3 micron C18 column, 30x4.6mm, gradient elution 10 % MeCN in water
(+0.1% TFA) to 100% MeCN over 10 min
Compounds of formula IIA wherein X1, R9 and R10 have the above meanings and X2 is a divalent group of formula
Figure imgf000012_0002
wherein R1A and R^ independently are d-C alkyl or, together with the N-atom to which they are attached, represent a 5 to 7 membered heterocyclic ring, may be prepared applying known techniques, e.g. in accordance with the following reaction scheme:
Figure imgf000013_0001
(CA) (V..A) (dA) ^A)
R150N ft /R 9
(V/^ »- C-X1-S-X2-NH-CH2-CH ^ *- (||A)
(€A) O O 10 (fA)
(IVA) wherein Hal is halogen, e.g. chlorine, R15 is d-C4alkyl, e.g. ethyl, and X1, X2, R A, R2*, R9 and R10 are as defined for formula IA.
Each of the above reaction steps may be carried out in accordance with conventional procedures as known in the art, e.g. as illustrated in the following examples or analogously thereto. For example in step (aA) the compound of formula XIIA may conveniently be reacted with e.g. chlorosulfonic acid or with chlorosulfonic acid followed by thionyl chloride. In step (bA) the compound of formula XIA may be reacted with the compound of formula XA and e.g. triethyl- amine in the presence of a solvent like acetonitrile and acetone at 0°C. In step (cA) the compound of formula IXA may be reacted with the compound of formula VINA at room temperature in the presence of a solvent like acetonitrile, acetone or ethyl acetate, ethyl acetate being preferred. Preferably an excess of the compound of formula VIIIA may be used, e.g. a 10 % excess. In step (dA) the compound of formula VIIA may be reacted with an excess of the compound of formula VIA, e.g. a 10 % excess, in the presence of, e.g. trifluoroacetic acid and a desiccant, e.g. trimethyl orthoacetate. The reduction of step (eA) may, e.g. be accomplished via hydrogenation over 10 % palladium on carbon in the presence of a solvent, e.g. tetrahydrofuran. The hydrolysis of the ester of formula IVA [step (fA)] may be accomplished in the presence of a base like NaOH, in a solvent like ethanol, methanol, acetone or tetrahydrofuran, preferably tetrahydrofuran. In some of the above steps the reac- tants may be warmed prior to reaction. Compounds of formula IIA wherein X1, R9 and R10 have the above meanings and X is a divalent group of formula
Figure imgf000014_0001
wherein R11 is d-C4alkyl, C3-C6cycloalkyl, may be prepared applying known techniques, e.g. in accordance with the following reaction scheme:
Figure imgf000014_0002
wherein Hal is halogen, e.g. chlorine, R15 is d-C alkyl, e.g. ethyl, y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal, and X1, R9, R10 and R11 are as defined for formula IA.
Examples of a metal include an alkali metal, e.g. lithium (Li), sodium (Na) and potassium (K), an alkaline earth metal, e.g. magnesium (Mg), or manganese (Mn), iron (Fe), zinc (Zn) or silver (Ag).
Compounds of formula IIA wherein X1, R9 and R10 have the above meanings and X2 is a divalent group of formula
Figure imgf000015_0001
wherein R1A and R^ independently are C C alkyl or, together with the N-atom to which they are attached, represent a 5 to 7 membered heterocyclic ring, may be prepared applying known techniques, e.g. in accordance with the following reaction scheme:
Figure imgf000015_0002
wherein Hal is halogen, e.g. chlorine, R 15 ; i„s r C.ι- _C-.4a „|l,kΛy,ιl, e Λ.g „. e „thL,ty,ιl, a „„n,dj X V1 , D R1A , D R2A , Γ RJ9 a a „nd . R ,-,10 are as defined for formula IA.
Compounds of formula VIIA wherein X1, R9 and R10 have the above meanings and X2 is a divalent group of formula
Figure imgf000015_0003
wherein R11 is Cι-C4alkyl, C3-C6cycloalkyl, may be prepared applying known techniques, e.g. in accordance with the following reaction scheme:
Figure imgf000016_0001
(IVD) wherein Hal is halogen, e.g. Cl, R ,15 is C C alkyl, e.g. ethyl, y is 1 and M is a monovalent metal or y is 1/2 and M is a divalent metal, and X1, R9, R10 and R11 are as defined for formula IA.
Compounds of formula II may be prepared applying known techniques, e.g. in accordance with the following reaction scheme:
Figure imgf000016_0002
(IX) (VII)
(II)
Figure imgf000016_0003
wherein Hal is halogen, e.g. chlorine, R15 is d-C4alkyl, e.g. ethyl, and R , R ,R , R , m and n are as defined for formula I.
Each of the above reaction steps may be carried out in accordance with conventional procedures as known in the art, e.g. as illustrated in the following examples or analogously thereto. For example in step (a) the compound of formula XII may conveniently be reacted with e.g. chlorosulfonic acid or with chlorosulfonic acid followed by thionyl chloride. In step (b) the compound of formula XI is reacted with the compound of formula X and e.g. triethylamine in the presence of a solvent like acetonitrile and acetone at 0°C. In step (c) the sulfonamide of formula IX is reacted with the compound of formula VIII at room temperature in the presence of a solvent like acetonitrile, acetone or ethyl acetate, ethyl acetate being preferred. Preferably an excess of the compound of formula VIII may be used, e.g. a 10 % excess. In step (d) the compound of formula VII may be reacted with an excess of the compound of formula VI, e.g. a 10 % excess, in the presence of, e.g. trifluoroacetic acid and a desiccant, e.g. tri- methyl orthoacetate. The reduction of step (e) may for example be accomplished via hydro- genation over 10 % palladium on carbon in the presence of a solvent, e.g. tetrahydrofuran. The hydrolysis of the ester of formula IV [step (f)] may be accomplished in the presence of a base like NaOH, in a solvent like ethanol, methanol, acetone or tetrahydrofuran, preferably tetrahydrofuran. In some of the above steps the reactants may be warmed prior to reaction.
Starting compounds of formula IIIA, VB, VIA, VIB, VIC, VID, VIIB, VINA, XA, XIB, XIC and XIIIB are known or may be prepared from corresponding known compounds. Starting compounds III, VI, VIII, X and XII are known or may be prepared from corresponding known compounds.
Example S1: Preparation of {2-(2,2-diphenyl-ethylamino)-5-[4-(4-carboxy)-piperidine-1- sulfonyl]-phenyl}-morpholin-4-yl-methanone (formula II: R + R2 + N = morpholin-4-yl, R3 + R4 = ethylene, m = 2, n = zero)
(a) A 2 liter flask is charged with isatoic anhydride (180.3 g) and chlorosulfonic acid (367 ml, 643.9 g). The mixture is stirred at ambient temperature for 21 h. Thionyl chloride (80.6 ml, 131.5 g) is added over 2 h and the mixture is stirred at ambient temperature for 16 h. The reaction is worked up by slowly pouring the reaction mixture over ice (4.5 kg) with stirring. The resulting suspension is filtered and the filtercake is washed with water (2 x 500 ml). The solid is dried (40°C, house vacuum, 48 h) to give compound 2. (b) A 5 liter flask is charged with 2 (270.2 g) and acetone (2.0 I). The suspension is cooled in an ice/methanol bath and a solution of ethyl isonipecotate (165.7 g) and TEA (156.8 g) in acetone (700 ml) is added over 1.43 h. After the addition is complete, the cooling bath is removed and the mixture is stirred for 2 h. The reaction is worked up by removing volatiles via rotary evaporation (35°C, house vacuum). The solid is triturated with 0.5 N HCI
(1763 ml). The suspension is filtered and the filtercake is washed with water (1.0 I). The solid is dried (40°C, house vacuum, 3 days) to give compound 4.
(c) A 12 liter flask is charged with 4 (342.4 g) and EtOAc (3.4 I). A solution of morpholine (85.80 g) in EtOAc (340 ml) is added at ambient temperature over 1.5 h. The mixture is stirred for 30 min. The reaction is worked up by adding charcoal (35.2 g) and filtering through Celite. The solids are washed with EtOAc and the filtrate is reduced to ~2 I by rotary evaporation. Heptane (1.7 I) is added at ambient temperature over 2 h and the resulting suspension is stirred overnight. The suspension is filtered, washed with mother liquor, and dried overnight (40°C, house vacuum) to give 6.
(d) A 12 liter flask is charged with compound 6 (324.7 g) and EtOAc (4.4 I). The mixture is heated until all of the solids dissolved (~35°C). 2,2-diphenyl ethanal (164.7 g), trimethyl orthoacetate (100.8 g), and TFA (4.35 g) are added and the mixture is stirred at ambient temperature for 3 days. The reaction is worked up by removing EtOAc via rotary evaporator. The residue is triturated with TBME (3.2 I). The resulting suspension is filtered, the filtercake is washed with TBME (320 ml) and dried (40°C, house vacuum, N2 purge) to give compound 8.
(e) A 2.5 liter Parr bottle is charged with compound 8 (118.8 g) and THF (1.2 I). The mixture is heated with stirring until all of the solids are dissolved (~55°C). Palladium on carbon (10 %, anhydrous, 10.47 g) is added and the mixture is shaken under a hydrogen atmosphere (50 psi) at ambient temperature for 24 h. The reaction is worked up by filtering the mixture through Celite. THF is removed by rotary evaporator. The residue is triturated with TBME (1.1 I). The resulting suspension is filtered, the filtercake is washed with TBME (110 ml) and dried (40°C, house vacuum, N2 purge) to give compound 9.
(f) A 12 liter flask is charged with 9 (326.8 g), THF (3.3 I), and 1.0 N NaOH (540 ml). The biphasic solution is stirred at ambient temperature for 24 h. The reaction is worked up by removing THF via rotary evaporator. Water (1.0 I) is added to the remaining aqueous portion and 1.0 N HCI (600 ml) is added with stirring at ambient temperature over 2 h. The resulting suspension is filtered, the filtercake is washed with water (1 I) and dried (40°C, house vacuum, N2 purge) to give the title compound.
Compounds of formula II, IV, V, VII and IX are new and also an embodiment of the present invention.
The following examples for compounds of formula IIA wherein R3A and R A together are ethylene and m is 2 are prepared analogously to Example S1 :
Figure imgf000019_0001
The following examples for compounds of formula II wherein R1 and R2 together with the N- atom to which they are attached are morpholinyl, and R4 is H are prepared analogously to Example S1 :
Figure imgf000019_0002
The compounds of the invention and their pharmaceutically acceptable acid addition salts (hereinafter Pharmaceutical Compounds) have pharmacological activity and are useful as pharmaceuticals. In particular Pharmaceutical Compounds exhibit bradykinin antagonist activity. In particular Pharmaceutical Compounds, e.g. compounds of Example 1 and 2, are active at the human Bi bradykinin receptor. Bradykinin receptor interaction of the Pharmaceutical Compounds is demonstrated by their ability to displace bradykinin at human bradykinin receptor sites, e.g. as demonstrated in accordance with the following test method.
Test I: Bradykinin receptor binding assay
Cloning of the human bradykinin B1 receptor cDNA: The human bradykinin B1 receptor is cloned from WI38 human foetal lung cell fibroblast cells by expression cloning in Xenopus laevis oocytes, which do not express bradykinin B1 receptors normally. A cDNA library is prepared in bacteriophage lambda ZAP express and grown in pools of approximately 10,000 clones per pool. Bacteriophage DNA is prepared from these pools and copy RNA is synthesised with T3 RNA polymerase and after phenol extraction and precipitation, the RNA is injected into Xenopus oocytes and allowed to be expressed for 3 days. The oocytes are then assayed electrophysiologically using two electrode voltage clamp, for a response in an endogenous chloride channel that can be activated by endogenous heterotrimeric GTP binding proteins of the Gq/G11 type that can couple to bradykinin receptors. A positive clone is isolated from a positive pool by several stages of splitting the pool into smaller pools and assaying, until a single clone is isolated. This cDNA is sequenced and subcloned into pcDNA3 (Clontech) and used to generate a cell-line which expresses the human bradykinin B1 receptor.
Making the HEK cells: The human bradykinin B1 receptor cDNA is subcloned into the Kpn1 and Not1 sites of pcDNA3 (HB1-pcDNA3), is grown up and transfected into human embryonic kidney fibroblast cell line, HEK 293 using the Calcium phosphate method. Cells are grown in Minimum Essential Medium with Earle's Salts (GIBCO) supplemented with 2 mM L-glutamine, 100 units/ml penicillin, 100 μg/ml streptomycin, 1 % nonessential amino acids and 10 % myoclone foetal calf serum (GIBCO) in a humidified atmosphere with 5 % C02 at 37°C.
The 293Hek cells are split 1 :2 the day prior to transfection. One 175 cm2 flask with approximately 50 % confluent cells is transfected with approximately 30 μg/ml HB1-pcDNA3 DNA using the calcium phosphate precipitate method of transfection. The flask of transfected cells is split 1 :3 on day 2 post transfection to prevent overgrowth. The following day the cells are split 1 :5 and selection in 700 μg/ml G418 begins. The selective medium is changed every 3-4 days. When distinct G418 resistant colonies of transfected cells are seen, approximately 4 weeks after transfection, the cells are cloned by limiting dilution and assayed for binding of [3H]desArg10-kallidin. The clone with the highest binding is chosen for further use. Care is taken not to allow the cells to overgrow and to maintain G418 in the growth medium.
These HEK 293 cells expressing the human bradykinin B. receptor are used to prepare membranes. Cells are homogenised in 50 mM Tris-HCI, 1 mM EDTA pH 7.4 at 10,000 rpm for 30 sec in a Polytron homogeniser. All subsequent operations are carried out at 4°C. The resultant suspension is centrifuged for 30 min at 28,000 x g. The pellet is washed a further two times by resuspension in Tris-HCI (50 mM, pH 7.4) and recentrifugation. The final pellet is resuspended in Tris-HCI (50 mM, pH 7.4), containing 5 % glycerol and frozen rapidly on dry ice in 500 μl aliquots and stored at -80°C.
For use in the binding assay, membranes are thawed, homogenised, and diluted with physiological binding buffer (10 mM HEPES, HBSS {137 mM NaCI, 5.4 mM KCI, 1.3 mM CaCI2, 0.4 mM KH2PO4, 0.3 mM NaHPO4, 0.5 mM MgCI2, 0.4 mM MgSO4, 5.6 mM glucose, pH 7.4} containing 1 mM 1 -10 phenanthroline and 0J4 g/l bacitracin. Binding assays are performed in 1.2 ml polypropylene assay tubes (incorporated into a deep well block of 96 or individual Micronics tubes) containing a final volume of 0.5 ml. The assay composition is 425 μl membrane suspension (approximately 20 μg protein per tube) in physiological binding buffer, 50 μl [3H]desArg10-kallidin (specific activity 95 Ci/mMol; 6.0 ± 0.5 nM), 25 μl of either DMSO, or unlabelled desArg10 kallidin (20 μM) or different concentrations of Pharmaceutical Compounds made up in DMSO. Specific binding to the bradykinin B. receptor is defined as the difference between that found in total bound tubes and that found in non-specific binding tubes. The reaction is initiated with the addition of membranes and incubated at 4°C for 60 min. The reaction is terminated by rapid filtration of the assay mixture through Canberra Packard Unifilter-96 GF/B filterplates (which have been pre-soaked in 0.6% polyethylene- imine for 2 to 3 h at RT). The filters are washed 4 times with 1 ml aliquots of ice cold wash buffer. Microscintillant-40 liquid scintillant is added to the filters and radioactivity bound is determined in a Canberra Packard Topcount scintillation counter. Binding parameters are derived from non-linear iterative curve fitting of three or four data sets simultaneously, using a logistic model in Microcal™ Origin.
K| values are 0.063 μM for the peptide antagonist desArg10HOE [(D-Arg-[Hyp3, Thi5, D-Tic7, Oic8]desArg9 bradykinin) = (D-Arginine-[hydroxyproline3, thienyamine5, D-tetrahydroxyquino- line-3-carboxylic acid7, octahydroindole-2-carboxylic acid8]desArginine9 bradykinin)] and in the range of 0.5 nM to 2 μM for Pharmaceutical Compounds. Activity specifically as analgesic agents may be demonstrated in accordance with standard test methods, e.g. as described in the following test.
Test II: Thermal antinociception in monkeys (warm water tail-withdrawal)
Carrageenan at a dosage of 2 mg in 100 μl saline is injected subcutaneously into the terminal 1 to 4 cm of the tail of adult rhesus monkeys (Macaca mulatta) followed by administration of Pharmaceutical Compound in 100 μl vehicle (0.5 % methylcellulose in distilled water) or vehicle to the animal.
The animals are seated in restraint chairs and the lower part of the shaved tail (approximately 15 cm) immersed into warm water maintained at temperatures of 42, 46, and 50°C. Tail-withdrawal latencies are recorded manually by a computerized timer. A maximum cutoff latency (20 sec) is recorded if the subjects fail to remove their tails by this time. A single dosing procedure is used in all test sessions. Each experimental session begins with control determinations at each temperature. Subsequent tail withdrawal latencies are determined based on each experimental condition. The subjects are tested 1 to 2 times at three temperatures in a varying order, with approximately 1 to 2 min interval between tests. Experimental sessions are conducted once per week.
In this test Pharmaceutical Compounds are efficient in preventing or reversing carrageenan- induced hyperalgesia at a dosage in the range of from 0.01 μMole/kg to 1 mMole/kg.
Pharmaceutical Compounds are accordingly useful as bradykinin Bi receptor antagonists, e.g. in the treatment of diseases and conditions in which B. receptor activation plays a role or is implicated. Such conditions include in particular pain, e.g. bone and joint pain (osteoarthritis), cancer pain, myofascial pain (muscular injury, fibromyalgia) and perioperative pain (general surgery, gynecologic surgery).
Pharmaceutical Compounds are particularly useful in the treatment or prevention of chronic pain, especially inflammatory, e.g. chronic inflammatory pain, inflammatory diseases for example inflammatory airways disease, e.g. COPD, or in asthma, rhinitis, inflammatory bowel disease, cystitis, e.g. interstitial cystistis, pancreatitis, uveitis, inflammatory skin disorders and rheumatoid arthritis. Pharmaceutical Compounds are thus useful as bradykinin B^ receptor antagonists, e.g. for the treatment of pain of various genesis or aetiology and as anti-inflammatory and/or anti-oedemic agents for the treatment of inflammatory reactions, diseases or conditions, as well as for the treatment of allergic responses mediated by bradykinin. Having regard to their analgesic/anti- inflammatory profile they are useful for the treatment of inflammatory pain, for the treatment of hyperalgesia and, in particular, for the treatment of severe chronic pain. They are, for example, useful for the treatment of pain, inflammation and or oedema consequential to trauma, e.g. associated with bums, sprains, fracture or the like, subsequent to surgical intervention, e.g. as post-operative analgesics, as well as for the treatment of inflammatory pain of diverse genesis, e.g. for the treatment of osteo and rheumatoid arthritis and rheumatic disease, teno-synovitis and gout. They are further suitable as analgesics for the treatment of pain associated with, e.g., angina, menstruation or cancer. As anti-inflammatory/anti-oedema agents, they are further useful, e.g., for the treatment of inflammatory skin disorders, for example psoriasis and eczema.
As bradykinin BK1 receptor antagonists Pharmaceutical Compounds are also useful as smooth muscle relaxants, e.g. for the treatment of spasm of the gastro-intestinal tract or uterus, e.g. in the therapy of Crohn's disease, ulcerative collitis or pancreatitis.
Pharmaceutical Compounds are in particular useful as agents for the therapy of airways hyperreactivity and for the treatment of inflammatory events associated with airways disease, in particular asthma. In addition, Pharmaceutical Compounds may, for example, be used for the control, restriction or reversal of airways hyperreactivity in asthma.
Inflammatory or obstructive airways diseases to which the present invention is applicable include asthma of whatever type or genesis including both intrinsic and, especially, extrinsic asthma. Thus, Pharmaceutical Compounds are useful for the treatment of allergic asthma, whether atopic (i.e. IgE-mediated) or non-atopic, as well as, for example, exercise induced asthma, occupational asthma, asthma induced following bacterial infection, other non-allergic asthmas and "wheezy-infant syndrome".
Efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g. of acute asthmatic or bronchoconstrictor attack and by reduced requirement for other, symptomatic therapy, for example anti-inflammatory (e.g. corticosteroid) or bronchodilator (e.g. β2 adrenergic) therapy. Inflammatory or obstructive airways diseases to which the present invention is applicable further include pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and, in particular, byssinosis.
Further inflammatory or obstructive airways diseases and conditions for which Pharmaceutical Compounds may be used include adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary or airways disease (COPD or COAD), and bronchitis. Pharmaceutical Compounds may also be used for the treatment of allergic and vasomotor rhinitis.
In addition to the foregoing Pharmaceutical Compounds are also indicated for use in the therapy of septic shock, e.g. as anti-hypovolaemic and/or anti-hypotensive agents, in the treatment of inflammatory bowel disease cerebral oedema, headache, migraine and inflammatory skin disease such as eczema and psoriasis, and inflammatory disorders of the gut, e.g. irritable bowel syndrome, Crohn's disease, ulcerative colitis, cystitis, e.g. interstitial cystitis, nephritis, uveitis.
For the above indications the appropriate dosage of Pharmaceutical Compounds will, of course, vary depending upon, for example, the host, the mode of administration and the nature and severity of the condition being treated as well as the relative potency of the particular Pharmaceutical Compound employed. For example, the amount of active agent required may be determined on the basis of known in vitro and in vivo techniques, determining how long a particular active agent concentration in the blood plasma remains at an acceptable level for a therapeutic effect. In general, satisfactory results in animals are indicated to be obtained at daily dosages of from about 0.01 to about 20.0 mg/kg p.o. In humans, an indicated daily dosage is in the range of from about 0.7 to about 1400 mg/day p.o., e.g. from about 50 to 200 mg (70 kg man), conveniently administered once or in divided doses up to 4 x per day or in sustained release form. Oral dosage forms accordingly suitably comprise from about 1.75 or 2.0 to about 700 or 1400 mg Pharmaceutical Compound admixed with an appropriate pharmaceutically acceptable diluent or carrier therefor. Pharmaceutical Compounds may alternatively be administered e.g. topically in the form of a cream, gel or the like for example for the treatment of conditions of the skin as hereinbefore described or by inhalation, e.g. in dry powder form, for example for the treatment of asthma.
Examples for compositions comprising Pharmaceutical Compound include, e.g. a solid dispersion, an aqueous solution, e.g. containing a solubilising agent, e.g. cyclodextrin, a microemulsion and a suspension of, e.g. a micronized hydrochloride salt of a compound of formula IA in, e.g. aqueous methyl cellulose in the range of from OJ to 1 %, e.g. 0.5 %. The composition may be buffered to, e.g. a pH in the range of from 3.5 to 9.5, e.g. to pH 4.5, by a suitable buffer, e.g. malic acid.
Pharmaceutical Compounds are also useful as research chemicals.
In accordance with the foregoing the present invention also provides:
(1) A pharmaceutical compound for use as a bradykinin BK, receptor antagonist, for example for use in any of the particular indications hereinbefore set forth;
(2) A pharmaceutical composition comprising a pharmaceutical compound as under (1) as active ingredient together with a pharmaceutically acceptable diluent or carrier therefor;
(2') A pharmaceutical composition for the treatment or prevention of a disease or condition in which bradykinin Bi receptor activation plays a role or is implicated comprising a compound of formula IA and a carrier.
(3) A method for the treatment of any of particular indication hereinbefore set forth in a subject in need thereof which comprises administering an effective amount of a pharmaceutical compound as under (1 );
(3') A method for treating or preventing a disease or condition in which bradykinin Bi receptor activation plays a role or is implicated comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula IA. (4) Use of a compound of formula IA for the manufacture of a medicament for the treatment or prevention of a disease or condition in which bradykinin Bi receptor activation plays a role or is implicated;
(5) A process for the preparation of a compound as under (1 ).
The preferred Pharmaceutical Compounds for use in accordance with the invention are those of Examples 1 and 2.

Claims

Claims
1. A compound of formula IA
(IA)
Figure imgf000027_0001
wherein
R5A is -XA-R6A or -N(R7A)R8A, wherein
XA is piperidinylene or piperazinylene,
R6A is H, d-dalkyl, C3-C4alkenyl, C3-C4alkinyl, d-C4(alkoxyalkyl), d-C4(carboxyalkyl), a C5-C7heterocyclic group or phenyl-d-C4alkyl;
R7A is amino-C2-C4alkyl or mono- or di-(Cι-C5alkyl)amino-C2-C5alkyl, and
RΘA is H, Cι-C4alkyl or has the meanings as given for R7A;
X1 is a divalent group of formula IA' — <CH2 ^ ^(CH2>'^— X~^_i wherein
R n is zero or 1 ; X3 is CH or N;
(a) X4 is a direct bond, R3A and R4A together are ethylene and m is 2; or
(b) X4 is a direct bond, R3A is H, d-C4alkyl, C3-C6cycloalkyl, C3-C6alkenyl, C3-C6alkinyl, C7-Cι0aralkyl or C6-C9heteroaralkyl, R4A is H and m is 1 or 2 or 3; or
(c) X4 is -CH(R12)-, R3A is H and R4A and R12 together are propylene and m is 1 , or ethylene and m is 2;
wherein
Figure imgf000027_0002
X3 is CH or N; and
R11 is d-dalkyl, C3-C6cycloalkyl or -NR1AR2A, wherein
R1A and R2 independently are Cι-C alkyl or, together with the N-atom to which they are attached, represent a 5 to 7 membered heterocyclic ring; and
R9 and R10 independently are a phenyl or pyridine ring; and salts thereof.
2. A 2-(2,2-diphenylethylamino)- -5-(4-aminocarbonyl-piperidine-1-sulfonyl)-benzoic acid amide or -5-(aminocarbonyl-C2-C4alkyleneaminosulfonyl)-benzoic acid amide, or salt thereof.
3. A compound of formula
Figure imgf000028_0001
wherein
R1 and R2 independently are Cι-C4alkyl or, together with the N-atom to which they are attached, represent a 5 to 7 membered heterocyclic ring;
(a) R3 and R4 together are ethylene and m is 2; or
(b) R3 is H, d-dalkyl, C5-C7cycloalkyl or phenyl-Cι-C4alkyl, R4 is H and m is 1 or 2 or 3; n is zero or 1 ; and
R5 is -X-R6 or -N(R7)R8, wherein
X is — N N— '
R6 is d-C4alkyl, C3-C4alkenyl, C3-C4alkinyl, d-d(alkoxyalkyl), C C4(carboxyalkyl), a
C5-C7heterocyclic group or phenyl-C C alkyl; R7 is amino-C2-C4alkyl or mono- or di-(C1-C5alkyl)amino-C2-C5alkyl, and R8 is H, d-C alkyl or has the meanings as given for R7; and salts thereof.
4. A compound according to claim 1 which is {2-(2,2-diphenyl-ethylamino)-5-[4-(4-isopropyl- piperazine-1 -carbonyl)-piperidine-1 -sulfonyl]-phenyl}-mo holin-4-yl-methanone, or {2-(2,2-diphenyl-ethylamino)-5-[4-(4-methyl-piperazine-1-carbonyl)-piperidine-1-sulfonyl]- phenyl}-morpholin-4-yl-methanone.
5. A process for the production of a compound of formula IA according to claim 1 which process comprises reacting a compound of formula IIA
Figure imgf000028_0002
wherein X1, X2, R9 and R10 have the meanings according to claim 1 , with an amine and recovering the obtained compound in free or in salt form.
6. A process for the production of a compound of formula I according to claim 3, which process comprises reacting a compound of formula II
Figure imgf000029_0001
wherein R1, R2, R3, R4, m and n have the meanings according to claim 3, with an amine and recovering the obtained compound in free or in salt form.
7. A process for the production of a compound of formula II according to claim 6, which process comprises the steps as outlined in the following scheme:
Figure imgf000029_0002
(IX) (VII)
Figure imgf000029_0003
wherein Hal is halogen, R15 is d-dalkyl, and R1, R2 ,R3, R4, m and n are as defined in claim 3.
8. A compound according to claim 1 for use in the treatment of the human or animal body.
9. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment or prevention of a disease or condition in which bradykinin B. receptor activation plays a role or is implicated.
10. A method for treating or preventing a disease or condition in which bradykinin B, receptor activation plays a role or is implicated comprising administering to a mammal in need thereof a therapeutically effective amount of a compound according to claim 1.
11. A pharmaceutical composition for the treatment or prevention of a diseases or condition in which bradykinin B. receptor activation plays a role or is implicated comprising a compound according to claim 1 and a carrier.
PCT/EP2000/005059 1999-06-04 2000-06-02 Bradykinin receptor antagonists WO2000075107A2 (en)

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DE60022999T DE60022999T2 (en) 1999-06-04 2000-06-02 BRADYKININE RECEPTORANT AGONIST
PL00352056A PL352056A1 (en) 1999-06-04 2000-06-02 Antagonists of bradykinin receptor
NZ515304A NZ515304A (en) 1999-06-04 2000-06-02 Bradykinin receptor antagonists
US10/009,009 US6958331B1 (en) 1999-06-04 2000-06-02 Bradykinin receptor antagonists
CA2372575A CA2372575C (en) 1999-06-04 2000-06-02 Bradykinin receptor antagonists
MXPA01012473A MXPA01012473A (en) 1999-06-04 2000-06-02 Bradykinin receptor antagonists.
AU55282/00A AU765628B2 (en) 1999-06-04 2000-06-02 Bradykinin receptor antagonists
BR0011329-8A BR0011329A (en) 1999-06-04 2000-06-02 Bradykinin receptor antagonists
IL14611200A IL146112A0 (en) 1999-06-04 2000-06-02 Bradykinin receptor antagonists
SK1749-2001A SK17492001A3 (en) 1999-06-04 2000-06-02 Sulfonyl amino derivatives, process for the preparation thereof and pharmaceutical compositions comprising same
JP2001501588A JP3820148B2 (en) 1999-06-04 2000-06-02 Bradykinin receptor antagonist
AT00940304T ATE305920T1 (en) 1999-06-04 2000-06-02 BRADYKININ RECEPTOR ANTAGONIST
EP00940304A EP1183233B1 (en) 1999-06-04 2000-06-02 Bradykinin receptor antagonists
NO20015779A NO20015779D0 (en) 1999-06-04 2001-11-27 Bradykinin receptor antagonists
HK02105567.0A HK1045834A1 (en) 1999-06-04 2002-07-29 Bradykinin receptor antagonists

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US7211566B2 (en) 2003-04-01 2007-05-01 Universite De Sherbrooke Selective bradykinin (BK) B1 peptidic receptor antagonists and uses thereof
WO2008050168A1 (en) 2006-10-27 2008-05-02 Richter Gedeon Nyrt. New sulfonamide derivatives as bradykinin antagonists
EP2305668A1 (en) 2007-03-23 2011-04-06 Jerini AG 8-oxy-quinoline derivatives as bradykinin B2 receptor modulators
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US8034827B2 (en) 2005-12-20 2011-10-11 Richter Gegeon Nyrt. Phenanthridine derivatives as bradykinin antagonists
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WO2019101906A1 (en) 2017-11-24 2019-05-31 Pharvaris B.V. Novel bradykinin b2 receptor antagonists
WO2020234480A1 (en) 2019-05-23 2020-11-26 Pharvaris Gmbh (r)-3-(chloro-5-fluoro-2-((4-(1h-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)morpholine derivatives and related compounds as bradykinin (bk) b2 receptor antagonist for treating skin diseases
WO2020234479A1 (en) 2019-05-23 2020-11-26 Pharvaris Gmbh 1-((s)-1-(3-chloro-5-fluoro-2-((4-(1h-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)-imidazolidine-2,4-dione derivatives and related compounds as bradykinin (bk) b2 receptor antagonist for treating skin diseases

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US7109203B2 (en) 2001-05-14 2006-09-19 Novartis Ag Sulfonamide derivatives
WO2002092556A1 (en) * 2001-05-14 2002-11-21 Novartis Ag Sulfonamide derivatives
FR2840897A1 (en) * 2002-06-14 2003-12-19 Fournier Lab Sa New N-((N,N-disubstituted carbamoyl)-alkyl)-arylsulfonamides, are bradykinin B1 receptor antagonists useful e.g. for treating inflammatory diseases or especially pain
WO2003106428A1 (en) * 2002-06-14 2003-12-24 Laboratoires Fournier Sa Novel arylsulphonamide derivatives and use thereof as therapeutic agents
US7361687B2 (en) 2002-06-14 2008-04-22 Laboratoires Fournier Sa Arylsulphonamide derivatives and methods of preparing
US7211566B2 (en) 2003-04-01 2007-05-01 Universite De Sherbrooke Selective bradykinin (BK) B1 peptidic receptor antagonists and uses thereof
WO2004092164A1 (en) * 2003-04-10 2004-10-28 Amgen, Inc. Cyclic amine derivatives and their use in the treatment of inflammation-related disorders mediated by bradykinin
US7199244B2 (en) 2003-04-10 2007-04-03 Amgen Cyclic amine derivatives and methods of use
EP2305652A2 (en) 2005-12-08 2011-04-06 Novartis AG Trisubstituted quinazolinone derivatives as vanilloid antagonists
US8034827B2 (en) 2005-12-20 2011-10-11 Richter Gegeon Nyrt. Phenanthridine derivatives as bradykinin antagonists
WO2008050168A1 (en) 2006-10-27 2008-05-02 Richter Gedeon Nyrt. New sulfonamide derivatives as bradykinin antagonists
US8481527B2 (en) 2006-10-27 2013-07-09 Richter Gedeon Nyrt. Benzamide derivatives as bradykinin antagonists
EP2305668A1 (en) 2007-03-23 2011-04-06 Jerini AG 8-oxy-quinoline derivatives as bradykinin B2 receptor modulators
WO2011051375A1 (en) 2009-10-28 2011-05-05 Dompé S.p.A. 2-aryl-propionamide derivatives useful as bradykinin receptor antagonists and pharmaceutical compositions containing them
US8394858B2 (en) 2009-12-03 2013-03-12 Novartis Ag Cyclohexane derivatives and uses thereof
WO2012164473A1 (en) 2011-05-27 2012-12-06 Novartis Ag 3-spirocyclic piperidine derivatives as ghrelin receptor agonists
WO2013164790A1 (en) 2012-05-03 2013-11-07 Novartis Ag L-malate salt of 2, 7 - diaza - spiro [4.5 ] dec- 7 - yle derivatives and crystalline forms thereof as ghrelin receptor agonists
WO2019101906A1 (en) 2017-11-24 2019-05-31 Pharvaris B.V. Novel bradykinin b2 receptor antagonists
US10836748B2 (en) 2017-11-24 2020-11-17 Pharvaris Netherlands B.V. Bradykinin B2 receptor antagonists
US11261173B2 (en) 2017-11-24 2022-03-01 Pharvaris Netherlands B.V. Bradykinin B2 receptor antagonists
EP3998259A1 (en) 2017-11-24 2022-05-18 Pharvaris Netherlands B.V. Novel bradykinin b2 receptor antagonists
US11820756B2 (en) 2017-11-24 2023-11-21 Pharvaris Netherlands B.V. Bradykinin B2 receptor antagonists
WO2020234480A1 (en) 2019-05-23 2020-11-26 Pharvaris Gmbh (r)-3-(chloro-5-fluoro-2-((4-(1h-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)morpholine derivatives and related compounds as bradykinin (bk) b2 receptor antagonist for treating skin diseases
WO2020234479A1 (en) 2019-05-23 2020-11-26 Pharvaris Gmbh 1-((s)-1-(3-chloro-5-fluoro-2-((4-(1h-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)-imidazolidine-2,4-dione derivatives and related compounds as bradykinin (bk) b2 receptor antagonist for treating skin diseases

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