WO2003037916A2 - Linear basic compounds having nk-2 antagonist activity and formulations thereof - Google Patents

Linear basic compounds having nk-2 antagonist activity and formulations thereof

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Publication number
WO2003037916A2
WO2003037916A2 PCT/EP2002/012022 EP0212022W WO03037916A2 WO 2003037916 A2 WO2003037916 A2 WO 2003037916A2 EP 0212022 W EP0212022 W EP 0212022W WO 03037916 A2 WO03037916 A2 WO 03037916A2
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WO
WIPO (PCT)
Prior art keywords
amide
phenyl
group
carboxylic acid
cyclopentyl
Prior art date
Application number
PCT/EP2002/012022
Other languages
French (fr)
Other versions
WO2003037916A3 (en
Inventor
Alessandro Sisto
Valerio Caciagli
Maria Altamura
Alessandro Giolitti
Valentina Fedi
Antonio Guidi
Danilo Giannotti
Nicholas Harmat
Rossano Nannicini
Franco Pasqui
Carlo Alberto Maggi
Original Assignee
Malesci Istituto Farmacobiologico S.P.A.
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 claimed from ITFI20010203 external-priority patent/ITFI20010203A1/en
Priority claimed from ITFI20020104 external-priority patent/ITFI20020104A1/en
Priority to BRPI0213574-4A priority Critical patent/BRPI0213574B1/en
Priority to HU0402081A priority patent/HUP0402081A3/en
Priority to MXPA04003974A priority patent/MXPA04003974A/en
Priority to JP2003540197A priority patent/JP4511835B2/en
Priority to EA200400588A priority patent/EA007855B1/en
Priority to AU2002351794A priority patent/AU2002351794B2/en
Priority to EP02787518A priority patent/EP1442050B1/en
Priority to IL16164902A priority patent/IL161649A0/en
Priority to SI200230451T priority patent/SI1442050T1/en
Priority to NZ533097A priority patent/NZ533097A/en
Application filed by Malesci Istituto Farmacobiologico S.P.A. filed Critical Malesci Istituto Farmacobiologico S.P.A.
Priority to CA2464353A priority patent/CA2464353C/en
Priority to BR0213574-4A priority patent/BR0213574A/en
Priority to DE60214750T priority patent/DE60214750T2/en
Priority to UA20040504087A priority patent/UA78975C2/en
Priority to YU36504A priority patent/RS52290B/en
Priority to US10/494,077 priority patent/US7273856B2/en
Publication of WO2003037916A2 publication Critical patent/WO2003037916A2/en
Publication of WO2003037916A3 publication Critical patent/WO2003037916A3/en
Priority to HRP20040360AA priority patent/HRP20040360B1/en
Priority to TNP2004000077A priority patent/TNSN04077A1/en
Priority to NO20042083A priority patent/NO331227B1/en
Priority to ZA2004/04163A priority patent/ZA200404163B/en
Priority to HK04106090A priority patent/HK1063326A1/en
Priority to CY20061101791T priority patent/CY1105847T1/en

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Definitions

  • the present invention relates to compounds antagonists of tachykinins in general, in particular of neurokinin A, and to their use in pharmaceutical formulations.
  • Tachykinins is a family including at least three peptides, known as Substance P,
  • NBA Neurokinin A
  • NKB Neurokinin B
  • NK1 antagonists we can also mention those described in Patent Application No. WO 200014109; among these compounds, there is not even one alpha,alpha-disubstituted amino acid, and the basic group, when present, is in positions that are very different from those in the compounds of the invention.
  • NK1 antagonists which exhibit a disubstituted alpha,alpha-amino acid whose structure do not correspond to the general formula (I), in particular for the presence -among other things - of a -O-CO- group in the place of XI.
  • the present invention refers therefore to linear compounds of general formula (I) comprising an alfa,alfa-disubstituted amino acid and at least an amino group capable of giving basic characteristics to the compounds
  • XI is a group selected from -NR6-CO-, -CO- and -NR6-CS- Rl is an aryl or aryl-alkyl or aryl-ethylene group containing from 7 to 12 carbon atoms, wherein aryl indicates a group selected from the group consisting of pyridine, pyrrol, thiophene, benzene, naphthalene, imidazol, diphenyl, phenyl-thiophene, and it can be possibly substituted by one or more groups independently chosen from the group consisting of halogen, C1-C6 alkyl possibly substituted by not more than three fluorine atoms (such as a trifluoromethylic group), C1-C6 alkyloxy possibly substituted by not more than three fluorine atoms (such as a trifluoromethoxylic group), OH, -NHR10, - N(R10)2, -SR10, -CONHR10, -COR10,
  • RIO is H or a linear or branched C1-C6 alkyl chain
  • R9 is a linear or branched C1-C6 alkylene chain
  • D O, S, CH2, O-CH2 or N-R7, wherein R7 is selected from the group consisting
  • n and m can independently be 0, 1 or 2;
  • R13 and R14 are independently selected from the group consisting of H, C1-C6 alkyl chain, or they can be linked to form an aromatic group selected from the group consisting of benzothiophene, indol, pyridine, pyrrol, benzofurane, thiophene, benzene, naphthalene, imidazol, and biphenyl, which can be possibly substituted by one or more substituents independently selected from halogen, C1-C6 alkyl possibly substituted by not more than three fluorine atoms (such as trifluoromethylic group), C1-C6 alkyloxy chain possibly substituted by not more than three fluorine atoms (such as trifluoromethoxylic group), -OH, -NHR10, -N(R10)2, -SR10, -CONHR10, -COR10, -COOR10, -R
  • R2 is selected from the group consisting of an aryl-alkyl or aryl radical wherein the aryl portion is selected, from the group consisting of benzothiophene, indol, pyridine, pyrrol, benzofurane, thiophene, benzene, naphthalene, imidazol, and biphenyl, and it can be possibly substituted by one or more substituents independently selected from halogen, Cl- C6 alkyl possibly substituted by not more than three fluorine atoms (such as a trifluoromethylic group), C1-C6 alkyloxy possibly substituted by not more than three fluorine atoms (such as a trifluoromethoxylic group), -OH, -NHR10, -N(R10)2, -SR10, - CONHR10, -COR10, -COOR10, -R9COOR10, -OR9COOR10, -R9COR10, -CONHR
  • R15 is selected from the group consisting of -NR11R12 and -OR11, wherein Rll and R12, independently from each other, are H or a linear or branched C1-C6 alkyl group;
  • aryl portion is selected from the group consisting of benzothiophene, indol, pyridine, pyrrol, benzofurane, thiophene, benzene, naphthalene, imidazol, and biphenyl, and it can be possibly substituted by one or more substituents independently selected from halogen, C1-C6 alkyl possibly substituted by not more than three fluorine atoms (such as a trifluoromethylic group), C1-C6 alkyloxy possibly substituted by not more than three fluorine atoms (such as a trifluoromethoxylic group), - OH, -NHR10, -N(R10)2, -SR10, -CONHR10, -COR10, -COOR10, -R9COOR10, - OR9COOR10, -R9COR10, -CONHR10, -R9CONHR10,
  • X3 is a single bond or it is selcted from the group consisting of -CH 2 -, -CH 2 -CH 2 -, -CO-, - OCH 2 -CH 2 O-, -O- , -NH-CO-CH 2 -, and -NH-CO-; or -R4-X3- taken together are a group -CO-CH - R5 is: an aliphatic heterocycle selected from the group consisting of pyrrolidine, piperidine, mo holine, chinuclidine, diazepan, tetrahydropyran, l,4-dioxa-8-azaspiro[4,5]decane, possibly substituted by one or more substituents selected from the group consisting of Cl- C6 alkyl, hydroxymethyl, -OH, cyanomethyl, and C1-C6 alkyloxy; - an azetidine possibly substituted by a group -(CH 2 ) n -R
  • a piperidine possibly C-substituted by a C1-C6 alkyl chain, substituted by a group X5- R18 wherein X5 is a bond or a group -C(R11)(R12 , -CO-, -COCH2-, -CH2CH2-, and R18 is selected from the group consisting of morpholine, piperidine, pyrrolidine, tetrahydropyran, tetrahydrothiopyran, cyclohexane, dioxane, l,4-dioxa-spiro(4,5)decyl and an aromatic selected from the group consisting of thiophene, pyridine, furane, pyrrol, thiadiazole, thiazole, and phenyl possibly substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl possibly substituted by not more than three fluorine atoms, C1-C
  • - a piperazine possibly C-substituted by one or two C1-C6 alkyl groups, and possibly N- substituted by a group chosen from -SO 2 NRl lR12,-(CH 2 ) 2 O(CH 2 ) 2 OH, -CH 2 CN, or by the group -X4-R16 wherein X4 is a bond or it is selected from the group consisting of -CO-, - CH 2 -, -CONR6-, -COCH 2 - and -CO-NR6-CH 2 -, and R16 is selected from the group consisting of pyrrolidine, morpholine, tetrahydropyran, tetrahydrofurane, dioxane, thiophene, pyridine, phenyl, naphthyl, diphenyl, pyrazol, oxazol, isoxazol and thiadiazol, possibly substituted by one or more groups selected from halogen,
  • - an amino group selected from the group consisting of -NR11R12, -NH(CH 2 )m- NR11R12, amino-tetrahydropyran, furylmethylamino, -NH(CH ) 2 O(CH 2 ) 2 OH, wherein m ranges from 3 to 6, and Rl 1 and R12 are as defined above
  • -a cycloalkyl group possibly substituted on the ring by a group selected from NR11R12, wherein Rl 1 and R12 are as defined above;
  • aryl group selected from the group consisting of thiophene, pyridine, furane or phenyl possibly substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkyloxy, and OH.
  • object of the present invention are the single enantiomers and diastereoisomers of the compounds of formula (I) or mixtures thereof, originating from the insertion into the structure of formula (I) of chiral residues or groups.
  • Preferred compounds of the invention are the compounds of general formula (I), wherein the aminoacidic residue of general formula (III)
  • aminoacidic residues of ⁇ , ⁇ - ⁇ ⁇ substituted glycine-type selected from the group consisting of 1-aminocyclohexane-l -carboxylic acid (Ac6c), 1-aminocyclopentane-l -carboxylic acid (Ac5c), l-aminocyclopent-3-ene-l- carboxylic acid (Ac5c), 1-aminoisobutyrric acid, 1-aminoindane-l -carboxylic acid (1-Aic), 2-aminoindane-2-carboxylic acid (2-Aic), 2-aminotetraline-2-carboxylic acid (2-Atc), 2- methyl-2-ethylglycine, 2-methyl-2-isopropylglycine, 2-methyl-2-n-propylglycine, 2- methyl-2-(2-butyl) glycine, 2-methyl-2-isobutylglycine, 2-methyl
  • - XI is a CO group
  • Rl is an aryl or aryl-ethylene group containing from 7 to 12 carbon atoms, wherein aryl is a group selected from benzene, naphthalene, and biphenyl possibly substituted by one or more groups independently selected from halogen, C1-C6 alkyl possibly substituted by not more than three fluorine atoms (such as a trifluoromethylic group), C1-C6 alkyloxy possibly substituted by not more than three fluorine atoms (such as a trifluoromethoxylic group), -OH, -NHR10, -N(R10) 2 , -SR10, -CONHR10, -COR10, -COOR10, -R9COOR10, -
  • OR9COOR10 -R9COR10, -CONHR10, -R9CONHR10, -NHCORIO, and -nitro, wherein
  • RIO is H or a linear or branched C1-C6 alkyl chain, and R9 is a linear or branched C1-C6 alkylene; or it is the following radical
  • RIO is H or linear or branched C1-C6 alkyl chain
  • R9 is a linear or branched C1-C6 alkylene chain
  • glycine-type residue selected from the group consisting of 1- aminocyclohexane-1 -carboxylic (Ac6c), 1-aminocyclopentane-l -carboxylic acid (Ac5c), 1-aminoindane-l -carboxylic acid (1-Aic), l-aminocyclopentan-3-ene 1- carboxylic acid (Ac5c), 2-methyl-phenylalanine, 2-methyl-2-ethyl-glicine,
  • R2 is a phenylmethyl group possibly substituted on the phenyl portion by one or two groups independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkyloxy, and OH;
  • - X2 is selected from -CONR6- and -CH 2 NR6;
  • R3 includes at least one basic amino group and it is the following group: " ⁇ R4 - X3- R5 wherein - R4 is selected from the group consisting of a group -(CH 2 ) n -, wherein n ranges from 1 to 3, a C5-C8 cycloalkylene group and an aliphatic heterocycle selected from piperidine, pyrrolidine or piperazine possibly substituted by one or two C1-C6 alkyl chains;
  • - X3 is a bond or it is selected from the group consisting of -CO-, -CH 2 -, -CH 2 -CH 2 -, -CO- CH 2 -, and -NH-CO-;
  • - R5 is selected from the group consisting of: a) an aliphatic heterocycle selected from piperidine, pyrrolidine, morpholine, diazepan, tetrahydropyran, tetrahydrothiopyran, and l,4-dioxa-8-azaspiro[4,5]decane, possibly substituted by one or two groups selected from C1-C6 alkyl, hydroxymethyl, cyanomethyl, C 1 -C6 alkyloxy, and OH; b) an azetidine possibly substituted by a -(CH 2 ) n -R17 group wherein R17 is selected from the group consisting of morpholine, piperidine, pyrrolidine, tetrahydropyr
  • XI is a -CO- group
  • Rl is an aromatic group selected from the group consisting of biphenyl, phenyl-ethylene, naphthyl, phenyl-thiophene, benzothiophene, benzofurane, and indole possibly N- substituted by a C1-C6 alkyl group, which can be possibly substituted by one, two or three groups independently selected from the group consisting of halogen, C1-C6 alkyl possibly substituted by not more than three fluorine atoms, C1-C6 alkyloxy, OH, NHR10, and
  • N(R10) 2 wherein RIO is selected from H and C1-C6 alkyl;
  • the amino acidic residue of general formula (III) is selected from the group consisting of 1- aminocyclohexane-1 -carboxylic acid (Ac6c), 1-aminocyclopentane-l -carboxylic acid (Ac5c), 1-aminoindane-l -carboxylic acid (1-Aic), l-aminocyclopentan-3-ene 1- carboxylic acid (Ac5c), 2-methyl-phenylalanine, and 2-methyl-2-ethyl-glycine;
  • R6 is H
  • R2 is a phenyl-methyl group, having the phenyl group possibly substituted by a C1-C6 alkyl group;
  • X2 is selected from -CONH- and CH 2 NH-;
  • R3 includes at least one basic amino group having the following formula:
  • - R4 is selected from the group consisting of a group -(CH 2 ) n - wherein n ranges from 1 to 3, a C5-C8 cycloalkylene group selected from cyclopentylene and cyclohexylene, and an aliphatic heterocycle selected from piperidine, pyrrolidine and piperazine possibly substituted by one or two C1-C6 alkyl groups;
  • - X3 is a bond or it is a group selected from -CO-, -CH 2 -, -CH 2 -CH 2 -, and -NH-CO-;
  • R5 is selected from: a) an aliphatic heterocycle selected from the group consisting of piperidine, pyrrolidine, morpholine, diazepan, tetrahydropyran, and l,4-dioxa-8-azaspiro[4,5]decane, possibly substituted by one or two groups selected from C1-C6 alkyl, C1-C6 alkyloxy, OH, and cyanomethyl; b) an azetidine substituted by a group -(CH_) n -R17, wherein R17 is tetrahydropyran; c) a piperidine possibly C-substituted by a C1-C6 alkyl group, and substituted by a group X5-R18 wherein X5 is a bond or it is selected from the group consisting of -C(R11)(R12)-, -CO-, -CH 2 CH 2 -, and -COCH 2 -, and
  • XI is a -CO- group
  • Rl is an aromatic group selected from the group consisting of phenyl-ethylene, naphthyl, benzothiophene, and benzofurane, possibly substituted by one, two or three groups independently selected from halogen, C1-C6 alkyl possibly substituted by not more than three fluorine atoms, C1-C6 alkyloxy, OH, NHR10, and N(R10) 2 wherein R10 is selected from H and C1-C6 alkyl; the amino acidic residue of general formula (III) is selected from 1-aminocyclohexane-l- carboxylic acid (Ac6c), and 1-aminocyclopentane-l -carboxylic acid (Ac5c); R6 is H;
  • R2 is phenyl-methyl; X2 is -CONH-;
  • R3 includes at least one basic amino group and it is the following group: ⁇ R_ ⁇ - X3- R5 wherein
  • R4 is selected from -(CH 2 ) n - wherein n ranges from 1 to 3, and piperidine possibly substituted by a C 1 -C6 alkyl group;
  • X3 is a bond or it is a group selected from -CO- and -CH 2 -;
  • R5 is selected from: a) an aliphatic heterocycle selected from piperidine and tetrahydropyran, possibly substituted by one or more C1-C6 alkyl groups; b) a piperidine possibly C-substituted by a C1-C6 alkyl group, substituted by a group X5-
  • R18 wherein X5 is a bond or it is a group selected from -C(R11)(R12)- and -CO-, and R18 is a group selected from tetrahydropyran, cyclohexane and 1-3-dioxane, possibly substituted by one or more groups selected from C1-C6 alkyl, -NHR10, and -N(R10) 2 , wherein RIO, Rl 1 and R12 are selected from H and linear or branched C1-C6 alkyl; c) a piperazine possibly C-substituted by one or two C1-C6 alkyl groups, and possibly N- substituted by a group X4-R16 wherein X4 is -CH 2 -, and R16 is selected from tetrahydropyran and 1,3-dioxane.
  • halogen refers to fluorine, chlorine, bromine or iodine
  • C1-C6 alkyl refers to a group selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, ter-butyl and, when possibly substituted by fluorine, trifluoromethyl
  • C1-C6 alkyloxy refers to a group wherein the alkyl part is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, ter-butyl and, when possibly substituted by fluorine, trifluoromethyl;
  • C1-C6 alkylene refers to a group selected from methylene, ethylene, trimethylene, and tetramethylene;
  • C5-C8 cycloalkylene refers to a group selected from cyclobutylene, cyclopentylene, cyclohexylene, and cycloheptylene;
  • cycloalkyl refers to a group selected from cyclobutane, cyclopentane and cyclohexane.
  • the compounds of the present invention have shown an antagonist activity to the action of Substance P, Neurokinin A, and Neurokinin B; and they demonstrated particularly selective against the action of Neurokinin A.
  • the present compounds of formula (I) can be used for prepararing pharmaceutical formulations, possibly comprising pharmaceutically acceptable diluents and excipients commonly used in drug products, useful for the treatment and prevention of diseases in which tachykinins in general, and namely Neurokinin A, are involved as neuromodulators; as an example we can list the following diseases: respiratory pathologies, such as asthma, allergic rhinitis, and chronic obstructive bronchitis; ophthalmic diseases, such as conjunctivitis, skin diseases, such as allergic and contact dermatitis, and psoriasis, intestinal disorders, such as irritable colon, ulcerous colitis and Chron disease, gastric diseases, urinary diseases, such as cystitis and incontinence, erectile dysfunctions, diseases of the nervous central system, such as anxiety, depression and schizophreny, tumoural pathologies, autoimmunitary diseases or diseases related to AIDS, cardiovascular pathologies, neuritis, neuralgia and treatment of pain
  • the substituents are as defined above.
  • the compounds of general formula (I) may be obtained according to the following Scheme 1 by reacting the activated carboxylic acid derivatives of general formula (IN) with the intermediate compound of general formula (N).
  • the compounds of general formula (I) can be obtained as described in the following Scheme 2, according to the following sequence of reactions: a) formation of the oxazolinone of formula (Nil) starting from activated carboxylic acid derivatives of formula (IN) and amino acids of formula (NI), with suitable activating and condensing agents; b) reaction of oxazolinone of formula (Nil) with amines of formula (NIII) protected with a suitable protective group P, followed by deprotection by methods known to the person skilled in the art, to obtain the compounds of formula (LX); c) acylation, alkylation or reductive amination with suitable reagents to yield the final compounds of formula (I).
  • the compounds of the present invention can occur in various isomeric forms.
  • the configuration of the carbon linked to R5 is uni vocally prefixed by using during the synthesis the specific isomer of the amino acid derivative, frequently the other starting products can be constituted by mixtures of stereo isomers of difficult separation. Therefore, the compounds of the present invention can be obtained as mixtures of diastereoisomers. These mixtures can be resolved by chromatography.
  • the compounds of formula (I) can however be used as single enantiomers as well as mixtures of isomers.
  • Example 1 N tx [N tx (benzo[b]thiophenyl-2-ylcarbonyl)-l-aminocyclopentane-l-carbonyl]-D- phenylalanine-N-[3(morpholin-4-yl)propyl]amide la) to a solution of 1-amino-cyclopentane-l -carboxylic acid (1 g, 7.66 mmol) in 30 ml of anhydrous dichloromethane (DCM) N,O-bis(trimethylsilyl)acetamide (BSA) (3.8 ml, 15.4 mmol) is added under magnetic stirring; after 15 min trimethylchlorosylane (TMSC1) (0.38 ml, 10 % of the BSA volume) is added.
  • TMSC1 trimethylchlorosylane
  • the obtained precipitate is filtered and dried, obtaining 0.55 g of a white solid which is the starting diamine cyclohexane.
  • the collected organic extracts are dried on anhydrous Na 2 SO , then filtered and brought to dryness.
  • Example 26 acid-3-cis-N ⁇ ⁇ N ⁇ [N ⁇ (benzo[b]thiophen-2-ylcarbonyl)-l-aminocyclopentane-l-carboxy]-L- phenylalanil ⁇ aminocyclohexane-1 -carboxylic -N-(2-cis-aminocyclohexyl) amide
  • Example 27 acid-3-cis-N ⁇ ⁇ N ⁇ [N ⁇ (benzo[b]thiophen-2-ylcarbonyl)-l-aminocyclopentane-l-carboxy]-L- phenylalanil ⁇ aminocyclohexane-1 -carboxylic -N-(2-cis-aminocyclohexyl) amide
  • Example 31 acid-3 -cis-N Y ⁇ N a [N (X (benzo[b]thiophen-2-ylcarbonyl)- 1 -aminocyclopentan- 1 -carboxy] -D- phenylalanil ⁇ aminocyclohexan-l-carboxylic-N-[(lS,2S)-aminocyclohexyl] amide
  • Example 38 (1 S,3R)- 1 -N ⁇ N ⁇ [N ⁇ (benzo[b]thiophen-2-ylcarbonyl)- 1 -aminocyclopentan- 1 -carboxy]-D- phenylalanil ⁇ -3- ⁇ [1 S-((2S)-aminocyclohexyl)amino]methyl ⁇ amino cyclopentane
  • Example 39 acid-3-cis-N ⁇ N ⁇ [N ⁇ (benzo[b]thiophen-2-ylcarbonyl)- 1 -aminocyclopentan- 1 -carboxy]-D- phenylalanil ⁇ aminocyclohexan-l-carboxylic-N-((lR,2S)-2-dimethylaminocyclohexyl) amide
  • Example 47 l-Methyl-lH-indole-2-carboxylic acid, ⁇ l-[l-(3-morpholin-4-yl-propylcarbamoyl)-2-(R)- phenyl-ethylcarbamoyl]-cyclopentyl ⁇ -amide
  • Example 48 l-Methyl-lH-indole-2-carboxylic acid, ⁇ l-[l-(3-morpholin-4-yl-propylcarbamoyl)-2-(R)- phenyl-ethylcarbamoyl]-cyclopentyl ⁇ -amide
  • Example 48 l-Methyl-lH-indole-2-carboxylic acid, ⁇ l-[l-(3-morpholin-4-yl-propylcarbamoyl)-2-(R)- phenyl-ethylcarbamoyl]-cyclopentyl ⁇ -amide
  • step 52d) To the product coming from step 52b) (1 g, 3.7 mmol) dissolved in anhydrous DMF (40 ml), the intermediate described in 53c) (1.11 g, 5.6 mmol) is added, and the reaction is kept at room temperature under magnetic stirring for 24 hours.
  • aldehyde (100 mg, 0.203 mmol) is dissolved in methanol (5 ml) and added with l-methyl-[l,4]diazepan (115 mg, 1.01 mmol) and glacial acetic acid (0.2 ml). After the solution has been stirred for 15 min, Na(CN)BH 3 (20 mg, 0.32 mmol) is added to the solution. After 12 hours the solvent is evaporated under reduced pressure and the raw product is dissolved in HCl IM. The acid extract is washed with AcOEt (10 ml) and brought up to alkaline pH by adding solid NaHCO 3 , then it is extracted with AcOEt (2 x 25 ml).
  • Example 55 Benzo[b]thiophene-2-carboxylic acid ( 1 -
  • Example 67 With the synthetic procedure described in Example 66 the following products have been prepared: Example 67
  • Example 70 Benzo[b]thiophene-2-carboxylic acid (1 - ⁇ 1 -(R)-[(l -isopropyl-piperidin-4-ylmethyl)- carbamoyl]-2-phenyl-ethylcarbamoyl ⁇ -cyclopentyl)-amide
  • 6-Bromo-naphthalene-2-carboxylic acid [ 1 -(2-phenyl- 1 (R)- ⁇ [ 1 -(tetrahydro-pyran-4-yl)- piperidin-4-ylmethyl]-carbamoyl ⁇ -ethylcarbamoyl)-cyclopentyl]-amide
  • Example 84 l-((E)
  • 6-Bromo-naphthalene-2-carboxylic acid (l- ⁇ l(R)-[( ⁇ -[l,3]dioxan-5-ylmethyl-piperidin-4 ylmethyl)-carbamoyl]-2-phenyl-ethylcarbamoyl ⁇ -cyclopentyl)-amide
  • a precipitate is obtained, which is first brought to dryness then dissolved in 200 ml of THF and this solution is added, drop by drop, in 20 min at 0°C, under stirring and under nitrogen atmosphere, to a solution of 400 ml of LiAlEU 0.62 M in THF. The mixture is heated and maintained under reflux for 4 hours. After the mixture has been brought to 0°C, 15 ml of distilled water, 15 ml of NaOH aq. 15% and 45 ml of water are added in this order. By filtration of the so obtained precipitate, l-trityl-2-(R)-benzyl- 1,2-ethylendiamine is obtained.
  • the raw product obtained from evaporation of the solvent (60 mg, 0.07 mmol), is dissolved in DMF (3 ml) and treated with diazabicycloundecene (DBU, 32 mg, 0.21 mmol) and 2-mercaptoefhanol (17 mg, 0.21 mmol) for 12 hours.
  • DBU diazabicycloundecene
  • Example 95 Benzo[b]thiophene-2-carboxylic acid [l-(l(R)- ⁇ 2-[(l-amino-cyclohexanecarbonyl)- amino]-ethylcarbamoyl ⁇ -2-phenyl-ethylcarbamoyl)-cyclopentyl]-amide [2-(2(R)-Amino-3-phenyl-propionylamino)-ethyl]-carbamic acid tert-butyl ester (200 mg, 0.65 mmol), obtained by coupling of N-Boc-ethylendiamine and Z-D-phenylalanine succinimidoester followed by hydrogenation, is added to a solution of 2-benzo[b]thiophen- 2-yl-3-oxa-l-azaspiro[4.4]-no ⁇ -l-en-4-one (176 mg, 0.65 mmol) in DMF and maintained under magnetic stirring at room temperature for 48 hours.
  • Example 100 Benzo[b]thiophene-2-carboxylic acid [ 1 -(2-phenyl- 1(R)- ⁇ 2-[4-(thiophen-2-yl-acetyl)- piperazin-1 -yl]-ethylcarbamoyl ⁇ -ethylcarbamoyl)-cyclopentyl]-amide.
  • Example 101 Benzo[b]thiophene-2-carboxylic acid [ 1 (2-phenyl- 1 (R)- ⁇ 2-[4-(tetrahydro-pyran-4- ylmemyl)-piperazin-l-yl]-ethylcarbamoyl ⁇ -ethylcarbamoyl)-cyclopentyl]-amide TFA salt
  • the compound of the title is obtained by a procedure analogous to that described in Example 100, but carrying out a reductive amination with tetrahydropyranyl 4- carboxyaldehyde in place of an acylation step with thiophen-2-yl-acethyl chloride.
  • HPLC (method A): Rt 3.24 min.
  • Example 102 Benzo[b]thiophene-2-carboxylic acid [ 1 (2-phenyl- 1 (R)- ⁇ 2-[4-(tetrahydr
  • acylic chloride 87 mg are added to a mixture of 132 mg of 1-amino- cyclopentanecarboxylic acid [ 1 (R)-(3 -morpholin-4-yl-propylcarbamoyl)-2-phenyl-ethyl] - amide bw-hydrochloride, 200 ⁇ l of TEA and 10 ml of anhydrous CH 2 C1 2 under magnetic stirring. Once the reaction is over, the solvent is evaporated and the residue is dissolved with a mixture of ethyl acetate and K 2 CO 3 aq. 10%, by vigorously stirring.
  • Example 104 5-Chloro-benzo[b]thiophene-2-carboxy
  • 6-Iodo-naphthalene-2-carboxylic acid [ 1 -(2-phenyl- li?- ⁇ [ 1 -(tetrahydro-pyran-4-ylmethyl)- piperidin-4-ylmethyl]-carbamoyl ⁇ -ethylcarbamoyl)-cyclopentyl]-amide 118a) 18.0 g of 4-tetrahydropyrancarboxylic acid are introduced in a 250 ml flask with a calcium chloride tube, and dissolved in 130 ml of C ⁇ 2 C1 2 . Under magnetic stirring, 15 ml of oxalyl chloride and 3 drops of DMF are added successively.
  • the solution that regularly degasses, is kept under magnetic stirring for 16 hours. After evaporation of the solvent, the residue is dried in hard vacuum at room temperature, dissolved in 100 ml of CH 2 C1 2 and put in a bath of ice and water, maintaining a vigorous magnetic stirring. A solution of 21.75 g of ethyl 4-piperidincarboxylate in 30 ml of CH 2 C1 2 containing 15.35 g of TEA is added to the mixture by means of a dripping funnel. During the addition, that lasts 3 hours, a clear suspension forms. The reaction mixture is left to stand overnight, then CH 2 C1 2 is evaporated and the residue is brought to dryness in hard vacuum.
  • Boc under the operative conditions well known to a skilled person, by reacting the above said amine with Boc-D-phenylalanine O-succinimidoester, deprotecting, reacting with N- Boc 1 -amino- 1-cyclopentancarboxylic acid and deprotecting, the compound 1-amino- cyclopentanecarboxylic acid (2-phenyl-l_R- ⁇ [l-(tefrahydro-pyran-4-ylmethyl)-piperidin-4- ylmethyl]-carbamoyl ⁇ -ethyl)-amide is obtained.
  • 6-Iodo-benzo[b]thiophene-2-carboxylic acid [ 1 -(2-phenyl- li?- ⁇ [ 1 -(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl ⁇ -ethylcarbamoyl)-cyclopentyl]-amide
  • Example 134 7-Methyl-benzo[b]thiophene-2-carboxylic acid [l-(2-phenyl-lR- ⁇ [l-(tetrahydro-pyran-4- ylmemyl)-piperidin-4-ylmethyl]-carbamoyl ⁇ -ethylcarbamoyl)-cyclopentyl]-amide
  • Example 136 7-Trifluoromethyl-benzo[b]thiophene-2-carboxylic acid [ 1 -(2-phenyl- li?- ⁇ [ 1 -(tetrahydro- pyran-4-ylmemyl)-piperimn-4-ylmemyl]-carbamoyl ⁇ -emylcarbamoyl)-cyclopentyl]-amide
  • Example 137 7-Chloro-benzo[b]thiophene-2-carboxylic acid [1 -(2-phenyl- li?- ⁇ [l -(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl ⁇ -ethylcarbamoyl)-cyclopentyl]-amide
  • Example 143 7-Chloro-l -methyl- IH-indole -2-carboxylic acid [li?-(2-phenyl-l- ⁇ [l-(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl ⁇ -ethylcarbamoyl)-cyclopentyl]-amide
  • Naphthalene-2-carboxylic acid [ 1 -(2-phenyl- li?- ⁇ [ 1 -(tetrahydro-pyran-4-ylmethyl)- piperidin-4-ylmethyl]-carbamoyl ⁇ -efhylcarbamoyl)-cyclopentyl]-amide
  • 6-Bromo-naphthalene-2-carboxylic acid [ 1 -( 1 (R)- ⁇ [ 1 -(4-methyl-tetrahydro-pyran-4- ylmethyl)-piperimn-4-ylmethyl]-carbamoyl ⁇ -2-phenyl-ethylcarbamoyl)-cyclopentyl]- amide, by using C-[l-(4-Me yl-tefrahydro-pyran-4-ylmethyl)-piperid -4-yl]-methylamine prepared as described in Example 117a).
  • 6-Bromo-naphthalene-2-carboxylic acid [ 1 -( 1 (R)- ⁇ [ 1 -(5 -ethyl-[ 1 ,3 ] dioxan-5-ylmethyl)- piperidin-4-ylmethyl]-carbamoyl ⁇ -2-phenyl-ethylcarbamoyl)-cyclopentyl] -amide, by using 5-ethyl-[l,3]dioxane-5 carboxylic acid in place of 4-tefrahydropyrancarboxylic acid.
  • Example 155 6-Bromo-naphthalene-2-carboxylic acid [ 1 -( 1 (R)- ⁇ [4-methyl- 1 -(4-methyl-tetrahydro- pyran-4-ylmethyl)-piperidin-4-ylmethyl]-carbamoyl ⁇ -2-phenyl-ethylcarbamoyl)- cyclopentyl] -amide, by using C-[4-methyl-l-(4-memyl-tetrahydro-pyran-4-ylmethyl)-piperidin-4-yl]- methylamine prepared as described in Example 117a).
  • Example 156 6-Bromo-naphthalene-2-carboxylic acid [ 1 -( 1 (R)- ⁇ [4-methyl- 1 -(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl ⁇ -2-phenyl-ethylcarbamoyl)-cyclopentyl]- amide, by using C-[4-methyl-l-(tefrahydro-pyran-4-ylmethyl)-piperidin-4-yl]-methylamine prepared as described in Example 117a).
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • TMSC trimethylsilylchloride
  • Z N-benzyloxycarbonyl.
  • NK-2 receptors The evaluation of the antagonist activity on NK-2 receptors has been assessed by binding and functional tests according to that already described in literature in relation to NK-2 antagonists.
  • the affinity of the present compounds for the human NK-2 receptor has been assessed by a binding test using Chinese hamster ovary (CHO) cell membranes transfected with NK-2 receptor of human ileum together with [ 125 I]NKA (Amersham, aspecific activity 2000 Ci/mmol) radiobinder at the concentration of 100 pM in competition studies.
  • the test substances have been tested within a concentration range from 0.01 nM to 10 nM.
  • the samples At the end of the incubation time (30 min, 20°C) the samples have been filtered and radioactivity has been determined using a gamma-counter.
  • the present compounds of formula (I) can be handled according to the common pharmacopoeial techniques in order to prepare formulations suitable for oral, intranasal, parentheral, sublingual, inhalatory, transdermic, local or rectal use according to the data known in literature for this kind of products; these formulations comprise oral formulations, such as tablets, capsules, powders, granulated preparations, and oral solutions or suspensions, formulations for sublingual admimstration, for intranasal administration, aerosol formulations, implantations, formulations for subcutaneous, intramuscular, intravenous ⁇ intraocular .and rectal administration.
  • the effective, doses are 0.1 to 50 mg/kg of body weight.
  • the effective dose may preferably range from 0.5 to 4000 mg/day, in particular from 2.5 to 1000 mg according to the age of patients and to the type of treatment.
  • the treatment is performed by administering to the patient the required amount 1 to 4 times-per-day for periods of time up to 2 weeks or in any case until remission of symptoms; for chronic pathologies, admimstration can be prolonged for significantly longer periods of time according to the physician judgement.
  • the present compounds are useful in the treatment of diseases in which Neurokinine A plays a pathogenetic role, and namely in the following pathologies: - chronic obstructive respiratory pathologies, such as asthma and allergic rhinitis, cough, bronchitis; - ophtalmic pathologies, such as conjunctivitis or vitreoretinopathy; - skin problems, such as allergic and contact dermatitis, atopic dermatitis, eczema, itch, psoriasis, burns, in particular solar burns;
  • - intestinal disorders such as irritable colon, ulcerous colitis, Crohn disease, diarrhoea;
  • - gastric diseases such as nausea or emesis
  • - urinary pathologies such as prostatitis, spinal reflex bladder, urinary incontinence, cystitis, urethritis, nephritis, erectile dysfunctions;
  • neurodegenerative diseases and somatic disorders such as stress;
  • cardiovascular diseases such as hypertension, edemas, thrombosis, angina, vascular spasmus; - inflammatory, such as arthritis, rheumatoid arthritis.

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Abstract

Described herein are compounds of formula (I) useful as antagonists of tachykinins in general, and in particular of neurokinin A; and the pharmaceutical formulations comprising the compounds of formula (I).

Description

LINEAR BASIC COMPOUNDS HAVING NK-2 ANTAGONIST ACTIVITY AND FORMULATIONS THEREOF Field of the invention
The present invention relates to compounds antagonists of tachykinins in general, in particular of neurokinin A, and to their use in pharmaceutical formulations.
State of the art
Tachykinins is a family including at least three peptides, known as Substance P,
Neurokinin A (NKA) e Neurokinin B (NKB).
The research in the field of the tachykinins antagonist, mainly based on single or multiple substitution of amino acids of the sequence of the peptidic agonists of Substance P and of the other tachykinins, lead to the discovery of nonapeptides containing one or more units of D-triptophan (Regoli et al., Pharmacol. 28,301 (1984)). However, the problems derived from the pharmacological use of high molecular weight peptides (multiple sites of enzymatic hydrolytic attack, poor bioavailability, rapid hepatic and renal excretion) induced to search the minimum peptidic fragment which is still capable of exerting an antagonist activity. These studies lead to the detection of adequately derivatised bicyclic and monocyclic peptides, antagonist of neuroldnin A (Patent Applications No. WO
9834949 and No. WO 200129066).
Various compounds have been claimed as selective antagonists of Substance P, for instance in Patent Applications No. WO 9519966 and NoTwO 9845262; but, besides being selective for NK1 receptor, these compounds have structural characteristics which are different from the compounds of the present invention, mainly the lack of a basic amino group.
Among NK1 antagonists, we can also mention those described in Patent Application No. WO 200014109; among these compounds, there is not even one alpha,alpha-disubstituted amino acid, and the basic group, when present, is in positions that are very different from those in the compounds of the invention.
Also in Patent No. EP 394 989 the compounds with NK1 activity do not usually have a basic group and do not exhibit ah alpha,alpha-disubstituted amino acid. In Biorganic & Med. Chem. (1994), 2 (2), 101-113 (S. Boile et; al.) compounds with NK2 activity are described, which contain an alpha-alpha-disubstituted phenylalanine (Phe), but they do not exhibit the basic characteristics nor they can be associated to the structure described by the general formula (I).
In Patent Application No. WO 9404494 NK1 antagonists are described, which exhibit a disubstituted alpha,alpha-amino acid whose structure do not correspond to the general formula (I), in particular for the presence -among other things - of a -O-CO- group in the place of XI.
Summary of the invention
It has been surprisingly found that the present non peptidic compounds of general formula
(I) as defined hereinafter, show a better behaviour in inhibiting the bonding of tachykniins onto the receptor NK2, and a better in vivo antagonist activity than that showed by the products disclosed in the above cited prior art patents.
The present invention refers therefore to linear compounds of general formula (I) comprising an alfa,alfa-disubstituted amino acid and at least an amino group capable of giving basic characteristics to the compounds
Figure imgf000003_0001
wherein:
XI is a group selected from -NR6-CO-, -CO- and -NR6-CS- Rl is an aryl or aryl-alkyl or aryl-ethylene group containing from 7 to 12 carbon atoms, wherein aryl indicates a group selected from the group consisting of pyridine, pyrrol, thiophene, benzene, naphthalene, imidazol, diphenyl, phenyl-thiophene, and it can be possibly substituted by one or more groups independently chosen from the group consisting of halogen, C1-C6 alkyl possibly substituted by not more than three fluorine atoms (such as a trifluoromethylic group), C1-C6 alkyloxy possibly substituted by not more than three fluorine atoms (such as a trifluoromethoxylic group), OH, -NHR10, - N(R10)2, -SR10, -CONHR10, -COR10, -COOR10, -R9COOR10, -OR9COOR10, - R9COR10, -CONHR10, -R9CONHR10, -NHCOR10, and -nitro, wherein R10 is H or a linear or branched C1-C6 alkyl chain, and R9 is a linear or branched C1-C6 alkylene chain; or the radical:
Figure imgf000004_0001
possibly substituted by one or more substituents independently chosen from halogen, Cl- C6 alkyl possibly substituted by not more than three fluorine atoms (such as a trifluoromethylic group), C1-C6 alkyloxy possibly substituted by not more than three fluorine atoms (such as a trifluoromethoxylic group), -OH, -NHR10, -N(R10)2, -SR10, - CONHR10, -COR10, -COOR10, -R9COOR10, -OR9COOR10, -R9COR10, -CONHR10, - R9CONHR10, -NHCOR10, and -nitro, wherein RIO is H or a linear or branched C1-C6 alkyl chain, and R9 is a linear or branched C1-C6 alkylene chain, and wherein D = O, S, CH2, O-CH2 or N-R7, wherein R7 is selected from the group consisting of H, a linear or branched C1-C6 alkyl chain, and acyl radical R8-CO, wherein R8 is selected from the group consisting of H and linear or branched C1-C6 alkyl chain; R6 is selected from the group consisting of H and linear or branched C1-C6 alkyl chain; A and B are independently selected from the group consisting of linear or branched C1-C6 alkyl chain, aryl or arylalkyl chain wherein the aryl portion is selected from the group consisting of benzothiophene, indol, pyridine, pyrrol, benzofurane, thiophene, benzene, naphthalene, imidazol, diphenyl- and it can be possibly substituted by one or more substituents independently chosen from halogen, C1-C6 alkyl chain possibly substituted by not more than three fluorine atoms (such as a trifluoromethylic group), C1-C6 alkyloxy possibly substituted by not more than three fluorine atoms (such as a trifluoromethoxylic group), -OH, -NHR10, -N(R10)2, -SR10, -CONHR10, -COR10, -COOR10, -R9COOR10, -OR9COOR10, -R9COR10, -CONHR10, -R9CONHR10, -NHCOR10, and -nitro, wherein RIO is H or a linear or branched C1-C6 alkyl chain, and R9 is a linear or branched C1-C6 alkylene group, or A and B, together with the carbon atom to which they are bound, may form a group having general formula (II):
Figure imgf000005_0001
wherein the broken line indicates a possible double bond; n and m can independently be 0, 1 or 2; R13 and R14 are independently selected from the group consisting of H, C1-C6 alkyl chain, or they can be linked to form an aromatic group selected from the group consisting of benzothiophene, indol, pyridine, pyrrol, benzofurane, thiophene, benzene, naphthalene, imidazol, and biphenyl, which can be possibly substituted by one or more substituents independently selected from halogen, C1-C6 alkyl possibly substituted by not more than three fluorine atoms (such as trifluoromethylic group), C1-C6 alkyloxy chain possibly substituted by not more than three fluorine atoms (such as trifluoromethoxylic group), -OH, -NHR10, -N(R10)2, -SR10, -CONHR10, -COR10, -COOR10, -R9COOR10, -OR9COOR10, -R9COR10, -CONHR10, -R9CONHR10, -NHCORIO, and -nitro, wherein RIO is H or linear or branched C1-C6 alkyl chain, and R9 is a linear or branched C1-C6 alkylene chain; X2 is selected from the group consisting of -CONR6- and -CH2NR6-, wherein R6 is as described above;
R2 is selected from the group consisting of an aryl-alkyl or aryl radical wherein the aryl portion is selected, from the group consisting of benzothiophene, indol, pyridine, pyrrol, benzofurane, thiophene, benzene, naphthalene, imidazol, and biphenyl, and it can be possibly substituted by one or more substituents independently selected from halogen, Cl- C6 alkyl possibly substituted by not more than three fluorine atoms (such as a trifluoromethylic group), C1-C6 alkyloxy possibly substituted by not more than three fluorine atoms (such as a trifluoromethoxylic group), -OH, -NHR10, -N(R10)2, -SR10, - CONHR10, -COR10, -COOR10, -R9COOR10, -OR9COOR10, -R9COR10, -CONHR10, - R9CONHR10, -NHCORIO, and -nitro, wherein R10 is H or a linear or branched C1-C6 alkyl chain, and R9 is a linear or branched C1-C6 alkylene chain, R3 includes at least a basic aniino group, and it is represented by the general formula: "~R - X3- R5 wherein R4 is selected from the group consisting of:
- C1-C6 alkylene, C5-C8 cycloalkylene,
- an aliphatic heterocycle containing at least one atom selected from N, S and O, and possibly substituted by one or two CI -C6 alkyl groups or a -COR15 group, in which R15 is selected from the group consisting of -NR11R12 and -OR11, wherein Rll and R12, independently from each other, are H or a linear or branched C1-C6 alkyl group;
- aryl-alkyl or aryl wherein the aryl portion is selected from the group consisting of benzothiophene, indol, pyridine, pyrrol, benzofurane, thiophene, benzene, naphthalene, imidazol, and biphenyl, and it can be possibly substituted by one or more substituents independently selected from halogen, C1-C6 alkyl possibly substituted by not more than three fluorine atoms (such as a trifluoromethylic group), C1-C6 alkyloxy possibly substituted by not more than three fluorine atoms (such as a trifluoromethoxylic group), - OH, -NHR10, -N(R10)2, -SR10, -CONHR10, -COR10, -COOR10, -R9COOR10, - OR9COOR10, -R9COR10, -CONHR10, -R9CONHR10, -NHCORIO, and -nitro, wherein RIO is H or a linear or branched C1-C6 alkyl group, and R9 is a linear or branched C1-C6 alkylene group,
X3 is a single bond or it is selcted from the group consisting of -CH2-, -CH2-CH2-, -CO-, - OCH2-CH2O-, -O- , -NH-CO-CH2-, and -NH-CO-; or -R4-X3- taken together are a group -CO-CH - R5 is: an aliphatic heterocycle selected from the group consisting of pyrrolidine, piperidine, mo holine, chinuclidine, diazepan, tetrahydropyran, l,4-dioxa-8-azaspiro[4,5]decane, possibly substituted by one or more substituents selected from the group consisting of Cl- C6 alkyl, hydroxymethyl, -OH, cyanomethyl, and C1-C6 alkyloxy; - an azetidine possibly substituted by a group -(CH2)n-R17, wherein R17 is selected from the group consisting of morpholine, piperidine, pyrrolidine, tetrahydropyran, and tetrahydrothiopyran;
- a piperidine possibly C-substituted by a C1-C6 alkyl chain, substituted by a group X5- R18 wherein X5 is a bond or a group -C(R11)(R12 , -CO-, -COCH2-, -CH2CH2-, and R18 is selected from the group consisting of morpholine, piperidine, pyrrolidine, tetrahydropyran, tetrahydrothiopyran, cyclohexane, dioxane, l,4-dioxa-spiro(4,5)decyl and an aromatic selected from the group consisting of thiophene, pyridine, furane, pyrrol, thiadiazole, thiazole, and phenyl possibly substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl possibly substituted by not more than three fluorine atoms, C1-C6 alkyloxy possibly substituted by not more than three fluorine atoms, -OH, -NHR10, -N(R10)2, and -SR10 wherein RIO, Rll and R12 are selected from H and linear or branched C 1 -C6 alkyl chain;
- a piperazine possibly C-substituted by one or two C1-C6 alkyl groups, and possibly N- substituted by a group chosen from -SO2NRl lR12,-(CH2)2O(CH2)2OH, -CH2CN, or by the group -X4-R16 wherein X4 is a bond or it is selected from the group consisting of -CO-, - CH2-, -CONR6-, -COCH2- and -CO-NR6-CH2-, and R16 is selected from the group consisting of pyrrolidine, morpholine, tetrahydropyran, tetrahydrofurane, dioxane, thiophene, pyridine, phenyl, naphthyl, diphenyl, pyrazol, oxazol, isoxazol and thiadiazol, possibly substituted by one or more groups selected from halogen, C1-C6 alkyl, C1-C6 alkyloxy, OH; and R6, Rl 1 and R12 are as defined above;
- an amino group selected from the group consisting of -NR11R12, -NH(CH2)m- NR11R12, amino-tetrahydropyran, furylmethylamino, -NH(CH )2O(CH2)2OH, wherein m ranges from 3 to 6, and Rl 1 and R12 are as defined above
- an amino-cycloalkyl group possibly substituted on the ring by a group selected from OH, and NR11R12, wherein Rl 1 and R12 are as defined above,
-a cycloalkyl group possibly substituted on the ring by a group selected from NR11R12, wherein Rl 1 and R12 are as defined above;
- an aryl group selected from the group consisting of thiophene, pyridine, furane or phenyl possibly substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkyloxy, and OH.
Further object of the present invention are the 'retro-inverted' compounds of the present formula (I) compounds, i.e. the compounds of general formula (I) in which one or more amidic bonds are inverted.
The presence of an alpha,alpha-disubstituted amino acid and the presence of at least one amino group in R3, which gives to the compounds a strong basicity, can be considered as a peculiar structural characteristic of the products belonging to the general formula (I). Further object of the present invention are the pharmaceutically acceptable salts of the compounds of general formula (I) with organic or inorganic acids selected from the group consisting of hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, trifluoroacetic acid,oxalic acid, malonic acid, maleic acid, fumaric acid, succinic acid, tartaric acid and citric acid.
Furthermore, object of the present invention are the single enantiomers and diastereoisomers of the compounds of formula (I) or mixtures thereof, originating from the insertion into the structure of formula (I) of chiral residues or groups.
Further object of the present invention are the pharmaceutical formulations comprising the compounds of general formula (I) and the use of said compounds for preparing pharmaceutical formulations for the treatment of diseases in which neurokinin A plays a pathogenetic role. Detailed description of the invention
Preferred compounds of the invention are the compounds of general formula (I), wherein the aminoacidic residue of general formula (III)
Figure imgf000008_0001
is selected from the group consisting of aminoacidic residues of α,α-φ (^substituted glycine-type selected from the group consisting of 1-aminocyclohexane-l -carboxylic acid (Ac6c), 1-aminocyclopentane-l -carboxylic acid (Ac5c), l-aminocyclopent-3-ene-l- carboxylic acid (Ac5c), 1-aminoisobutyrric acid, 1-aminoindane-l -carboxylic acid (1-Aic), 2-aminoindane-2-carboxylic acid (2-Aic), 2-aminotetraline-2-carboxylic acid (2-Atc), 2- methyl-2-ethylglycine, 2-methyl-2-isopropylglycine, 2-methyl-2-n-propylglycine, 2- methyl-2-(2-butyl) glycine, 2-methyl-2-isobutylglycine, 2-methyl-phenylalanine; and the other groups are as defined above. Preferred compounds according to the present invention are the compounds of formula (I) wherein:
- XI is a CO group;
Rl is an aryl or aryl-ethylene group containing from 7 to 12 carbon atoms, wherein aryl is a group selected from benzene, naphthalene, and biphenyl possibly substituted by one or more groups independently selected from halogen, C1-C6 alkyl possibly substituted by not more than three fluorine atoms (such as a trifluoromethylic group), C1-C6 alkyloxy possibly substituted by not more than three fluorine atoms (such as a trifluoromethoxylic group), -OH, -NHR10, -N(R10)2, -SR10, -CONHR10, -COR10, -COOR10, -R9COOR10, -
OR9COOR10, -R9COR10, -CONHR10, -R9CONHR10, -NHCORIO, and -nitro, wherein
RIO is H or a linear or branched C1-C6 alkyl chain, and R9 is a linear or branched C1-C6 alkylene; or it is the following radical
Figure imgf000009_0001
possibly substituted by one or more substituents independently selected from halogen, Cl- C6 alkyl possibly substituted by not more than three fluorine atoms (such as trifluoromethylic group), C1-C6 alkyloxy possibly substituted by not more than three fluorine atoms (such as trifluoromethoxylic group), -OH, -NHR10, -N(R10)2, -SR10, - CONHR10, -COR10, -COOR10, -R9COOR10, -OR9COOR10, -R9COR10, -CONHR10, - R9CONHR10, -NHCORIO, and -nitro, wherein RIO is H or linear or branched C1-C6 alkyl chain, and R9 is a linear or branched C1-C6 alkylene chain, and whereiϋJD = O, S or-N=R7^ wherein RZ-is selected from the group consisting of H, linear or branched C1-C6 alkyl chain, acyl radical R8-CO, wherein R8 is selected from the group consisting of H and linear or branched C1-C6 alkyl chain; - R6 is selected from the group consisting of H and linear or branched C1-C6 alkyl; - the amino acidic residue of general formula (III)
Figure imgf000009_0002
is an α, -disubstituted glycine-type residue selected from the group consisting of 1- aminocyclohexane-1 -carboxylic (Ac6c), 1-aminocyclopentane-l -carboxylic acid (Ac5c), 1-aminoindane-l -carboxylic acid (1-Aic), l-aminocyclopentan-3-ene 1- carboxylic acid (Ac5c), 2-methyl-phenylalanine, 2-methyl-2-ethyl-glicine,
R2 is a phenylmethyl group possibly substituted on the phenyl portion by one or two groups independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkyloxy, and OH;
- X2 is selected from -CONR6- and -CH2NR6;
R3 includes at least one basic amino group and it is the following group: "~R4 - X3- R5 wherein - R4 is selected from the group consisting of a group -(CH2)n-, wherein n ranges from 1 to 3, a C5-C8 cycloalkylene group and an aliphatic heterocycle selected from piperidine, pyrrolidine or piperazine possibly substituted by one or two C1-C6 alkyl chains;
- X3 is a bond or it is selected from the group consisting of -CO-, -CH2-, -CH2-CH2-, -CO- CH2-, and -NH-CO-; - R5 is selected from the group consisting of: a) an aliphatic heterocycle selected from piperidine, pyrrolidine, morpholine, diazepan, tetrahydropyran, tetrahydrothiopyran, and l,4-dioxa-8-azaspiro[4,5]decane, possibly substituted by one or two groups selected from C1-C6 alkyl, hydroxymethyl, cyanomethyl, C 1 -C6 alkyloxy, and OH; b) an azetidine possibly substituted by a -(CH2)n-R17 group wherein R17 is selected from the group consisting of morpholine, piperidine, pyrrolidine, tetrahydropyran, and tetrahydrothiopyran; c) a piperidine, possibly C-substituted by a C1-C6 alkyl chain, substituted by a group X5- R18, wherein X5 is a bond or it is selected from the group consisting of -C(R11)(R12)-, - CO-, -CH2CH2-, and -COCH2-; and R18 is selected from the group consisting of furane, morpholine, pyrrole, thiophene, tetrahydropyran, tetrahydrothiopyran, pyrrolidine, cyclohexane, cyclopentane, 1-3-dioxane, thiazole and l,4-dioxa-spiro(4,5)decyl, possibly substituted by one or more groups selected from halogen, C1-C6 alkyl, C1-C6 alkyloxy, - OH, -NHR10, -N(R10)2, and -SR10, wherein RIO, Rll and R12 are selected from H and linear or branched C 1 -C6 alkyl; d) a piperazine possibly C-substituted by one or two C1-C6 alkyl groups and possibly N- substituted by a group selected from -(CH2)2O(CH2)2OH, -CH2CN and a group X4-R16, wherein X4 is a bond or it is selected from the group consisting of -CH2-,-CH2-CH2-, and -COCH2-, and R16 is selected from the group consisting of pyridine, thiophene, tetrahydropyran, morpholine, tetrahydrofurane, and 1,3-dioxane; e) an amino group selected from -NR11R12 and -NH-(CH2)m-NRllR12 wherein Rll, Rl 2 and m are as defined above; f) an amino-cycloalkyl possibly substituted on the ring by a group selected from OH and - NR11R12, or a cycloalkyl possibly substituted by a group NR11R12, wherein Rll and R12 are as defined above; g) an heteroaromatic selected from pyridine and thiazole. Amongst these compounds particularly preferred are the compounds wherein:
XI is a -CO- group;
Rl is an aromatic group selected from the group consisting of biphenyl, phenyl-ethylene, naphthyl, phenyl-thiophene, benzothiophene, benzofurane, and indole possibly N- substituted by a C1-C6 alkyl group, which can be possibly substituted by one, two or three groups independently selected from the group consisting of halogen, C1-C6 alkyl possibly substituted by not more than three fluorine atoms, C1-C6 alkyloxy, OH, NHR10, and
N(R10)2, wherein RIO is selected from H and C1-C6 alkyl; the amino acidic residue of general formula (III) is selected from the group consisting of 1- aminocyclohexane-1 -carboxylic acid (Ac6c), 1-aminocyclopentane-l -carboxylic acid (Ac5c), 1-aminoindane-l -carboxylic acid (1-Aic), l-aminocyclopentan-3-ene 1- carboxylic acid (Ac5c), 2-methyl-phenylalanine, and 2-methyl-2-ethyl-glycine;
R6 is H;
R2 is a phenyl-methyl group, having the phenyl group possibly substituted by a C1-C6 alkyl group; X2 is selected from -CONH- and CH2NH-;
R3 includes at least one basic amino group having the following formula:
— R4 " ^3" 5 wherein:
- R4 is selected from the group consisting of a group -(CH2)n- wherein n ranges from 1 to 3, a C5-C8 cycloalkylene group selected from cyclopentylene and cyclohexylene, and an aliphatic heterocycle selected from piperidine, pyrrolidine and piperazine possibly substituted by one or two C1-C6 alkyl groups; - X3 is a bond or it is a group selected from -CO-, -CH2-, -CH2-CH2-, and -NH-CO-;
- R5 is selected from: a) an aliphatic heterocycle selected from the group consisting of piperidine, pyrrolidine, morpholine, diazepan, tetrahydropyran, and l,4-dioxa-8-azaspiro[4,5]decane, possibly substituted by one or two groups selected from C1-C6 alkyl, C1-C6 alkyloxy, OH, and cyanomethyl; b) an azetidine substituted by a group -(CH_)n-R17, wherein R17 is tetrahydropyran; c) a piperidine possibly C-substituted by a C1-C6 alkyl group, and substituted by a group X5-R18 wherein X5 is a bond or it is selected from the group consisting of -C(R11)(R12)-, -CO-, -CH2CH2-, and -COCH2-, and R18 is a group selected from thiophene, tetrahydropyran, tetrahydrothiopyran, pyrrolidine, cyclohexane, cyclopentane, and 1-3- dioxane, possibly substituted by one or more groups selected from C1-C6 alkyl, -NHR10, and -N(R10)2, wherein RIO, Rl 1 and R12 are selected from H and linear or branched Cl- C6 alkyl; d) a piperazine possibly C-substituted by one or two C1-C6 alkyl group, and possibly N- substituted by a group selected from -CH2CN and X4-R16, wherein X4 is a bond or it is selected from -CH2- and -COCH2-, and R16 is selected from the group consisting of pyridine, thiophene, tetrahydropyran, morpholine, tetrahydrofurane, and 1,3 -dioxane; e) an amino group selected from -NR11R12 and -NH-(CH2)m-NRl lR12, wherein Rll, Rl 2 and m are as defined above; f) an amino-cyclohexane or a cyclohexane possibly substituted on the ring by the group - NR11R12, wherein Rl 1 and R12 are as defined above; g) an heteroaromatic group represented by pyridine.
Amonst these compounds more preferred are the present compounds of formula (I) wherein:
XI is a -CO- group;
Rl is an aromatic group selected from the group consisting of phenyl-ethylene, naphthyl, benzothiophene, and benzofurane, possibly substituted by one, two or three groups independently selected from halogen, C1-C6 alkyl possibly substituted by not more than three fluorine atoms, C1-C6 alkyloxy, OH, NHR10, and N(R10)2 wherein R10 is selected from H and C1-C6 alkyl; the amino acidic residue of general formula (III) is selected from 1-aminocyclohexane-l- carboxylic acid (Ac6c), and 1-aminocyclopentane-l -carboxylic acid (Ac5c); R6 is H;
R2 is phenyl-methyl; X2 is -CONH-;
R3 includes at least one basic amino group and it is the following group: ~R_ι - X3- R5 wherein
- R4 is selected from -(CH2)n- wherein n ranges from 1 to 3, and piperidine possibly substituted by a C 1 -C6 alkyl group;
X3 is a bond or it is a group selected from -CO- and -CH2-;
R5 is selected from: a) an aliphatic heterocycle selected from piperidine and tetrahydropyran, possibly substituted by one or more C1-C6 alkyl groups; b) a piperidine possibly C-substituted by a C1-C6 alkyl group, substituted by a group X5-
R18 wherein X5 is a bond or it is a group selected from -C(R11)(R12)- and -CO-, and R18 is a group selected from tetrahydropyran, cyclohexane and 1-3-dioxane, possibly substituted by one or more groups selected from C1-C6 alkyl, -NHR10, and -N(R10)2, wherein RIO, Rl 1 and R12 are selected from H and linear or branched C1-C6 alkyl; c) a piperazine possibly C-substituted by one or two C1-C6 alkyl groups, and possibly N- substituted by a group X4-R16 wherein X4 is -CH2-, and R16 is selected from tetrahydropyran and 1,3-dioxane.
Among the terms used for describing the present invention the following are preferred:
- the term "halogen" refers to fluorine, chlorine, bromine or iodine; - the term "C1-C6 alkyl" refers to a group selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, ter-butyl and, when possibly substituted by fluorine, trifluoromethyl;
- the term "C1-C6 alkyloxy" refers to a group wherein the alkyl part is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, ter-butyl and, when possibly substituted by fluorine, trifluoromethyl; - the term "C1-C6 alkylene" refers to a group selected from methylene, ethylene, trimethylene, and tetramethylene; - the term "C5-C8 cycloalkylene" refers to a group selected from cyclobutylene, cyclopentylene, cyclohexylene, and cycloheptylene;
- the term "cycloalkyl" refers to a group selected from cyclobutane, cyclopentane and cyclohexane. The compounds of the present invention have shown an antagonist activity to the action of Substance P, Neurokinin A, and Neurokinin B; and they demonstrated particularly selective against the action of Neurokinin A.
Thus the present compounds of formula (I) can be used for prepararing pharmaceutical formulations, possibly comprising pharmaceutically acceptable diluents and excipients commonly used in drug products, useful for the treatment and prevention of diseases in which tachykinins in general, and namely Neurokinin A, are involved as neuromodulators; as an example we can list the following diseases: respiratory pathologies, such as asthma, allergic rhinitis, and chronic obstructive bronchitis; ophthalmic diseases, such as conjunctivitis, skin diseases, such as allergic and contact dermatitis, and psoriasis, intestinal disorders, such as irritable colon, ulcerous colitis and Chron disease, gastric diseases, urinary diseases, such as cystitis and incontinence, erectile dysfunctions, diseases of the nervous central system, such as anxiety, depression and schizophreny, tumoural pathologies, autoimmunitary diseases or diseases related to AIDS, cardiovascular pathologies, neuritis, neuralgia and treatment of pain, in particular visceralgia, inflammatory processes, such as osteoarthritis or rheumatoid arthritis.
The present compounds of formula (I), as defined above, can be prepared according to methods described in literature and well known to the person skilled in the art, such as by reactions of amidic condensation, substitution, addition or reductive animation. As an example the synthetic paths described in the general guidelines in the following reaction schemes can be followed by making the obvious and suitable changes according to the substituents.
In the following schemes, unless otherwise clearly specified, the substituents are as defined above. For example, the compounds of general formula (I) may be obtained according to the following Scheme 1 by reacting the activated carboxylic acid derivatives of general formula (IN) with the intermediate compound of general formula (N).
Figure imgf000015_0001
( IV ) ( V ) ( I )
Scheme 1
In this case, as an example, X. = CO.
Again, as an example, the compounds of general formula (I) can be obtained as described in the following Scheme 2, according to the following sequence of reactions: a) formation of the oxazolinone of formula (Nil) starting from activated carboxylic acid derivatives of formula (IN) and amino acids of formula (NI), with suitable activating and condensing agents; b) reaction of oxazolinone of formula (Nil) with amines of formula (NIII) protected with a suitable protective group P, followed by deprotection by methods known to the person skilled in the art, to obtain the compounds of formula (LX); c) acylation, alkylation or reductive amination with suitable reagents to yield the final compounds of formula (I).
Figure imgf000015_0002
( IV ) ( VI ) ( VII )
Figure imgf000016_0001
Figure imgf000016_0002
(IX)
Scheme 2
In this case, as an example, X. = CO and n = 0, 1, 2.
The compounds of the present invention can occur in various isomeric forms. In fact, whereas the configuration of the carbon linked to R5 is uni vocally prefixed by using during the synthesis the specific isomer of the amino acid derivative, frequently the other starting products can be constituted by mixtures of stereo isomers of difficult separation. Therefore, the compounds of the present invention can be obtained as mixtures of diastereoisomers. These mixtures can be resolved by chromatography. The compounds of formula (I) can however be used as single enantiomers as well as mixtures of isomers.
Some examples of the present compounds and of the preparation method thereof are provided in the following for illustrative and non limiting purposes of the present invention. Example 1 Ntx[Ntx(benzo[b]thiophenyl-2-ylcarbonyl)-l-aminocyclopentane-l-carbonyl]-D- phenylalanine-N-[3(morpholin-4-yl)propyl]amide la) to a solution of 1-amino-cyclopentane-l -carboxylic acid (1 g, 7.66 mmol) in 30 ml of anhydrous dichloromethane (DCM) N,O-bis(trimethylsilyl)acetamide (BSA) (3.8 ml, 15.4 mmol) is added under magnetic stirring; after 15 min trimethylchlorosylane (TMSC1) (0.38 ml, 10 % of the BSA volume) is added. The amino acid is completely sylanised (the \6
solution at the end of the addition is clear), and after about 2 hours of stirring at room temperature benzo[b]thiophene-2-carbonyl chloride (7.66 mmol) dissolved in 10 ml of DCM is added to the reaction mixture. The reaction is kept for 12 hours under stirring at room temperature. The solution is concentrated under reduced pressure, then 50 ml of NaHCO3 aq. IM are added, and is kept under stirring for 30'. Everything is transferred into a separatory funnel, then ethyl acetate (AcOEt) (50 ml) is added; the mixture is shaked and the organic phase is removed. The aqueous solution is acidified up to pH = 1 with HCl 6N and washed with AcOEt (3 x 50 ml). The organic phases are collected together, transferred in a separatory funnel and washed with H2O and brine up to pH = 5-6. The organic phase is dried on anhydrous Na2SO , then brought to dryness. The isolated residue is crystallised from acetonitrile, thus obtaining 1.4 g (4.84 mmol, yield - 63%) of Nα(benzo[b]thiophene-2-carbonyl)-l- aminocyclopentane-1- carboxylic acid. HPLC (method E): Rt = 14.04 min. lb) To a solution in anhydrous THF (25 ml) of the product coming from Example la) (500 mg, 1.73 mmol), l-emyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (2.08 mmol, 0.402 g) and diisopropylethylamide (DiPEA) (5.2 mmol, 0.89 ml) are added. The solution is kept under stirring for 2 hours at room temperature. The solvent is evaporated, and the residue is dissolved with AcOEt (50 ml); the organic phase is washed with NaHCO3 IM (3 x 50 ml), HCl IM (3 x 50 ml), saturated aqueous solution of sodium chloride (3 x 50 ml). The orgamc solution is dried on anhydrous Na2SO4 and then it is brought to dryness. 0.450 g of 2-(benzo[b]thiophen-2-yl)-4-cyclopentyl-l,3-oxazolin-5-one (1.66 mmol, yield = 96%) are obtained. HPLC (method E): Rt = 21.86 min. lc) To a solution in 15 ml of anhydrous THF of tert-butyloxycarbonyl-D-phenylalanine N- hydroxysuccinimmidyl ester (500 mg, 1.38 mmol), N-(3-aminopropyl)-morpholine (1.328 mmol, 0.201 ml) is added. The stirring is maintained for 90 min. The solvent is then evaporated, and the residue dissolved with AcOEt (50 ml); the organic phase is washed with NaHCO3 IM (3 x 50 ml), HCl IM (3 x 50 ml), saturated aqueous solution of sodium chloride (3 x 50 ml). The solution dried on anhydrous Na2SO4. Following the evaporation of the solvent, 474 mg of (ter-butyloxycarbonyl-D-phenylalanine-N-[3(morpholin-4- yl)propyl] amide) (1.21 mmol, yield = 88%) are obtained. HPLC (method E): Rt = 10.35 min.
Id) The product coming from Example lc) (0.474 g, 1.21 mmol) is dissolved in 50 ml of a solution of HCl 4N in dioxane. After 30' the solvent is evaporated, and the residue is dissolved and brought to dryness with toluene and with absolute ethanol. The so obtained solid is transferred into a separatory funnel with 50 ml of NaHCO3 and 50 ml of CHC13. After shaking, the organic phase is collected and the aqueous phase is washed with other 5 portions of CHC13. All the organic phases are collected, then transferred into a separatory funnel; one washing is made with a sodium chloride saturated solution. The organic phase is dried on Na2SO4. The solvent is evaporated. 0.291 g (1 mmol, yield = 83%) of clear oil of D-phenylalanine-N-[3(morpholin-4-yl)propyl]amide hydrochloride. le) To a solution in a mixture of 10 ml of anhydrous CH3CN and 1 ml of anhydrous THF of the product coming from Example lb) (66.5 mg; 0.245 mmol), a solution of the product coming from Example Id) (72 mg, 0.247 mmol) in 5 ml of anhydrous CH3CN is added. The reaction is allowed to reflux for 48 hours.
After removing the solvent at reduced pressure, the residue is dissolved with AcOEt (50 ml), and the solution is transferred in a separatory funnel, and washed once with a sodium chloride saturated solution. The organic phase is dried on Na2SO and the solvent evaporated. 135 mg of the product are obtained, which is then purified by reverse phase chromatography, using a column Hibar Merck LiChrospher 100, RP-18e (5 μm), eluents = A: H2O + 0.1% TFA; B: CH3CN + 0.1% TFA; elution with a linear gradient from 10%B at 50%B in 40 min, flow 10 ml/min; UN detection ( λ =230 nm). The fractions corresponding to the peak of the product have been collected, concentrated to small volume at reduced pressure and lyophilised, yielding 0.124 mmol of Να Να(benzo[b]thiophen-2-ylcarbonyl)- l-aminocyclopentane-l-carbonyl]-D-phenylalanine-N-[3(morpholin-4-yl)propyl]amide (yield = 51% after purification).
MS (m/z): 563.3 (MH+). HPLC (method E): Rt = 14.03 min. Example 2 (lR,3S)-acid-Nγ{Nα| f (benzo[b]tωophen-2-yl-carbonyl)-l-aminocyclopentan-l-carboxy]- D-phenylalanil}-3-aminocyclopentan-l-carboxylic-N-[(lS,2S)-2-aminocyclohexyl] amide 2a) To a solution of (lS,2S)-diaminocyclohexane (1.14 g, 10 mmol) in 50 ml of DCM, dibenzyl dicarbonate (2 g ,7 mmol) dissolved in 20 ml of DCM is added drop by drop. When the addition is over, the obtained precipitate is filtered and dried, obtaining 0.55 g of a white solid which is the starting diamine cyclohexane. The organic filtrate (80 ml) is extracted with HCl IN (3x10 ml) and the aqueous extract are collected, alkalinise to pH = 10 and extracted with DCM (3x10 ml). The collected organic extracts are dried on anhydrous Na2SO , then filtered and brought to dryness. The residue is dissolved in 3 ml of methanol, then ethyl acetate saturated of hydrochloric acid (EtOAc/HCl) (2 ml) is added and, subsequently, ethyl ether (20 ml) yielding a white precipitate in suspension. This precipitate is filtered and dried thus obtaining 1.44 g of (1S,2S)-N- monobenzyloxycarbonyldiaminocyclohexane hydrochloride (yield = 50,5 %). HPLC (E): Rt = 7.85 min.
2b) 360 mg (1.26 mmol) of the product coming from Example la) are dissolved in 10 ml of DMF and added with 0.296 g (1.29 mmol) of (lR,3S)-Nγ-ter-butyloxycarbonyl-3- aminocyclopentan-3-carboxylic acid, 245 mg of EDC, 173 mg of HOBt and DiPEA until an alkaline reaction is achieved. The mixture is kept to react for 18 hours, then added with DCM (50 ml). The organic phase is washed with KHSO4 5% (3x50 ml), NaHCO3 (3x50 ml), H2O (3x50 ml) and dried on anhydrous Na2SO4. The organic solution is then filtered and brought to dryness yielding 0.610 g of a yellow solid, which is then dissolved in 5 ml of MeOH and added with 50 ml of Et2O. A white solid precipitates and, after filtration, 440 mg (yield = 68 %) are obtained. HPLC(E): Rt = 15.5 min.
The residue is then dissolved in 10 ml of EtOAc and added with 20 ml of EtOAc/HCl; after 1 hour 100 ml of Et2O are added to the mixture, thus obtaining a white precipitate that, after filtration, gives 0.425 g of hydrochloride of (lR,3S)-3-aminocyclopentan-3- carboxylic-N-[(l S,2S)-2-N-(benzyloxycarbonyl)aminocyclohexyl] amide acid. HPLC(E): Rt = 8.9 min.
2c) 0.425 g of the product coming from Example 2b) are dissolved in DMF (10 ml) and added with Nα(tert-butyloxycarbonyl)-D-ρhenylalanine (0.312 g, 1.29 mmol), EDC (0.230 g, 1.29 mmol), HOBt (0.175 g, 1.29 mmol) and DiPEA until an alkaline reaction is achieved. The mixture is kept to react overnight, then 30 ml of DCM are added and the organic phase is washed with KHSO4 5% (3x50 ml), NaHCO3 (3x50 ml), H2O (3x50 ml), and dried on anhydrous Na2SO4. After filtration and removal of the solvent, 531 mg of raw product are obtained from which, after grinding in Et2O, 470 mg of a white solid (yield = 83 %) are obtained. HPLC(E): Rt = 16.06 min.
The release of the Boc group with EtOAc/HCl and subsequent precipitation with Et2O (70 ml) allows the isolation of 410 mg of hydrochloride of (lR,3S)-Nγ-[D-phenylalanil]-3- aminocyclopentan-3-carboxylic-N-[(lS,2S)-2-N-(benzyloxycarbonyl) aminocyclohexyl] amide acid. HPLC(E) = 11.27 min.
2d) Into a 100 ml glass protected with a CaCl2 tube 1.29 g (10 mmol) of 1- aminocyclohexan-1 -carboxylic acid are suspended in 20 ml of DCM, and added with 5 ml of N,O-bis-(trimethylsilyl)-acetamide. The reaction mixture is kept under stirring for 2 hours until the amino acid derivative is completely dissolved. To the solution 1.8 g (0.92 mmol) of chloride of benzothiophene-2-carboxylic acid are added drop by drop in 20 ml of DCM, and the mixture is allowed to react for 1 hour at room temperature. The organic solution is then washed with water (5x50 ml), dried on anhydrous Na2SO4, filtered, brought to dryness and grinded with Et2O, thus yielding 2.60 g (yield = 90.2 %) of a white solid of Nα(benzo[b]thiophen-2-yl-carbonyl)-l-aminocyclohexane-l-carboxylic acid. HPLC (method E): Rt = 17.7 min.
2e) To a solution in anhydrous THF (25 ml) of the product coming from Example 2d) (0.50 g, 1.67 mmol), EDC (2.08 mmol, 0.402 g) and DiPEA (5.2 mmol, 0.890 ml) are added. The solution is maintained under stirring for 2 hours at room temperature. The solvent is then evaporated, the residue is dissolved in AcOEt (50 ml), the organic phase is washed with NaHCO3 IM (3 x 50 ml), HCl IM (3 x 50 ml), sodium chloride saturated aqueous solution (3 x 50 ml). The organic solution is anhydrified on anhydrous Na2SO and then brought to dryness. 0.450 g of 2-(benzo[b]thiophen-2-yl)-4-cyclohexyl-oxazol-5- one (1.57 mmol, yield = 94 %) are obtained. HPLC (method E): Rt = 22.1 min.
2f) 0.176 g of the product coming from Example 2c), dissolved in 5 ml of anhydrous CH3CN, are added with 82 mg of the product coming from Example 2d) and with DiPEA until an alkaline reaction is achieved. The mixture is then heated to reflux for 18 hours. The reaction mixture is then diluted with DCM (20 ml ) and washed with KHSO 5% (3x50 ml), NaHCO3 (3x50 ml), H2O (3x50 ml), and dried on anhydrous Na2SO4. The mixture is filtered, brought to dryness and grinded with Et2O, thus obtaining 185 mg of a white solid. HPLC(E): Rt = 17.08 min. The so obtained solid product is dissolved in 12 ml of MeOH and 1 ml of acetic acid. The resulting solution is added with 250 mg of palladium on carbon and insufflated with hydrogen for 2 hours until, under HPLC at the above described conditions, the peak at
Rt=17.08 min disappears and a main peak at Rt = 11.78 min appears. After filtration of the catalyst and removal of the solvent, the reaction mixture is then purified in 10 runs of preparative chromatography using a column Nydac Peptide&Protein
(250 x 22 mm), lOμ, eluting with H2O + 0,1% TFA (A) and CH3CΝ + 0,1 % TFA (B)
(gradient 10% to 50% of B in 110 min; flow 12 ml/min.).
The chromatographic fractions which resulted pure from HPLC analysis are collected and evaporated to yield a residue of 70 mg of (lR,3S)-acid-NΥ{Ntx[N (benzo[b]thiophen-2-yl- carbonyl)-l-aminocyclopentan-l-carboxy]-D-phenylalanil}-3-aminocyclopentan-l- carboxylic-N-[(l S,2S)-2-aminocyclohexyl] amide.
1H-NMR (δ, DMSO-de): 1.2-1.9 (m, 22H, CH2); 2.6 (m, IH, CH-CO-3Ac5c); 2.9-3.20 (m,
2H, (β)CH2-D-Phe); 3.85 (m, IH, CH-NH. 1,2 di-NH2-cyclohexane); 4.2 (m, IH, CH-NH- 3Ac5c); 4.45 (m, IH, (α)CH-D-Phe)); 7.1-7.25 (m, 5H, Carom-D-Phe); 7.45-7.85 (m, 8H,
C(5)H+C(6)H+_ NHCH-l,2di-NH2-cyclohexane+NHCH-3Ac6c + NH3 + + NHCH-D-
Phe); 7.90-8.02 (m, 2H, C(4)H+C(7)H); 8.3 (s, IH, C(3)H); 8.9 (s, IH, NH-lAc5c).
MS-FAB: 644,3 (M+H)+
Figure imgf000021_0001
With analogous methods or by obvious changes for a skilled person, the following products have been prepared:
Example 3
N7{NαpSrα(biphen-4-ylcarboxy)-l-aminocyclopentan-l-carboxy]-D-phenylalanyl}-
( 1 R,3 S)-3-aminocyclopentane- 1 -carboxylic-acid-N-(( 1 S ,2S)-2-aminocyclohexyl)amide trifluoroacetate salt
MS-FAB: 664.32 (M+H)+
HPLC (method E): Rt = 10.5 min.
Example 4
Nγ{N [Nα(N-(methyl)indol-2-ylcarboxy)- 1 -aminocyclopentan- 1 -carboxy]-D- phenylalanyl}-(lR,3S)-3-aminocyclopentane-l -carboxylic-acid-N-((l S,2S)-2- aminocyclohexyl) amide trifluoroacetate salt
MS-FAB: 641.32 (M+H)+ HPLC (method F): Rt = 4.8 min.
Example 5
Nγ{Nα[Nα[4-(methyl)cynnamoyl] - 1 -aminocyclopentan- 1 -carboxy] -D-phenylalanyl} -
(lR,3S)-3-aminocyclopentane-l-carboxylic-acid-N-((lS,2S)-2-aminocyclohexyl)amide trifluoroacetate salt
MS-FAB: 628.4 (M+H)+
HPLC (method F): Rt = 3.37 min.
Example 6
Nγ{Nα[Nα(benzonιran-2-ylcarboxy)-l-aminocyclopentan-l-carboxy]-D-phenylalanyl}- (lR,3S)-3-aminocyclopentane-l-carboxylic-acid-N-((l S,2S)-2-aminocyclohexyl) amide trifluoroacetate salt
MS-FAB: 628.3 (M+H)+
HPLC (method E): Rt = 9.25 min.
Example 7 Nα[Nα(4-(methyl)cinnamoyl)-(R,S) 1 -aminoindane- 1 -carboxy] -D-phenylalanine amide-N-
[(lS,3R)-3-(morpholin-4-ylmethyl)cyclopentyl]
MS-FAB: 635.2 (M+H)+
HPLC (method E): Rt = 12.9 min.
Example 8 NΥ{Nα[Nα(benzo[b]thiopheri-2-ylcarbonyl)- 1 -aminocyclopentan- 1 -carboxy]-D- phenylalanyl}-(lR,3S)-3-aminocyclopentane-l-carboxylic-acid-N-((lS,2S)-2- dimethylaminocyclohexyl) amide hydrochloride salt
MS-FAB: 572.3 (M+H)+
HPLC (method E): Rt = 12.0 min. Example 9
NY{Nα[Nα(benzo[b]thiophen-2-ylcarbonyl)-l-aminocyclopentan-l-carboxy]-D-4-methyl- phenylalanyl}-(lR,3S)-3-aminocyclopentane-l-carboxylic-acid-N-(lS,2S)-2-dimethyl aminocyclohexyl)amide hydrochloride salt
MS-FAB: 686.3 (M+H)+ HPLC (method E): Rt = 12.1 min.
Example 10 ^{^[N^-methyl-cinnamoy^-l-aminocyclopentan-l-carboxyl-D-phenylalanyl}-
(1 R,3 S)-3-aminocyclopentane- 1 -carboxylic-acid-N-((l S,2S)-2- dimethylaminocyclohexyl)amide hydrochloride salt
MS-FAB: 656.3 (M+H)+ HPLC (method E): Rt = 11.9 min.
Example 11
Nγ{Nα[^α(ber_zofuran-2-ylcarboxy)-l-aminocyclopentan-l-carboxy]-D-phenylalanyl}-
(lR,3S)-3-aminocyclopentane-l-carboxylic-acid-N-((lS,2S)-2- dimethylaminocyclohexyl)amide hydrochloride salt MS-FAB: 656.3 (M+H)+
HPLC (method E): Rt = 11.8 min.
Example 12
Nγ{Nα[Nα(biphen-4-ylcarbonyl)- 1 -aminocyclopentan- 1 -carboxy]-D-phenylalanyl} -
(lR,3S)-3-aminocyclopentane-l-carboxylic-acid-N-((lS,2S)-2- dimethylaminocyclohexyl)amide hydrochloride salt
MS-FAB: 692.4 (M+H)+
HPLC (method E): Rt = 12.7 min.
Example 13
Nγ.{NαpSIα(N-(methyl indol-2-ylcarboxy)-l -aminpcyclopentan-l-carboxy]-D- phenylalanyl}-(lR,3S)-3-aminocyclopentane-l-carboxylic-acid-N-((lS,2S)-2- dimethylaminocyclohexyl)amide hydrochloride salt
1H-NMR (δ, DMSO-de): 1.2-1.9 (m, 22H, CH2); 2.6 (m, IH, CH-CO-3Ac5c); 2.90-3.20
(m, 2H, (β)CH2-D-Phe); 2.75 (m, 6H,
Figure imgf000023_0001
3.8 (s, 3H, 1-(CΑ_) indole) 4.2 (m, IH,
CH-NH-3Ac5c); 4.45 (m, IH, (α)CH -D-Phe); 7.10-7.25 (m, 5H, Carom-D-Phe); 7.45-7.85 (m, 6H, C(5)H+C(6)H+J__HCH-l,2di-NH2-cyclohexane+ _lHCH- 3Ac6c+ HN(CH3)2 + +
NHCH-D-Phe); 7.90-8.02 (m, 2H, C(4)H+C(7)H); 8.5 (s, IH, C(3)H); 8.9 (bs, IH, NH-
1AC5C).
MS-FAB: 669.3 (M+H)+
HPLC (method E): Rt = 12.2 min. Example 14 Nγ{Nαp^α(benzo[b]thiophen-2-ylcarbonyl)-(R)-α-mefhyl-α-ethylglycyl]-D- phenylalanyl}-(lR,3S)-3-amino cyclopentane-l-carboxylic-acid-N-((lS,2S)-2- aminocyclohexyl) amide trifluoroacetate salt
MS-FAB: 632.2 (M+H)+ HPLC (method F): Rt = 5.51 min.
Example 15
NΥ{Nα|^α(4-methylcinnamoyl)-(R)-α-methyl-α-ethylglycyl]-D-phenylalanyl}-(lR,3S)-3- amino cyclopentane-l-carboxylic-acid-N-((lS,2S)-2-aminocyclohexyl) amide trifluoroacetate salt MS-FAB: 616.3 (M+H)+
HPLC (method F): Rt = 5.58 min.
Example 16
Nγ{Nα[N0C(biphenyl-4-carboxy)- 1 -aminocyclopentan- 1 -carboxy] -R-3 (4(methyl) phenyl)alanyl}-(lR,3S)-3-aminocyclopentane-l-carboxylic-acid-N-((lS,2S)-2- aminocyclohexyl) amide hydrochloride salt
MS-FAB: 678 (M+H)+
HPLC (method E): Rt = 12.8 min.
Example 17
Nγ{Nα[Nα(N-(methyl)indol-2-ylcarboxy)-l-aminocyclopentan-l-carboxy}-R-3-(4- methyl)phenyl)alanyl}-(lR,3S)-3-aminocyclopentane-l-carboxylic-acid-N-((lS,2S)-2- aminocyclohexyl)amide hydrochloride salt
MS-FAB: 655 (M+H)+
HPLC (method E): Rt = 12.2 min.
Example 18 Nγ{Nα[Nα(4-(methyl)cynnamoyl)- 1 -aminocyclopentan- 1 -carboxy] -R-3 [4- methyl)phenyl]alanyl}-(lR,3S)-3-aminocyclopentane-l-carboxylic-acid-N-((lS,2S)-2- aminocyclohexyl)amide hydrochloride salt
MS-FAB: 642.2 (M+H)+
HPLC (method E): Rt = 12.0 min. Example 19 Nα| f (benzo[b]tMophen-2-yl-carbonyl)-l-aminocyclohexan-l-carboxy]-D-phenylalanine-
N- {3-[bis(n-butyl)amino]proρyl} amide
Example 20
Nα|^α(benzo[b]tWophen-2-yl-carbonyl)-l-ammocyclohexan-l-carboxy]-D-phenylalanine- N-[3(morpholin-4-yl)propyl]amide
Example 21
3-cz5,-Nγ{Nα[^α(benzo[b]tWophen-2-ylcarbonyl)-l-aminocyclohexan-l-carboxy]-D- phenylalanil}ammocyclohexan-l-carboxylic acid -N-((lR,2S)-2-aminocyclohexyl)amide
1H-NMR (δ, DMSO-de): 1.2-1.9 (m, 26H, CH2); 2.3 (m, IH, CH-CO-3Ac6c); 2.8-3.15 (m, 2H, fβ CHrD-Phe): 3.55 (m, IH, CH-NH 1,2 di-NH2-cyclohexane); 4.1 (m, IH, CH-NH-
3Ac6c); 4.35 (m, IH, (α)CH -D-Phe); 7.05-7.18 (m, 5H, Carom-D-Phe); 7.39-7.45 (m, 2H,
C(5)H + C(6)H); 7.59-7.65 (m, 3H, NHCH); 7.89-7.96 (m, 2H, C(4)H+C(7)H); 8.3 (s, IH,
C(3)H); 8.42 (s, IH, NH-lAc6c).
MS-FAB: 672,45 (M+H)+ HPLC(method E): Rt = 12.7 min.
Example 22
Nγ{Nαp fα(benzo[b]thiophen-2-ylcarbonyl)-l-aminocyclohexan-l-carboxy]-D- phenylalanyl}-3-cw-aminocyclohexan-l-carboxylic-acid-N-(5-aminopentyl)-amide trifluørOaeetate-salt- 1H-NMR (δ, DMSO-de): 1.2-1.9 (m, 24H, -CH2-); 2.2 (m, IH, CH-CO-3Ac6c); 2.7 (m,2H,
NH- CH2); 2.8-3.15 (m, 2H, (β)CH2-D-Phe); 3.0 (m, 2H, CHZ-NH 4.1 (m, IH, CH-NH-
3Ac6c); 4.35 (m, IH, ( )CH -D-Phe); 7.05-7.18 (m, 5H, Carom-D-Phe); 7.59-7.65 (m, 3H,
NHCH); 7.40-7.55 (m, 5H,C(5)H+C(6)H+ NH-^; 7.89-7.96 (m, 2H,C(4)H+C(7)H); 8.3
(s, IH, C(3)H), 8.42 (s, IH, NH-lAc6c). MS-FAB: 660.22 (M+H)+
HPLC (method E): Rt = 12.4 min.
Example 23
Nα Nα enzo[b]tluophen-2-ylcarbonyl)-l-(R)-amino-indan-l-carboxy]-D-phenylalanine-
N-[3(morpholin-4-yl)propyl]amide Example 24
Nα[Nα(benzo[b]thiophen-2-ylcarbonyl)- 1 -aminocyclopentane- 1 -carboxy] -L- phenylalanine-N-[3(morpholin-4-yl)propyl]amide Example 25
(lR,3S) acid 3-NΥ{Nαp^α(benzo[b]tMophen-2-ylcarbonyl)-l-anιinocyclohexan-l- carboxy] -D-phenylalanil} aminocyclopentane- 1 -carboxylic -N-(l S ,2R)-2- aminocyclohexyl) amide 1H-NMR (δ, DMSO-de): 1.2-1.9 (m, 24H, CH2); 2.2 (m, IH, CH-CO-3Ac5c); 2.8-3.25 (m,
2H, (β)CH2-D-Phe); 4.0 (m, IH, CH-NH-3Ac5c); 4.25 (m, IH, CH-NH, 1,2 di-NH2-); 4.5
(m, IH, (α)CH -D-Phe); ); 7.1-7.25 (m, 5H, Car0m-D-Phe); 7.45-7.55 (m, 2H,
C(5)H+C(6)H); 7.6-7.75 (m, 3H, NHCH); 7.93-8.02 (m, 2H, C(4)H+C(7)H); 8.3 (s, IH,
C(3)H); 8.42 (s, IH, NH-lAc6c). MS-FAB: 658.30 (M+H)+
HPLC (method E): Rt = 12.5 min.
Example 26 acid-3-cis-Nγ{Nα[Nα(benzo[b]thiophen-2-ylcarbonyl)-l-aminocyclopentane-l-carboxy]-L- phenylalanil} aminocyclohexane-1 -carboxylic -N-(2-cis-aminocyclohexyl) amide Example 27
NΥ{Nα[Nα(benzo[b]thiophen-2-ylcarbonyl)-l-aminocyclohexane-l-carboxy]-D- phenylalanil} -(L-(4R)amino-proline-N-(lR,2R)-aminocyclohexyl) amide
MS-FAB: 659.20 (M+H)+
HPLC (method E): Rt = 11.4 min. Example 28 acid-3- cis-Nγ{Nα[Ηα(benzo[b]thiophen-2-ylcarbonyl)-l-aminocyclohexan-l-carboxy]-D- phenylalanil}-aminocyclohexan-l-carboxylic- -N-[(lS,2S)-2-aminocyclohexyl]amide
MS-FAB: 672.24 (M+H)+
HPLC (method E): Rt = 12.8 min. Example 29 acid-3-cis-Nγ{Nα[Nα(benzo[b]thiophen-2-ylcarbonyl)-l-aminocyclopentan-l-carboxy]-D- phenylalanil}aminocyclohexane-l-carboxylic-N-[(lS,2R)-2-dimethylaminocyclohexyl] amide _ _ . _ .
Example 30 acid-3-cis-Nγ{Nα| rα(benzo[b]thiophen-2-ylcarbonyl)- 1 -aminocyclopentane- 1 -carboxy] -D- phenylalanil}aminocyclohexane-l-carboxylic-N-[(lS,2R)-aminocyclohexyl] amide 1H-NMR (δ, DMSO-de): 1.2-1.9 (m, 24H, CH2); 2.2 (m, IH, CH-CO-3Ac6c); 2.80-3.20
(m, 2H, (β)CH2-D-Phe); 3.75 (m, IH, CH-NH 1,2 di-NH2-cyclohexane); 4.2 (m, IH, CH-
NH-3Ac6c); 4.45 (m, IH, (α)CH -D-Phe); 7.1-7.25 (m, 5H, Carom-D-Phe); 7.40-7.50 (m,
3H, C(5)H+C(6)H+ NHCH-3Ac6c); 7.60-7.70 (m, 4H, NHCH-l,2di-NH2-cyclohexane + NHs1"); 7.85 (IH, NHCH-D-Phe);7.90-8.02 (m, 2H, C(4)H+C(7)H); 8.25 (s, IH, C(3)H);
8.9 (s, 1H, NH-1AC5C).
MS-FAB: 658.35 (M+H)+
HPLC(method E): Rt = 12.0 min.
Example 31 acid-3 -cis-NY{Na[N(X(benzo[b]thiophen-2-ylcarbonyl)- 1 -aminocyclopentan- 1 -carboxy] -D- phenylalanil}aminocyclohexan-l-carboxylic-N-[(lS,2S)-aminocyclohexyl] amide
MS-FAB: 658.30 (M+H)+
HPLC(method E): Rt = 11.9 min.
Example 32 Nα[N (benzo[b]thiophen-2-ylcarbonyl)- 1 -aminocyclopentane- 1 -carboxy] -D-phenylalanina amide-N-[(l S,3R)-3-(4-(methyl)piperazin- 1 -yl)methyl)cyclopenthyl]
Example 33
Nα[Ηα(benzo[b]thiophen-2-ylcarbonyl)- 1 -aminocyclopentan-1 -carboxy]-D-phenylalanine amide-N-[(lS,3R)-3-(4-(methyl)piperazin-l-yl)carbonyl)cyclopentane Example 34
Nα[Nα(benzo[b]tWophen-2-ylcarbonyl)-D-α-methylphenylalam^]-D-phenylalanine-N-[3-
(morpholin-4-yl)propyl] amide
Example 35 acid-3-cis-Nα|^α(benzo[b]thiophen-2-ylcarbonyl)-l-aminocyclohexan-l-carboxy]-D- phenylalanil}aminocyclohexan-l-carboxylic -N-((lR,2S)-2-methylaminocyclohexyl)amide
Example 36
Nα[Nα enzo[b]thiophen-2-ylcarbonyl)-l-aminocyclopentan-l-carboxy]-D-phenylalanil}-
L-(4R)amino-proline-N-(-2-cis-aminocyclohexyl) amide
Example 37 (1 R,3 S) acid-3-Nγ{Nα| fα(benzo[b]thiophen-2-ylcarbonyl)- 1 -aminocyclopentan-1 - carboxy]-D-phenylalanil}aminocyclopentane-l-carboxylic-N-(2-cis- aminocyclohexyl)amide 1H-NMR (δ, DMSO-dg): 1.2-1.9 (m, 22H, CH2); 2.2 (m, IH, CH-CO-3Ac5c); 2.70-3.25
(m, 2H, (β)CH2-D-Phe): 4.0 (m, IH, CH-NH-3Ac5c); 4.2 (m, IH, CH-NH 1,2 di-NH2- cyclohexane_CH-NH-3Ac6c); 4.45 (m, IH, ( )CH-D-Phe)); 7.10-7.25 (m, 5H, Carom-D- Phe); 7.45-7.70 (m, 7H, C(5)H+C(6)H+ NHCH- 1,2 di-NH?-cvclohexane+ NHCH- 3Ac6c+ NHs' .δS (d, IH, NHCH-D-Phe);« 7.90-8.02 (m, 2H, C(4)H+C(7)H); 8.25 (s, IH,
C(3)H); 8.9 (s, IH, NH-lAc5c).
MS-FAB: 644.3 (M+H)+
HPLC(method E): Rt = 11.8 min.
Example 38 (1 S,3R)- 1 -N {Nα[Nα(benzo[b]thiophen-2-ylcarbonyl)- 1 -aminocyclopentan- 1 -carboxy]-D- phenylalanil}-3- {[1 S-((2S)-aminocyclohexyl)amino]methyl}amino cyclopentane
Example 39 acid-3-cis-N {Nα[Nα(benzo[b]thiophen-2-ylcarbonyl)- 1 -aminocyclopentan- 1 -carboxy]-D- phenylalanil} aminocyclohexan-l-carboxylic-N-((lR,2S)-2-dimethylaminocyclohexyl) amide
Example 40
( 1 R,3 S) acid-3 -N {Nα[Nα(benzo[b] thiophen-2-ylcarbonyl)- 1 -aminocyclohexan- 1 -carboxy] -
D-phenylalanil } aminocyclopentan- 1 -carboxylic-N-(( 1 R,2R)2-aminocyclohexyl) amide
Example-41- Biphenyl-4-carboxylic acid, {l-[l-(3-morpholin-4-yl-propylcarbamoyl)-2-(R)-phenyl- ethylcarbamoylj-cyclopentyl} -amide
Example 42
Benzofuran-2-carboxylic acid, {l-[l-(3-morpholin-4-yl-propylcarbamoyl)-2-(R)-phenyl- ethylcarbamoyl] -cyclopentyl } -amide Example 43
Benzo[b]thiophene-2-carboxylic acid, methyl- { 1 -[ 1 -(3-moφholin-4-yl-propylcarbamoyl)-
2(R)-phenyl-ethylcarbamoyl]-cyclohexyl}-amide
Example 44 l-[3-(3,4-(hchlorophenyl)-acryloylamino]-cyclopentanecarboxylic acid, [l-(3-morpholin- 4-yl-propylcarbamoyl)-2-(R)-phenyl-ethyl]-amide
Example 45 Benzo[b]thiophene-2-carboxylic acid { 1 -[ lR-(3-morpholin-4-yl-propylcarbamoyl)-2- phenyl-ethylcarbamoyl]-cyclopent-3-enyl}-amide
MS m/z: 561.3 (M+H*). HPLC (method C) Rt = 12.16 min.
Example 46 Benzo[b]thiophen-2-carboxylic acid, [l-(l-aminomethyl-2-(R)-phenyl-ethylcarbamoyl)- cyclohexyl] -amide
Example 47 l-Methyl-lH-indole-2-carboxylic acid, {l-[l-(3-morpholin-4-yl-propylcarbamoyl)-2-(R)- phenyl-ethylcarbamoyl]-cyclopentyl}-amide Example 48
Benzo[b]thiophene-2-carboxylic acid (1 - { 1 -[3-(2,6-dimethyl-morpholin-4-yl)- propylcarbamoyl]-2-(R)-phenyl-ethylcarbamoyl}-cyclohexyl)-amide
MS (m/z): 605.4 (MΗ*). ΗPLC (method B): Rt = 4.57 min.
Example 49 lH-indol-2-carboxylic acid, {l-[l-(3-morpholin-4-yl-propylcarbamoyl)-2-(R)-phenyl- efhylcarbamoyl]-cyclopentyl}-amide
Example 50
1 -[3-(3,4-dibromophenyl)-acryloylamino]-cyclopentanecarboxylic acid [ 1 -(3-morpholin-4- yl-propylcarbamoyl)-2-(R)-phenyl-ethyl]-amide Example 51
5-phenyl-thiophene-2-carboxylic acid, { 1 -[ 1 -(3-morpholin-4-yl-propylcarbamoyl)-2-(R)- phenyl-ethylcarbamoyl]-cyclopentyl}-amide
Example 52
Benzo[b]fhiophen-2-carboxylic acid, ( 1 - { 1 (R)-[3-(4-methyl-[ 1 ,4]diazepan- 1 -yl)- propylcarbamoyl]-2-phenylethyl carbamoyl}-cyclopentyl)-amide TFA salt.
52a) To a suspension of 1 -amino- 1-cyclopentancarboxylic acid (19.2 g, 149 mmol) in 500 ml of anhydrous CΗ2C12, is added, under magnetic stirring, N,O- bis(trimefhylsilyl)acetamide (BSA) (54 g, 268 mmol, containing 5% of TMSC1). After about 1 hour under stirring at room temperature, to this solution benzo[b]fhiophene-2- carbonylchloride (29.2 g, 149 mmol) dissolved in 200 ml of CH2C12 is added in about 2 hours; the reaction mixture is kept under stirring for further 3 hours. The solution is then evaporated under reduced pressure, and the residue is treated with 200 ml of aqueous K2CO3 5% for 15 min, then extracted with AcOEt (2 x 100 ml). The aqueous phase is then acidified with aqueous HCl 37% until complete precipitation of a white solid, which is extracted with AcOEt (2 x 200ml) and dried on anhydrous Na2SO4. The organic phase is filtered and evaporated, thus obtaining l-[(benzo[b]tMophene-2-carbonyl)-amino]- cyclopentanecarboxylic acid (38.7 g, 134 mmol). HPLC (method A): Rt = 3.51 min.
With analogous procedures the following intermediate products have also been obtained: l-[(6-Bromo-benzo[b]thiophene-2-carbonyl)-amino]-cyclopentanecarboxylic acid
HPLC (method A): Rt = 4.08 min. l-[(6-Bromo-naphmalene-2-carbonyl)-amino]-cyclopentanecarboxylic acid HPLC (method A): Rt = 4.03 min. l-(3-(E)-j!7-Tolyl-acryloylamino)-cyclopentanecarboxylic acid
HPLC (method A): Rt = 3.47 min.
1 -[(5-CWoro-berizofuran-2-carbonyl)-amino]-cyclopentanecarboxylic acid
HPLC (method A): Rt = 3.74 min. 52b) To a solution in anhydrous THF (500 ml) of the product coming from Example 52a)
(16 g, 55 mmol), EDC.HCl (12.7 g, 66 mmol) and diisopropylethylamine (30 ml) are added under magnetic stirring at room temperature. The reaction mixture is kept under stirring for 4 hours, then the solvent is evaporated to dryness, and the residue is dissolved in AcOEt (1000 ml) and washed with NaHCO3 10% (3 x 300 ml), citric acid 10% (3 x 300 ml), H2O (3 x 500 ml), then dried on Na2SO4 and brought to dryness, thus obtaining a whitish solid of 2-benzo[b]thiophen-2-yl-3-oxa-l-azaspiro[4.4]-non-l-en-4-one (13 g, 47.9 mmol).
HPLC (A): Rt = 4.97 min.
With analogous procedures the following intermediate products have also been obtained: 2-(6-Bromo-benzo[b]thiophen-2-yl)-3-oxa-l-aza-spiro[4.4]-non-l-en-4-one,
HPLCfmethod A): Rt = 5.55 min.
2-(6-Bromo-naphthalen-2-yl)-3-oxa-l-aza-spiro[4.4]-non-l-en-4-one, HPLC (method A):
Rt = 5.65 min.
2-(5-Chloro-berιzofuran-2-yl)-3-oxa-l-aza-spiro[4.4]non-l-en-4-one, HPLC (method A): Rt = 4.97 min.
52c) To a solution in anhydrous DMF (100 ml) of Z-D-phenylalanine (5 g, 16.7 mmol)
HOBt (2.34 g, 17.6 mmol) and EDC.HCl (8.73 g, 17.55 mmol) are added under magnetic stirring. After 30 min 3-aminopropanol (1.25 g, 16.72 mmol) dissolved in DMF (60 ml) is added to the solution, and the reaction mixture is kept at room temperature for 12 hours. The mixture is then diluted with AcOEt (200 ml) and extracted with KHSO4 (5% solution, 200 ml) and with NaHCO3 (saturated solution, 200 ml). The organic phase, dried on Na2SO , filtered and brought to dryness, is then washed with ethyl ether and the white solid in suspension is filtered to give the desired product (5.15 g, 14.5 mmol). HPLC (method B): Rt = 3.48 min.
The product coming from the previous reaction, is deprotected by hydrogenation (H2, Pd/C 10%) according to a procedure known to any person skilled in the art, to give a white solid of 2(R)-amino-N-(3-hydroxypropyl)-3-phenyl-propionamide (2.91 g, 14.5 mmol), which is used directly in the subsequent reaction.
52d) To the product coming from step 52b) (1 g, 3.7 mmol) dissolved in anhydrous DMF (40 ml), the intermediate described in 53c) (1.11 g, 5.6 mmol) is added, and the reaction is kept at room temperature under magnetic stirring for 24 hours. Then the mixture is diluted with AcOEt (150 ml) and the organic phase is washed with distilled water (3 x 50 ml) and a saturated solution of ΝaHCO3 (2 x 50 ml), then dried on anhydrous Na2SO4 and brought to dryness to give a white solid of benzo[b]thiophene-2-carboxylic acid {l-[l(R)-(3- hydroxypropylcarbamoyl)-2-phenyl-ethylcarbamoyl]-cyclopentyl} -amide (1.51 g, 3 mmol). HPLC (method A): Rt = 3.73 min. 52e) The so obtained product (1.2 g, 2.44 mmol), without further purification, is dissolved in AcOEt (30 ml). To this solution, maintained at 0° C with an ice bath, an aqueous solution of NaBr (0.5 M, 5.35 ml, 2.68 mmol), 2,2,6,6-tetramethyl-l-piperidinyloxy (TEMPO, 3.4 mg, 0.022 mmol) is added and, drop by drop, aqueous NaCIO (1.83 M, 1.55 ml). The biphasic mixture is kept at 0°C under stirring for further 20 min, then the organic phase is separated and the aqueous phase is extracted with AcOEt (20 ml). The organic fractions are collected and washed with a buffered solution of KI (20 ml), 10% solution of Na2S2O3 (20 ml) and NaHCO3 (5%, 20 ml); they are then dried and evaporated to give a product, which is purified by flash chromatography (EtOAc/hexane, 80/20) to yield 0.82 g of a white solid of 4-[2(R)-({l-[(Benzo[b]tluophene-2-carbonyl)-amino]- cyclopentanecarbonyl} -amino)-3-phenyl-propionylamino]-propanal. HPLC (method B): Rt = 3.99 min. The so obtained aldehyde (100 mg, 0.203 mmol) is dissolved in methanol (5 ml) and added with l-methyl-[l,4]diazepan (115 mg, 1.01 mmol) and glacial acetic acid (0.2 ml). After the solution has been stirred for 15 min, Na(CN)BH3 (20 mg, 0.32 mmol) is added to the solution. After 12 hours the solvent is evaporated under reduced pressure and the raw product is dissolved in HCl IM. The acid extract is washed with AcOEt (10 ml) and brought up to alkaline pH by adding solid NaHCO3, then it is extracted with AcOEt (2 x 25 ml). The organic phase is evaporated, then purified by means of preparative HPLC (colonna: Combi HT™ (SB C18, 5μm, lOOA, 21 x 50 mm), Method: H2O+0.1%TFA/ MeCN+0.1% TFA, 95/5>5/95 in 10 min, flow = 40 ml/min, λ=220, 270 nm) to yield benzo[b]thiophene-2-carboxylic acid (l-{l-[3-(4-methyl-[l,4]diazepan-l-yl)- propylcarbamoyl]-2-(R)-phenylethylcarbamoyl}-cyclopentyl)-amide TFA salt (40 mg, 0.067 mmol). MS (m/z): 590.5 (MH÷). HPLC (method A): Rt = 3.05 min. With analogous methods the following products have also been prepared: Example 53 Benzo "b]thiophene-2-carboxylic acid (l-{l(R)-[3-(4-methoxy-piperidin-l-yl)- propylcarbamoyl]-2-phenyl-ethylcarbamoyl}-cyclopentyl)-amide TFA salt MS (m/z): 591.3 (MH+). HPLC (method A): Rt = 3.64 min. Example 54 Benzo[b]thiophene-2-carboxylic acid ( 1 - { 1 -(R)-[3-(4-hydroxy-piperidin- 1 -yl)- propylcarbamoyl]-2-phenylethyl carbamoyl}-cyclopentyl)-amide. MS (m/z): 577.3 (MH*). HPLC (method A): Rt = 3.31 min. Example 55
Benzo[b]thiophene-2-carboxylic acid (1- { 1 (R)-[3-(l ,4-dioxa-8-aza-spiro[4.5]dec-8-yl)- propylcarbamoyl]-2-phenyl-ethylcarbamoyl}-cyclopentyl)-amide TFA salt MS (m/z): 619.3 (MH+). HPLC (method A): Rt = 3.68 min. Example 56
Benzo[b]thiophene-2-carboxylic acid (1 - { 1 (R)-[3-(3,5-c/5'-dimethylpiperazin-l-yl)-3-oxo- propylcarbamoyl]-2-phenyl-ethylcarbamoyl}-cyclopentyl)-amide TFA salt 56a) Boc-D-phenylalanine O-succinimidoester (5 g, 16.56 mmol) is dissolved in CH3CN (60 ml) and added to a solution of β-alanine (2.08 g, 16.56 mmol) and TEA (4.61 ml) in 60 ml of water. After 30' min the orgamc solvent is evaporated and the aqueous residue, acidified by adding HCl, is extracted with AcOEt (3 x 100 ml). The orgamc extract is washed with water, dried and brought to dryness to give a colourless oil (4.19 g, 12.08 mmol). HPLC (B): Rt = 3.19 min.
The so obtained product is deprotected under standard conditions (HCl, dioxane) and the so obtained amine (2.9 g, 12 mmol) is used, without further purification steps, in the reaction with the mtrmediate product described in Example 52b), in the presence of stoichiometric DiPEA, in the conditions above described, to yield 3-[2(R)-({l-
[(Benzo[b]thiophene-2-carbonyl)-amino]-cyclopentanecarbonyl}-amino)-3-phenyl- propionylamino]-propionic acid (5.17 g, 10.2 mmol). HPLC (B): Rt = 3.98 min.
56b) The so obtained acid (100 mg, 0.2 mmol) is caused to react with 2,6-cis- dimethylpiperazine by a standard method for the formation of the amidic bond (EDC,
HOBt, CH2C12). The raw product of the reaction is purified by preparative HPLC (same conditions of Example 52) to yield benzo[b]thiophene-2-carboxylic acid (l-{l(R)-[3-(3,5- cw-dimethyl-piperazin- 1 -yl)-3 -oxo-propylcarbamoyl] -2-phenyl-ethylcarbamoyl} - cyclopentyl)-amide TFA salt (25 mg, 0.035 mmol). MS (m/z): 604.2 (MH+). HPLC (method A): Rt = 3.36 min.
With analogous methods, starting from suitable intermediate products as described in
Example 52b) and using the obtained suitable amines when necessary, the following products have been prepared according to methods known to the skilled person:
Example 57 Benzo[b]thiophene-2-carboxylic acid (l-{l(R)-[3-oxo-3-(4-pyridin-2-yl-piperazin-l-yl)- propylcarbamoyl]-2-phenyl-efhylcarbamoyl}-cyclopentyl)-amide
MS (m/z): 653.3 (MH+). HPLC (method A): Rt = 3.40 min.
Example 58
6-Bromo-naphthalene-2-carboxylic acid (1 - { 1 (R)-[3-oxo-3-(4-pyridin-2-yl-piperazin-l- yl)-propylcarbamoyl]-2-phenyl-ethylcarbamoyl}-cyclopentyl)-amide TFA salt
MS (m/z): 725 (MH"1", monoisotopic). HPLC (method A): Rt = 3.76 min.
Example 59
6-Bromo-benzo[b]thiophene-2-carboxylic acid (l-{l(R)-[3-oxo-3-(4-pyridin-2-yl- piperazin-l-yl)-propylcarbamoyl]-2-phenyl-ethylcarbamoyl}-cyclopentyl)-amide 7 MS (m/z): 731 (MH4", monoisotopic). HPLC (method A): Rt = 3.73 min.
Example 60 Benzo[b]thiophene-2-carboxylic acid [l-(l(R)-{3-oxo-3-[4-(tetrahydro-pyran-4-ylmethyl)- piperazm-l-yl]-propylcarbamoyl}-2-phenyl-ethylcarbamoyl)-cyclopentyl]-amide TFA salt
MS (m/z): 674.2 (MH4). HPLC (method A): Rt = 3.43 min.
Example 61 Benzo[b]thiophene-2-carboxylic acid [l-(l(R)-{3-oxo-3-[4-(tetrahydro-pyran-4-yl)- piperazin-l-yl]-propylcarbamoyl}-2-phenyl-ethylcarbamoyl)-cyclopentyl]-amide TFA salt
MS (m/z): 660.3 (MH1). HPLC (method A): Rt = 3.40 min.
Example 62
Benzo[b]thiophene-2-carboxylic acid (1 - { 1 (R)-[3-(4-[ 1 ,3]dioxan-5-ylmethyl-piperazin- 1 - yl)-3-oxo-propylcarbamoyl]-2-phenyl-ethylcarbamoyl}-cyclopentyl)-amide TFA salt
MS (m/z): 676.2 (MH*). HPLC (method A): Rt = 3.43 min.
Example 63
Benzo[b]thiophene-2-carboxylic acid [ 1 -( 1 (R)- { [ 1 -( 1 -amino-cyclopentanecarbonyl)- piperidin-4-ylmethyl]-carbamoyl}-2-phenyl-ethylcarbamoyl)-cyclopentyl]-amide MS (m/z): 644.3 (MH4). HPLC (method A): Rt = 3.55 min.
Example 64
Benzo[b]thiophene-2-carboxylic acid [1 -(1 (R)- {3-oxo-3-[4-(tetrahydro-furan-2(R)- ylmethyl)-piperazin- 1 -yl]-propylcarbamoyl} -2-phenyl-ethylcarbamoyl)-cyclopentyl]- amide TFA salt MS (m/z): 660.2 (MH"). HPLC (method A): Rt = 3.68 min.
Example 65
Benzo[b]thiophene-2-carboxylic acid (1 - { 1 (R)-[3-(4-cyanomethyl-piperazin- 1 -yl)-3-oxo- propylcarbamoyl]-2-phenyl-ethylcarbamoyl}-cyclopentyl)-amide
MS (m/z): 615.1 (MH"1). HPLC (method A): Rt = 3.79 min. Example 66
Benzo[b]thiophene-2-carboxylic acid { 1 -[2-phenyl-l (R)-( 1 -pyridin-2-ylmethyl-piperidin-
4-ylcarbamoyl)-ethylcarbamoyl]-cyclopentyl} -amide TFA salt.
66a) Z-D-phenylalanina (3.28 g, 11 mmol) is caused to react with N-Boc-(4- amino)piperidine hydrochloride (2.6 g, 11 mmol) under the usual conditions for peptidic coupling (HOBt, EDC, DIPEA, CH2C12) as described in Example 56b). The so obtained adduct (5 g, 10.3 mmol), after a simple extractive processing, is hydrogenated in the presence of Pd/C as the catalyst, so to obtain 4-(2(R)-ammo-3-phenyl-propionylamino)- piperidine-1 -carboxylic acid tert-butyl ester (3.21g, 9.27 mmol). HPLC (method B): Rt = 3.22 min.
With analogous procedures the following intermidiates have also been obtained: 4-[(2(R)-amino-3-phenyl-propionylarnino)-methyl]-piperidine-l-carboxylic acid tert-butyl ester
4-[2-(2(R)-amino-3-phenyl-propionylamino)-ethyl]-piperidine-l-carboxylic acid tert-butyl ester (in this case, the N-Boc-(4-aminoethyl)piperidine obtained starting from the corresponding alcohol by obvious reaction for a skilled person, has been used). 66b) II composto ottenuto nell'Example 66a) (1.69 g, 4.87 mmol) viene fatto reagire in DMF a temperatura ambiente per 24 ore con l'ossazolinone descritto nell'Example 52b) (1.29 g, 4.8 mmol). L'intermedio cosi ottenuto (2.9 g, 4.7 mmol, HPLC (B): Rt = 4.85 min), dopo semplice lavorazione estrattiva, e deprotetto per reazione con TFA in CH2C12, a dare benzo[b]thiophene-2-carboxylic acid {1 -[2-phenyl- l(R)-(piperichn-4-ylcarbamoyl)- ethylcarbamoyl]-cyclopentyl}-amide TFA salt. MS (m/z): 519.2 (MH+). HPLC (method A): Rt = 3.29 min.
With analogous methods the following compounds have been prepared: benzo[b]thiophene-2-carboxylic acid (1 - {2-phenyl- 1 (R)-[(piperidin-4-yl-methyl)- carbamoyl]-ethylcarbamoyl}-cyclopentyl)-amide TFA salt MS (m/z): 533.3 (MIT). HPLC (method A): Rt = 3.29 min. benzo[b]thiophene-2-carboxylic acid {1 -[2-phenyl- l(R)-(2-piperidin-4-yl-ethyl carbamoyl)
-ethylcarbamoyl]-cyclopentyl} -amide TFA salt
MS (m/z): 547.3 (MH4). HPLC (method A): Rt = 3.39 min.
66c) 200 mg (0.31 mmol) of benzo[b]thiophene-2-carboxylic acid { 1 -[2-phenyl- 1(R)- (piperidin-4-ylcarbamoyl)-ethylcarbamoyl]-cyclopentyl} -amide are used for the reaction of reductive amination with pyridine 2-carboxaldehyde (64 mg, 0.6 mmol), to yield, after purification by preparative HPLC according to the method already described in the previous Examples, the desired product benzo[b]thiophene-2-carboxylic acid {l-[2- phenyl- 1 (R)-(l -pyridin-2-ylmethyl-piperidin-4-ylcarbamoyl)-ethylcarbamoyl]- cyclopentyl} -amide TFA salt (120 mg, 0.16 mmol).
MS (m/z): 610.3 (MH4). HPLC (method A): Rt = 3.58 min. In analogy to what described in Example 66c), the reaction in DMF, at room temperature and for times ranging from 12 to 48 hours, of the intermediate products described in Example 66a) with oxazolinones described in Example 52b), and the reaction of the intermediate products described in Example 66a) with l-(3-(E)-_r>-Tolyl-acryloylamino)- cyclopentanecarboxylic acid described in Example 52a) under conditions of peptidic coupling, gives, after deprotection of the amino groups, intermediates analogous to those described in Example 66b). Such intermediates are alkylated under conditions which are widely reported in the literature and well known to any person skilled in the art, such as:
- aldehyde or ketone, cyanoborohydride supported on resine in anhydrous CH2C12 - aldehyde or ketone, Na(AcO)3BH, in CH2C12 or THF
- alkyl halide, KI, DiPEA in DMF, or under the conditions described abovein Example 52d).
With the synthetic procedure described in Example 66 the following products have been prepared: Example 67
Benzo[b]thiophene-2-carboxylic acid (1 - {2-phenyl- 1 (R)-[ 1 -(tetrahydro-pyran-4-ylmethyl)- piperidin-4-ylcarbamoyl]-ethylcarbamoyl}-cyclopentyl)-amide TFA salt
MS (m/z): 617.3 (MH4). HPLC (method A): Rt = 3.44 min.
Example 68 Benzo[b]thiophene-2 -carboxylic acid [ 1 -(2-phenyl- 1(R)-{1 -[2-(tetrahydro-pyran-4-yl)- ethyl]-piperidin-4-ylcarbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide TFA salt
MS (m/z): 631.3 (MH4). HPLC (method A): Rt = 3.57 min.
Example 69
6-Bromo-benzo[b]thiophene-2-carboxylic acid [ 1 -(2-phenyl- 1 (R)- { [ 1 -(tetrahydro-pyran-4- ylmemyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide TFA salt
MS (m/z): 709 (MH4, isotopic pattern of Br). HPLC (method A): Rt = 3.82 min.
1H NMR (400 MHz): (δ, DMSO-d6) 1.12-2.13 (m, 17 H); 2.17-2.30 (m, IH); 2.74-3.00
(m, 5H), 3.02-3.38 (m, 5H); 3.44-3.57 (m, 2H); 3.80-3.93 (m, 2H); 4.39-4.50 (m, IH); 7.11-7.24 (m, 5H); 7.55-7.66 (m, 2H); 7.85-7.92 (m, IH); 7.93-7.98 (m, IH); 8.30 (s, IH);
8.34-8.38 (m, IH); 8.97 (s, IH); 8.78 and 9.01 (2 broad signal, IH total).
Example 70 Benzo[b]thiophene-2-carboxylic acid (1 - { 1 -(R)-[(l -isopropyl-piperidin-4-ylmethyl)- carbamoyl]-2-phenyl-ethylcarbamoyl}-cyclopentyl)-amide
MS (m/z): 575.3 (MH4). HPLC (method A): Rt = 3.56 min.
Example 71 Benzo[b]thiophene-2-carboxylic acid [l-(2-phenyl-l(R)-{[l-(tetrahydro-pyran-4- ylmethyl)-ρiperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
MS (m/z): 631.3 (MH4). HPLC (method A)= Rt = 3.51 min.
1H NMR (500 MHz): (δ, DMSO-d6) amongst the others 0.99-1.14 (m, 4H); 2.18-2.29 (m,
IH), 2.65-2.75 (m, 2H); 2.78-3.02 (m, 3H); 3.75-3.85 (m, 2H); 4.41-4.50 (m, IH); 7.09- 7.23 (m, 5H); 7.43-7.52 (m, 3H); 7.86 (d, IH, J=8.6); 7.94-8.07 (m, 2H); 8.30 (s, IH); 8.89
(s, IH).
Example 72
6-Bromo-naphthalene-2-carboxylic acid [ 1 -(2-phenyl- 1 (R)- {[1 -(tetrahydro-pyran-4- ylme yl)-piperidin-4-ylme yl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide MS (m/z): 703.3 (MH4, isotopic pattern of Br). HPLC (method A): Rt = 3.88 min.
1H NMR (600 MHz): (δ, DMSO-d6) 0.90-1.11 (m, 4H); 1.18-1.29 (m, IH); 1.38-1.73 (m,
12H); 1.74-1.82 (m, IH); 1.87-1.91 (m, 2H); 1.92-1.99 (m, IH); 2.27-2.34 (m, IH); 2.50-
2.56 (m, 2H); 2.81-2.89 (m, 2H); 2.94-3.02 (m, IH); 3.16-3.28 (m, 3H); 3.75-3.83 (m, 2H);
4.44-4.50 (m, IH); 7.11-7.21 (m, 5H); 7.46 ft, IH, J=5.77 Hz); 7.71-7.75 (m, IH); 7.82(d, IH, J=8.65 Hz); 7.98-8.04 (m, 3H); 8.29-8.31 (m, IH); 8.53 (s, IH); 8.83 (s, IH).
Example 73
Benzo[b]thiophene-2-carboxylic acid [ 1 -(2-phenyl- 1 (R)- { [ 1 -(tetrahydro-pyran-4-yl)- piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
MS (m/z): 614.4 (MH4). HPLC (method A): Rt = 3.46 min. Example 74
1 -(3-E-J -Tolyl-acryloylamino)-cyclopentanecarboxylic acid (2-phenyl- 1 (R)- {[ 1 -
(tetrahydro-pyran-4-ylmethyl)-ρiperidin-4-ylmethyl]-carbamoyl} -ethyl)-amide TFA salt
MS (m/z): 615.4 (MH4). HPLC (method A): Rt = 3.56 min.
1H NMR (400 MHz): (δ, DMSO-d6) amongst the others 1.13-1.25 (m, 2H); 2.15-2.23 (m, IH); 2.34 (s, 3H); 3.80-3.87 (m, 2H); 4.36-4.44 (2 m, IH total); 6.68 and 6.69 (2 d, IH total J=15.81 for both); 7.13-7.30 (m, 7H); 7.375 and 7.38 (2 d, 1 H total, J=15.81 for both); 7.45-7.51 (m, 2H); 7.66 and 7.73 (2 1, 1 H total, J=5.8 Hz for both); 7.82 and 7.83 (2 d, IH total, J=8.67 for both); 8.54 and 8.55 (2 s, IH total); 8.80 and 8,97 (2 broad signal,
IH total).
Example 75
Benzo[b]thiophene-2-carboxylic acid [ 1 -(2-phenyl- 1 (R)- {2-[ 1 -(tetrahydro-pyran-4- ylmethyl)-piperidin-4-yl]-ethylcarbamoyl} -ethylcarbamoyl)-cyclopentyl]-amideTFA salt
MS (m/z): 645.5 (MH4). HPLC (method A): Rt = 3.63 min.
Example 76
6-Bromo-naphthalene-2-carboxylic acid ( 1 - { 1 (R)- [(1 -ethyl-piperidin-4-ylmethyl)- carbamoyl] -2-phenyl-ethylcarbamoyl } -cyclopentyl)-amide MS (m/z): 633.4 (MH4, con isotopic pattern of Br). HPLC (method A): Rt = 3.86 min.
Example 77
Benzo[b]thiophene-2-carboxylic acid [ 1 -(2-phenyl- 1 (R)- {2-[ 1 -(tetrahydro-pyran-4-yl)- piperidin-4-yl]-ethylcarbamoyl}-ethylcarbamoyl)-cyclopentyl]-amideTFA salt
MS (m/z): 631.4 (MH4). HPLC (method A): Rt = 3.53 min. Example 78
Benzo[b]thiophene-2-carboxylic acid { 1 -[2-phenyl- 1 (R)-( { 1 -[2-(tetrahydro-pyran-4-yl)- emyl]-piperidin-4-ylme yl}-carbamoyl)-emylcarbamoyl]-cyclopentyl}-amide
MS (m/z): 645.3 (MH4). HPLC (method A): Rt = 3.61 min.
Example 79 Benzo[b]thiophene-2-carboxylic acid (l-{l(R)-[(l-cyclohexylmethyl-piperidin-4- ylmethyl)-carbamoyl]-2-phenyl-ethylcarbamoyl}-cyclopentyl)-amide
MS (m/z): 629.3 (MH4). HPLC (method A): Rt = 4.11 min.
Example 80
6-Bromo-naphthalene-2-carboxylic acid [ 1 -(2-phenyl- 1 (R)- { [ 1 -(tetrahydro-pyran-4-yl)- piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
MS (m/z): 689.3 (MH , isotopic pattern of Br). HPLC (method A): Rt = 3.83 min.
Example 81
Benzo[b]thiophene-2-carboxylic acid [ 1 -(2-phenyl- 1 (R)- { [ 1 -(tetrahydro-thiopyran-4-yl)- piperidin-4-ylmethyl] -carbamoyl } -ethyϊcarbamoyl)-cyclopentyl] -amide TFA salt MS (m/z): 633.5 (MH4). HPLC (method A): Rt = 3.79 min.
Example 82 Benzo[b]thiophene-2-carboxylic acid [1 -(2-phenyl- 1(R)-{[1 -(tetrahydro-thiopyran-4- ylmethyl)-piperidn-4-ylmemyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide MS (m/z): 647.3 (MH4). HPLC (method A): Rt = 3.91 min. Example 83 l-((E)-3- -Tolyl-acryloylamino)-cyclopentanecarboxylic acid {2-phenyl- 1(R)-[(1- thiophen-2-ylmethyl-piperidin-4-ylmethyl)-carbamoyl]-ethyl} -amide TFA salt MS (m/z): 613.3 (MH4). HPLC (method A): Rt = 3.82 min. Example 84
6-Bromo-naphthalene-2-carboxylic acid (1 - {2-phenyl-l (R)-[2-(l -pyrrolidin-2(S)- ylmethyl-piperidin-4-yl)-ethylcarbamoyl]-ethylcarbamoyl}-cyclopentyl)-amide TFA salt MS (m/z): 702 (MH4, isotopic pattern of Br). HPLC (method A): Rt = 3.55 min. Example 85
6-Bromo-naphthalene-2-carboxylic acid (1 - {2-phenyl- 1 (R)-[(piperidin-4-ylmethyl)- carbamoyl]-ethylcarbamoyl} -cyclopentyl)-amide MS (m/z): 605 (MH , isotopic pattern of Br). HPLC (method A): Rt = 3.71 min. Example 86
1 -(3 -_z?-Tolyl-acryloylamino)-cyclopentanecarboxylic acid (2-phenyl- 1 (R)- {2-[ 1 - (tefrahydro-pyran-4-ylmemyl)-piperidin-4-yl]-ethylcarbamoyl}-ethyl)-amide TFA salt MS (m/z): 628.4 (MH4). HPLC (method A): Rt = 3.60 min. Example 87
Benzo[b]thiophene-2-carboxylic acid ( 1 - { 1 (R)-[2-(l -cyanomethyl-piperidin-4-yl)- ethylcarbamoyl]-2-phenyl-ethylcarbamoyl} -cyclopentyl)-amide TFA salt MS (m/z): 586.3 (MH4). HPLC (method A): Rt = 3.60 min. Example 88 Benzo[b]thiophene-2-carboxylic acid (l-{l(R)-[(l-[l,3]dioxan-5-ylmethyl-piperidin-4- ylmethyl)-carbamoyl]-2-phenyl-ethylcarbamoyl}-cyclopentyl)-amide TFA salt MS (m/z): 633.3 (MH4). HPLC (method A): Rt = 3.50 min. Example 89
6-Bromo-naphthalene-2-carboxylic acid (l-{l(R)-[(ϊ-[l,3]dioxan-5-ylmethyl-piperidin-4 ylmethyl)-carbamoyl]-2-phenyl-ethylcarbamoyl}-cyclopentyl)-amide
MS (m/z): 705.3 (MH4, isotopic pattern of Br). HPLC (method A): Rt = 3.62 min. Example 90 Benzo[b]thiophene-2-carboxylic acid (1 - { 1 (R)-[(l -[ 1 ,3]dioxan-2-ylmethyl-piperidin-4- ylmethyl)-carbamoyl]-2-phenyl-ethylcarbamoyl}-cyclopentyl)-amide MS (m/z): 633.4 (MH4). HPLC (method A): Rt = 3.66 min. Example 91 5-Chloro-benzofuran-2-carboxylic acid (l-{l(R)-[(l-[l,3]dioxan-5-ylmethyl-piperidin-4- ylmethyl)-carbamoyl]-2-phenyl-ethylcarbamoyl}-cyclopentyl)-amide MS (m/z): 651.3 (MH , isotopic pattern of CI). HPLC (method A): Rt = 3.73 min. Example 92 5-Chloro-benzofuran-2-carboxylic acid [ 1 -(2-phenyl- 1 (R)- {[ 1 -(tetrahydro-pyran-4-yl)- piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
MS (m/z): 635.3 (MH4, isotopic pattern of CI). HPLC (method A): Rt = 3.70 min. Example 93
5-Chloro-benzofuran-2-carboxylic acid [ 1 -(2-phenyl- 1 (R)- { [ 1 -(tetrahydro-thiopyran-4- yl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide MS (m/z): 651.3 (MH4, isotopic pattern of CI). HPLC (method A): Rt = 3.98 min. Example 94
Benzo[b]thiophene-2-carboxylic acid [ 1 -(1 (R)-benzyl-2- {2-[ 1 -(thiophen-2-yl-acetyl)- piperidin-4-yl]-ethylamino}-ethylcarbamoyl)-cyclopentyl]-amide TFA salt 94a) 1 -trityl-2-(R)-benzyl- 1 ,2-ethylendiamine. To a suspension of 24 g of D-phenylalaninamide in DMF (200 ml) 41.0 g di trityl chloride are added under stirring at room temperature and, after 1 hour, 80 ml of TEA diluted in 100 ml of DMF are also added. Stirring is maintained for 10 hours, then the solvent is evaporated, the residue is dissolved in ethyl acetate and washed with NaCl aq. 10%, citric acid aq. 10% and again with NaCl aq. 10%. After drying and evaporation, the residue is then dissolved in 200 ml of DMF. To th eso obtained solution 2000 ml of distilled water are added drop by drop. A precipitate is obtained, which is first brought to dryness then dissolved in 200 ml of THF and this solution is added, drop by drop, in 20 min at 0°C, under stirring and under nitrogen atmosphere, to a solution of 400 ml of LiAlEU 0.62 M in THF. The mixture is heated and maintained under reflux for 4 hours. After the mixture has been brought to 0°C, 15 ml of distilled water, 15 ml of NaOH aq. 15% and 45 ml of water are added in this order. By filtration of the so obtained precipitate, l-trityl-2-(R)-benzyl- 1,2-ethylendiamine is obtained. 94b) To a solution of l-trityl-2-(R)-benzyl-l,2-ethylendiamine coming from Example 94a) (21.6 g, 55 mmol) in anhydrous CH2C12 (300 ml) and TEA (8.4 ml, 60.5 mmol) maintained at 0°C, 2-nitrobenzensolphonylchloride (12.2 g, 55 mmol) is added in small portions. Once the addition is over, the mixture is kept under stirring at room temperature for 4 hours more, then it is washed with NaCl aq. 15% (150 ml), NaHCO3 aq. 5% (150 ml) and again with NaCl aq. 15% (150 ml). The organic phase dried and evaporated at reduced temperature yield a solid product, which is then dissolved in 150 ml of CH3CN, cooled at 0°C and treated with an excess of HCl in dioxane. After 2 hours at room temperature the solvent is evaporated to dryness, and the solid residue is dissolved in ethyl ether and filtered to yield a white solid of N-(2(R)-Amino-3-phenyl-propyl)-2-nitro- benzenesulphonamide hydrochloride. HPLC (method A): Rt = 2.70 min.
94c) The oxazolinone described in Example 52b) (407 mg, 1.5 mmol) and the intermediate 94b) described above (670 mg, 1.5 mmol) are dissolved in DMF (8 ml), added with TEA (0.64 ml, 4.5 mmol) and maintained at 80°C under stirring for 2 hours. The residue obtained from evaporation of the solvent is dissolved with AcOEt (30 ml) and washed with HCl IM (10 ml), ΝaHCO3 (5%, 10 ml), and NaCl aq. 15% (10 ml). The so obtained raw product is purified by flash chromatography (AcOEt/hexane 1/1) to give 0.5 g (0.8 mmol) of the intermediate benzo[b]thiophene-2-carboxylic acid {l-[l(R)-benzyl-2-(2-nitro- benzenesulphonylamino)-ethylcarbamoyl] -cyclopentyl } -amide. HPLC (method B): 4.74 min.
94d) 1.2 g (3.36 mmol, 3 mmol/g of loading) of triphenylphosphinic resin are maintained to swell for 30 min in CH2C12 (25 ml) under balancing stirring; to the suspension the intermediate described in Example 94c) (0.5 g, 0.84 mmol), N-Boc-4-hydroxyethyl- piperidine (600 mg, 2.52 mmol) and tert-butyl-diazodicarboxylate (600 mg, 2.52 mmol) are added. After 16 hours under stirring the resin is removed by filtration and the solution is brought to small volume (10 ml). 5 ml of trifluoroacetic acid are added under stirring. After 1 hour the solution is brought to dryness, the residue is dissolved with AcOEt (30 ml) and the solution washed with Na2CO3 aq. 5% (15 ml) e NaCl aq. 15% (10 ml), dried and evaporated. Benzo[b]thiophene-2-carboxylic acid (l-{l(R)-benzyl-2-[(2-nitro- benzenesulphonyl)-(2-piperidin-4-yl-emyl)-amino]-ethylcarbamoyl}-cyclopentyl)-amide is obtained as a foamy solid (553 mg, 0.77 mmol). HPLC (method A): Rt = 4.20 min
95e) The product coming from the previous step (60 mg, 0,084 mmol) is dissolved in CH2C12 (2 ml) and to this solution 60 μl of TEA and 13.5 μl of thiophen-2-yl-acethyl chloride are added. The magnetic stirring is maintained for 12 hours, then the solvent is evaporated and the residue, dissolved with AcOEt (10 ml), is washed with Na2CO3 aq. 5% (2 x 5 ml). The raw product obtained from evaporation of the solvent (60 mg, 0.07 mmol), is dissolved in DMF (3 ml) and treated with diazabicycloundecene (DBU, 32 mg, 0.21 mmol) and 2-mercaptoefhanol (17 mg, 0.21 mmol) for 12 hours. The residue obtained from evaporation of the solvent at reduced pressure is washed with ethyl ether and purified by preparative HPLC yielding 10 mg (0.013 mmol) of benzo[b]thiophene-2-carboxylic acid [ 1 -(1 (R)-benzyl-2- {2-[ 1 -(thiophen-2-yl-acetyl)-piperidin-4-yl]-ethylamino} - ethylcarbamoyl)-cyclopentyl]-amide TFA salt as white lyophilic product. MS (m/z): 657.3 (MH4). HPLC (method A): Rt = 4.12 min. Example 95 Benzo[b]thiophene-2-carboxylic acid [l-(l(R)-{2-[(l-amino-cyclohexanecarbonyl)- amino]-ethylcarbamoyl}-2-phenyl-ethylcarbamoyl)-cyclopentyl]-amide [2-(2(R)-Amino-3-phenyl-propionylamino)-ethyl]-carbamic acid tert-butyl ester (200 mg, 0.65 mmol), obtained by coupling of N-Boc-ethylendiamine and Z-D-phenylalanine succinimidoester followed by hydrogenation, is added to a solution of 2-benzo[b]thiophen- 2-yl-3-oxa-l-azaspiro[4.4]-noή-l-en-4-one (176 mg, 0.65 mmol) in DMF and maintained under magnetic stirring at room temperature for 48 hours. The so obtained product is deprotected (HCl, dioxane), acylated with 1-Boc-amino-l-cyclohexancarboxylic acid (156 mg, 0.65 mmol), by standard activation as described above, then again deprotected (HCl, dioxane). The raw product obtained from extractive work up is purified by flash chromatography (eluent: CHCl3/MeOH 9:1) to give benzo[b]thiophene-2-carboxylic acid [ 1 -( 1 (R)- {2-[( 1 -amino-cyclohexanecarbonyl)-amino]-ethylcarbamoyl } -2-phenyl- ethylcarbamoyl)-cyclopentyl]-amide (160 mg, 0.27 mmol). MS (m/z): 604.3 (MH4). HPLC (method A): Rt = 3.58 min. With analogous methods the following products have been prepared: Example 96
Benzo[b]thiophene-2-carboxylic acid [ 1 -( 1 (R)- { [ 1 -( 1 -amino-cyclohexanecarbonyl)- piperidin-4-ylmethyl]-carbamoyl}-2-phenyl-ethylcarbamoyl)-cyclopentyl]-amide TFA salt MS (m/z): 658.3 (MH4). HPLC (method A): Rt = 3.62 min. Example 97
6-Bromo-naphthalene-2-carboxylic acid [ 1 -( 1 (R)- { [ 1 -(1 -amino-cyclohexanecarbonyl)- piperidin-4-ylmethyl]-carbamoyl}-2-phenyl-ethylcarbamoyl)-cyclopentyl]-amide MS (m/z): 730.2 (MH4, isotopic pattern of Br). HPLC (method A): Rt = 4.00 min. Example 98
6-Bromo-naphthalene-2-carboxylic acid [l-(2-phenyl-l(R)-{2-[l-(pyrrolidine-2(S)- carbonyl)-piperidin-4-yl]-ethylcarbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide MS (m/z): 716.3 (MH , isotopic pattern of Br). HPLC (method A): Rt = 3.95 min. Example 99
6-Bromo-naphthalene-2-carboxylic acid [ 1 -(2-phenyl- 1 (R)- {2- [ 1 -(pyrrolidine-2(R)- carbonyl)-piperidin-4-yl]-ethylcarbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide MS (m/z): 716.3 (MH4, isotopic pattern of Br). HPLC (method A): Rt = 3.97 min. Example 100 Benzo[b]thiophene-2-carboxylic acid [ 1 -(2-phenyl- 1(R)- {2-[4-(thiophen-2-yl-acetyl)- piperazin-1 -yl]-ethylcarbamoyl} -ethylcarbamoyl)-cyclopentyl]-amide. Analogously to Example 95) 4-[2-(2(R)-amino-3-phenyl-propionylamino)-ethyl]- piperazine-1 -carboxylic acid tert-butyl ester (obtained starting from Z-D-phenylalanine and N-Boc-4-hydroxyethylpiperazine by reactions and couplings widely described in literature and in part already reported in previous examples) (100 mg, 0.26 mmol) and 2- benzo[b]thiophen-2-yl-3-oxa-l-azaspiro[4.4]-non-l-en-4-one (72 mg, 0.26 mmol) are caused to react in DMF to yield a product which is deprotected and subsequently acylated with thiophen-2-yl-acethyl chloride in CH2C12 (as described in Example 94 and purified by flash chromatography using AcOEt as the eluent. 69 mg (0.10 mmol) of benzo[b]thiophene-2-carboxylic acid [l-(2-phenyl-l(R)-{2-[4-(thiophen-2-yl-acetyl)- piperazin-l-yl]-ethylcarbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide are so obtained. MS (m/z): 672.3 (MH4). HPLC (method A): Rt = 3.87 min. Example 101 Benzo[b]thiophene-2-carboxylic acid [ 1 (2-phenyl- 1 (R)- {2-[4-(tetrahydro-pyran-4- ylmemyl)-piperazin-l-yl]-ethylcarbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide TFA salt The compound of the title is obtained by a procedure analogous to that described in Example 100, but carrying out a reductive amination with tetrahydropyranyl 4- carboxyaldehyde in place of an acylation step with thiophen-2-yl-acethyl chloride. MS (m/z): 646.2 (MH4). HPLC (method A): Rt = 3.24 min. Example 102
5-Chloro-benzofuran-2-carboxylic acid { 1 -[ lR-(3 -mo holin-4-yl-propylcarbamoyl)-2- phenyl-ethylcarbamoyl]-cyclopentyl}-amide
196 mg of 5-chlorobenzofuran-2-carboxylic acid are suspended in 12 ml of anhydrous CH2C12, in nitrogen atmosphere. 100 μl of oxalyl chloride and one drop of DMF are then added. The stirring is maintained until the reaction is finished. The solvent is then evaporated and the residue is brought to dryness in a hard vacuum. 87 mg of the so obtained acylic chloride are added to a mixture of 132 mg of 1-amino- cyclopentanecarboxylic acid [ 1 (R)-(3 -morpholin-4-yl-propylcarbamoyl)-2-phenyl-ethyl] - amide bw-hydrochloride, 200 μl of TEA and 10 ml of anhydrous CH2C12 under magnetic stirring. Once the reaction is over, the solvent is evaporated and the residue is dissolved with a mixture of ethyl acetate and K2CO3 aq. 10%, by vigorously stirring. After separation of the organic phase, washings with basic water, drying on anhydrous Na2SO4, filtration and evaporation of the solvent, 134 mg of a residue are obtained, which are then purified by flash chromatography, eluting with increasing amounts of methanol in ethyl acetate until MeOH/AcOH = 1/6 v/v, so to obtain the desired amide. MS (m/z): 581.3 (MH4). HPLC (method C): Rt = 13.14 min. With analogous procedure the following compounds have been prepared: Example 103 5-Chloro-benzo[b]thiophene-2-carboxylic acid { 1 -[ lR-(3-morpholin-4-yl- propylcarbamoyl)-2-phenyl-ethylcarbamoyl] -cyclopentyl } -amide MS (m/z): 597.3 (M+H4). HPLC (method C): Rt = 13.80 min. Example 104
5-Bromo-benzofuran-2-carboxylic acid {l-[li?-(3-moφholin-4-yl-propylcarbamoyl)-2- phenyl-ethylcarbamoyl] -cyclopentyl} -amide MS m/z: 625.2 (M+H4, monoisotopic). HPLC (method C): Rt = 13.41 min. Example 105 6-Chloro-benzo[b]fhiophene-2-carboxylic acid {l-[lR-(3-morpholin-4-yl- propylcarbamoyl)-2-phenyl-ethylcarbamoyl]-cyclopentyl}-amide
MS m/z: 597.3 (M+H4). HPLC (method C): Rt = 13.58 min.
Example 106 6-Methoxy-benzo[b]thiophene-2-carboxylic acid {l-[lR-(3-morpholin-4-yl- propylcarbamoyl)-2-phenyl-ethylcarbamoyl]-cyclopentyl}-anιide
MS m/z: 593.3 (M+H4). HPLC (method C): Rt = 12.62 min.
Example 107
4-Chloro-benzo[b]thiophene-2-carboxylic acid { l-[lR-(3-moιpholin-4-yl- propylcarbamoyl)-2-phenyl-ethylcarbamoyl]-cyclopentyl} -amide
MS m/z: 597.3 (M+H4). HPLC (method C): Rt = 13.79 min.
Example 108 6-Bromo-benzo [b]thiophene-2-carboxylic acid { 1 -[ li?-(3 -morpholin-4-yl- propylcarbamoyl)-2-phenyl-ethylcarbamoyl]-cyclopentyl}-amide MS m/z: 641.3 (M+H4, monoisotopic). HPLC (method C): Rt = 13.86 min.
Example 109 6-Bromo-benzo[b]thiophene-2-carboxylic acid { l-[lR-(3-moφholin-4-yl- propylcarbamoyl)-2-phenyl-ethylcarbamoyl] -cyclohexyl} -amide
MS m/z: 655.2 (M+H4, monoisotopic). HPLC (method C): Rt = 14.63 min. Example 110
5-Fluoro-l -methyl- lH-indole-2-carboxylic acid { 1 -[ lR-(3-morpholin-4-yl- propylcarbamoyl)-2-phenyl-ethylcarbamoyl]-cyclopentyl}-amide
MS m/z: 578.3 (M+Η4). ΗPLC (method C): Rt = 13.18 min.
Example 111 6-Chloro-l-methyl-lH -indole-2-carboxylic acid {l-[lR-(3-moφholin-4-yl- propylcarbamoyl)-2-phenyl-ethylcarbamoyl]-cyclopentyl}-amide
MS m/z: 594.3 (M+Η4). ΗPLC (method C): Rt = 14.03 min.
Example 112
7-Memyl-benzo[b]thiophene-2-carboxylic acid~ {l-[lR-(3-moφholin-4-yl- propylcarbamoyl)-2-phenyl-ethylcarbamoyl]-cyclopentyl} -amide
MS m/z: 577.3 (M+Η ). ΗPLC (method C): Rt = 13.26 min.
Example 113 5 -Methyl-benzofuran-2-carboxylic acid { 1 -[ lR-(3 -moφholin-4-yl-propylcarbamoyl)-2- phenyl-ethylcarbamoyl]-cyclopentyl}-amide MS m/z: 561.3 (M+H4). HPLC (method C): Rt = 13.01 min. Example 114 l,5-Dimethyl-lH-indole-2-carboxylic acid {1-[1R -(3-moφholin-4-yl-propylcarbamoyl)- 2-phenyl-ethylcarbamoyl]-cyclopentyl}-amide MS m/z: 574.3 (M+Η4). ΗPLC (method D): Rt = 13.62 min. Example 115 6-Amino-benzo[b]thiophene-2-carboxylic acid {1-[1E -(3-moφholin-4-yl- propylcarbamoyl)-2-phenyl-ethylcarbamoyl] -cyclopentyl} -amide MS m/z: 578.2 (M+Η4). ΗPLC (method D): Rt = 8.62 min. Example 116
6,7-Dichloro-benzo[b]thiophene-2-carboxylic acid {1-[1R -(3-moφholin-4-yl- propylcarbamoyl)-2-phenyl-ethylcarbamoyl]-cyclopentyl}-amide MS m/z: 631.3 (M+Η4). ΗPLC (method C): Rt = 14.57 min. Example 117
6-Iodo-naphthalene-2-carboxylic acid [ 1 -(2-phenyl- li?- { [ 1 -(tetrahydro-pyran-4-ylmethyl)- piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide 118a) 18.0 g of 4-tetrahydropyrancarboxylic acid are introduced in a 250 ml flask with a calcium chloride tube, and dissolved in 130 ml of CΗ2C12. Under magnetic stirring, 15 ml of oxalyl chloride and 3 drops of DMF are added successively. The solution, that regularly degasses, is kept under magnetic stirring for 16 hours. After evaporation of the solvent, the residue is dried in hard vacuum at room temperature, dissolved in 100 ml of CH2C12 and put in a bath of ice and water, maintaining a vigorous magnetic stirring. A solution of 21.75 g of ethyl 4-piperidincarboxylate in 30 ml of CH2C12 containing 15.35 g of TEA is added to the mixture by means of a dripping funnel. During the addition, that lasts 3 hours, a clear suspension forms. The reaction mixture is left to stand overnight, then CH2C12 is evaporated and the residue is brought to dryness in hard vacuum. The residue is dissolved in 110 ml of ammonia aq. 25%, then methanol is added until complete solubilisation. Methanol is refluxed until the ester disappears (samples are taken, evaporated and analised by 1H-NMR). The solution is brought to small volume and extracted 25 times with 100 ml of chloroform to give, after evaporation of the solvent, 21.4 g of raw diamide. 14.79 g of the so obtained diamide are added in portions to 175 ml of a solution IM of borane in THF. The addition lasts about 1 hour and it is carried out under a nitrogen flow, so that the temperature does not exceed 35°C. Once the addition is completed, the reaction mixture is heated to reflux and the reflux is maintained for 11 hours. In a bath of ice and water, 130 ml of a solution 4M of HCl in 1,4-dioxane, previously diluted with 100 ml of methanol, are added drop by drop to the solution obtained as above. The the reaction mixture is heated to reflux, and the eflux is maintained for 12 hours before cooling at 0- 4°C. By filtration 7.95 g of C-[l-(tefrahydro-pyran-4-ylmethyl)-piperidin-4-yl]-methylamine bts-hydrochloride are recovered. From mother liquor, by dilution to doubled volume with diethyl ether, further 1.85 g of the desired product are recovered.
1H-NMR (200 MHz, DMSO-dβ), • (ppm): 1.09-1.33 (m, 2H); 1.51-2.20 (m, 8H); 2.59- 3.08 (m, 6H); 3.09-3.58 (m, 4H); 3.76-3.91 (m, 2H); 8.18 (br, 3H); 10.20 (br, IH). Analogously, the following amines have also been prepared: C-[ 1 -(4-Memyl-tefrahydro-pyran-4-ylmethyl)-piperidin-4-yl] -methylamine MS (m/z): 227.2 (MH4)
1H NMR (200MHz): (δ, CDC13) 0.94 (s, 3H); 1.08-1.69 (m, 9H); 2.10 (s, 2H); 2.10-2.30 (m, 2H); 2.48-2.59 (m, 2H); 2.67-2.83 (m, 2H); 3.47-3.79 (m, 4H). C-[4-Methyl-l-(4- methyl-tefrahvdro-pwan-4-vlmemyl)-piperid -4-yl]-memylarnine MS (m/z): 227.3 (MH4)
C-[4-Methyl- 1 -(tetrahydro-pyran-4-ylmethyl)-piperidin-4-yl] -methylamine
MS (m/z): 241.2 (MH4)
117b) Starting from the amine obtained in Example 117a), by a peptidic synthesis using
Boc, under the operative conditions well known to a skilled person, by reacting the above said amine with Boc-D-phenylalanine O-succinimidoester, deprotecting, reacting with N- Boc 1 -amino- 1-cyclopentancarboxylic acid and deprotecting, the compound 1-amino- cyclopentanecarboxylic acid (2-phenyl-l_R-{[l-(tefrahydro-pyran-4-ylmethyl)-piperidin-4- ylmethyl]-carbamoyl}-ethyl)-amide is obtained. This compound is caused to react with the chloride of 6-iodonaphthalen-2-carboxylic acid, by a procedure analogous to that described in Example 102), thus obtaining the final product 6-iodo-naphfhalene-2-carboxylic acid [l-(2-phenyl-lR-{[l-(tetrahydro-pyran-4- ylmemyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide. MS m/z: 751.3 (M+H4). HPLC (method D): Rt = 14.00 min.
Analogously to that described in Example 117), by reaction of the corresponding carboxylic acids activated with 1-amino-cyclopentanecarboxylic acid (2-phenyl-li?-{[l- (tefrahydro-pyran-4-ylmethyl)-piperidin-4-ylmemyl]-carbamoyl}-emyl)-amide, the following compounds have been obtained: Example 118
6-Methoxy-naphthalene-2-carboxylic acid [ 1 -(2-phenyl- 1R- { [ 1 -(tetrahydro-pyran-4- ylmemyl)-piperidm-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide MS m/z: 655.2 (M+H4). HPLC (method D): Rt = 12.42 min. IH-NMR (DMSO-d6). δ (amongst the others): 0.94-1.07 (m, 4H); 1.42-1.72 (m, 12H); 1.74-1.81 (m, IH); 1.89-2.00 (m, 3H); 2.24-2.33 (m, IH); 2.55-2.63 (m, 2H); 2.82-2.90 (m, 2H); 2.94-3.01 (m, IH); 3.74-3.83 (m, 2H); 3.91 (s, 3H); 4.42-4.49 (m, IH); 7.10-7.21 (m, 5H); 7.23-7.27 (m, IH); 7.38-7.41 (m, IH); 7.51 (t, J = 5.7 Hz, IH); 7.79 (d, J = 8.6, IH); 7.86-7.97 (m, 3H); 8.45 (s, IH); 8.69 (s, IH). Example 119
6-Bromo-benzofuran-2-carboxylic acid [ 1 -(2-phenyl- li?- { [ 1 -(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide MS m/z: 693.5 (M+H4, monoisotopic). HPLC (method D): Rt = 13.18 min. IH-NMR (DMSO-d6). δ (amongst the others): 0.97-1.12 (m, 4H); 1.39-1.73 (m, 12H); 1.74-1.81 (m, IH); 1.89-1.96 (m, IH); 1.97-2.04 (m, 2H); 2.21-2.29 (m, IH); 2.63-2.71 (m, 2H); 2.79-2.92 (m, 2H); 2.95-3.03 (m, IH); 3.77-3.85 (m, 2H); 4.40-4.48 (m, IH); 7.10- 7.22 (m, 5H); 7.45 (t, J = 5.7 Hz, IH); 7.54 (dd, J = 1.7 and 8.4Hz, IH); 7.67 (d, J = 0.8Hz, IH) 7.79 (d, J = 8.4, IH); 7.85 (d, J = 8.6Hz, IH); 7.95 (s ,br, IH); 8.85 (s, IH). Example 120 6-Chloro-benzofuran-2-carboxylic acid [l-(2-phenyl-lR-{[l-(tetrahydro-pyran-4- ylmemyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide MS m/z: 649.3 (M+H ). HPLC (method D): Rt = 13.00 min.
IH-NMR (DMSO-d6). • (amongst the others): 0.97-1.12 (m, 4H); 1.42-1.73 (m, 12H); 1.74-1.81 (m, IH); 1.89-1.96 (m, IH); 1.97-2.04 (m^ 2H); 2.21-2.29 (m, IH); 2.63-2.71 (m, 2H); 2.79-2.92 (m, 2H); 2.95-3.03 (m, IH); 3.77-3.85 (m, 2H); 4.40-4.48 (m, IH); 7.10- 7.22 (m, 5H); 7.42 (dd, J = 1.8 and 8.4Hz, IH); 7.46 (t, J = 5.8 Hz, IH); 7.66 (d, J = 0.9Hz, IH) 7.81-7.86 (m, 2H); 8.84 (s, IH). Example 121 5-Fluoro-benzofuran-2-carboxylic acid [l-(2-phenyl-li?-{[l-(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
MS m/z: 633.5 (M+H1). HPLC (method D): Rt = 12.10 min. IH-NMR (DMSO-d6). • (amongst the others): 0.97-1.12 (m, 4H); 1.42-1.73 (m, 12H);
1.74-1.81 (m, IH); 1.89-1.96 (m, IH); 1.97-2.04 (m, 2H); 2.21-2.29 (m, IH); 2.63-2.71 (m,
2H); 2.78-2.93 (m, 2H); 2.95-3.03 (m, IH); 3.75-3.85 (m, 2H); 4.40-4.48 (m, IH); 7.10-
7.22 (m, 5H); 7.32 -7.37 (m, IH); 7.46 (t, J = 5.8 Hz, IH); 7.60-7.66 (m, 2H); 7.71 (dd, J =
4.1 and 9.0Hz, IH) 7.83 (d, J= 8.6Hz, IH); 8.84 (s, IH). Example 122
5-Chloro-benzofuran-2-carboxylic acid [l-(2-phenyl-li?-{[l-(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
MS m/z: 649.5 (M+H4). HPLC (method D): Rt = 12.78 min.
IH-NMR (DMSO-d6). • (amongst the others): 0.97-1.12 (m, 4H); 1.42-1.73 (m, 12H); 1.74-1.81 (m, IH); 1.89-1.96 (m, IH); 1.97-2.04 (m, 2H); 2.21-2.29 (m, IH); 2.63-2.71 (m,
2H); 2.78-2.93 (m, 2H); 2.95-3.03 (m, IH); 3.75-3.85 (m, 2H); 4.40-4.48 (m, IH); 7.10-
7.22 (m, 5H); 7.46 (t, J = 5.8 Hz, IH); 7.50-7.53 (m, IH); 7.61 (s, br, IH); 7.71 (d, J =
8.8Hz, IH) 7.85 (d, J = 8.6Hz, IH); 7.92 (d, J =2.2, IH); 8.87 (s, IH).
Example 123 5-Bromo-benzofuran-2-carboxylic acid [l-(2-phenyl-li?-{[l-(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
MS m/z: 693.5 (M+H4, monoisotopic). HPLC (method D): Rt= 13.14 min.
IH-NMR (DMSO-d6). • (amongst the others): 0.97-1.12 (m, 4H); 1.42-1.73 (m, 12H);
1.74-1.81 (m, IH); 1.89-1.96 (m, IH); 1.97-2.04 (m, 2H); 2.21-2.29 (m, IH); 2.63-2.71 (m, 2H); 2.78-2.93 (m, 2H); 2.95-3.03 (m, IH); 3.75-3.84 (m, 2H); 4.40-4.48 (m, IH); 7.11-
7.21 (m, 5H); 7.44 (t, J = 5.8 Hz, IH); 7.58-7.69 (m, 3H) 7.85 (d, J = 8.6Hz, IH); 8.06 (d, J
=2.0, IH); 8.87 (s, IH).
Example 124
7-tert-Butyl-berizofuran-2-carboxylic acid [ 1 -(2-phenyl- li?- { [ 1 -(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
MS m/z: 671.6 (M+H4). HPLC (method D): Rt = 15.16 min.
Example 125 6-Methyl-benzofuran-2-carboxylic acid [ 1 -(2-phenyl- 1R- { [ 1 -(tetrahydro-pyran-4- ylmemyl)-piperidm-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
MS m/z: 629.5 (M+H ). HPLC (method D): Rt = 12.69 min.
Example 126 5-Methyl-benzofuran-2-carboxylic acid [1 -(2-phenyl- li?-{[l -(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
MS m/z: 629.5 (M+H4). HPLC (method D): Rt = 12.66 min.
IH-NMR (DMSO-d6). • (amongst the others): 0.97-1.12 (m, 4H); 1.42-1.73 (m, 12H);
1.74-1.81 (m, IH); 1.89-1.96 (m, IH); 1.97-2.04 (m, 2H); 2.21-2.29 (m, IH); 2.44 (s, 3H) 2.63-2.71 (m, 2H); 2.78-2.93 (m, 2H); 2.95-3.03 (m, IH); 3.75-3.84 (m, 2H); 4.40-4.48 (m,
IH); 7.11-7.21 (m, 5H); 7.29-7.33 (m, IH) 7.49 (t, J = 5.7 Hz, IH); 7.53-7.60 (m, 3H);
7.86 (d, J = 8.5Hz, IH); 8.76 (s, IH).
Example 127
5-Iodo-berιzoιuran-2-carboxylic acid [ 1 -(2-phenyl- 1 R- { [ 1 -(tetrahydro-pyran-4-ylmethyl)- piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
MS m/z: 741.5 (M+H4). HPLC (method D): Rt = 13.42 min.
IH-NMR (DMSO-d6). • (amongst the others): 0.97-1.12 (m, 4H); 1.42-1.73 (m, 12H);
1.74-1.81 (m, IH); 1.89-1.96 (m, IH); 1.97-2.04 (m, 2H); 2.21-2.29 (m, IH); 2.63-2.71 (m,
2H); 2.78-2.93 (m, 2H); 2.95-3.03 (m, IH); 3.75-3.84 (m, 2H); 4.40-4.48 (m, IH); 7.11- 7.21 (m, 5H); 7.43 (t, J = 5.8 Hz, IH); 7.53 (d, J = 8.7 Hz, IH) 7.58 (s, IH); 7.76 (dd, J =
1.8 and 8.7 Hz, IH); 7.86 (d, J = 8.6Hz, IH); 8.22 (d, J =1.7, IH); 8.88 (s, IH).
Example 128
5-tert-Butyl-benzofuran-2-carboxylic acid [ 1 -(2-phenyl- li?- { [ 1 -(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide MS m/z: 671.5 (M+H4). HPLC (method D): Rt = 14.90 min.
Example 129
6-Iodo-benzo[b]thiophene-2-carboxylic acid [ 1 -(2-phenyl- li?- { [ 1 -(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
MS m/z: 757.2 (M+H4). HPLC (method D): Rt = 13.85 min. Example 130
6-Chloro-benzo[b]thiophene-2-carboxylic acid [ 1 -(2-phenyl- li?- { [ 1 -(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide MS m/z: 665.4 (M+H ). HPLC (method D): Rt = 13.32 min.
IH-NMR (DMSO-d6). • (amongst the others): 0.97-1.12 (m, 4H); 1.42-1.73 (m, 12H);
1.74-1.81 (m, IH); 1.87-1.94 (m, IH); 2.17-2.28 (m, IH); 2.65-2.71 (m, 2H); 2.79-2.87 (m,
IH); 2.88-2.99 (m, 2H); 3.31-3.20 (m, IH); 3.76-3.84 (m, 2H); 4.42-4.49 (m, IH); 7.10- 7.21 (m, 5H); 7.44 (t, J = 5.8Hz, IH); 7.49 (dd, J = 2.0 and 8.5, IH), 7.85 (d, J = 8.6 Hz,
IH); 8.00 (d, J = 8.5 Hz, IH); 8.22 (d, J = 1.9 Hz, IH); 8.28 (s, IH); 8.93 (s, IH).
Example 131
7-Bromo-benzo[b]thiophene-2-carboxylic acid [ 1 -(2-phenyl- 1R- {[ 1 -(tetrahydro-pyran-4- ylmemyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide MS m/z: 709.4 (M+H , monoisotopic). HPLC (method D): Rt = 13.12 min.
Example 132
7-Iodo-benzo[b]thiophene-2-carboxylic acid [ 1 -(2-phenyl- li?- { [ 1 -(tetrahydro-pyran-4- ylmemyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
MS m/z: 757.4 (M+H4). HPLC (method D): Rt = 13.38 min. Example 133
6-Trifluoromethyl-benzo[b]thiophene-2-carboxylic acid [ 1 -(2-phenyl- li?- { [ 1 -(tetrahydro- pyran-4-ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
MS m/z: 699.5 (M+H4). HPLC (method D): Rt = 13.88 min.
Example 134 7-Methyl-benzo[b]thiophene-2-carboxylic acid [l-(2-phenyl-lR-{[l-(tetrahydro-pyran-4- ylmemyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
MS m/z: 645.5 (M+H4). HPLC (method D): Rt = 12.83 min.
IH-NMR (DMSO-d6). • (amongst the others): 0.98-1.12 (m, 4H); 1.36-1.82 (m, 14H);
1.87-1.95 (m, IH); 1.95-2.06 (m, 2H); 2.19-2.29 (m, IH); 2.53 (s, 3H); 2.67-2.74 (m, 2H); 2.80-2.94 (m, 2H); 3.15-3.28 (m, 3H); 3.76-3.83 (m, 2H); 4.41-4.48 (m, IH); 7.10-7.23 (m,
5H); 7.29-7.33 (m, IH); 7.37-7.41 (m, IH); 7.44 (t, J = 5.7 Hz, IH); 7.86-7.83 (m, IH);
7.86 (d, J = 8.6 Hz, 1H>; 8.31 (s, IH); 8.86 (s, IH).
Example 135
6-Methoxy-benzo[b]thiophene-2-carboxylic acid [ 1 -(2-phenyl- li?- {[ 1 -(tetrahydro-pyran- 4-ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide MS m/z: 661.5 (M+H4). HPLC (method D): Rt = 12.32 min. Example 136 7-Trifluoromethyl-benzo[b]thiophene-2-carboxylic acid [ 1 -(2-phenyl- li?- {[ 1 -(tetrahydro- pyran-4-ylmemyl)-piperimn-4-ylmemyl]-carbamoyl}-emylcarbamoyl)-cyclopentyl]-amide
MS m/z: 699.5 (M+H4). HPLC (method D): Rt = 13.31 min.
Example 137 7-Chloro-benzo[b]thiophene-2-carboxylic acid [1 -(2-phenyl- li?-{[l -(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
MS m/z: 665.4 (M+H4). HPLC (method D): Rt = 12.99 min.
Example 138
5-Methyl-benzo[b]thiophene-2-carboxylic acid [l-(2-phenyl-lR-{[l-(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
MS m/z: 645.5 (M+H4). HPLC (method D): Rt = 13.03 min.
IH-NMR (DMSO-d6). • (amongst the others): 1.00-1.11 (m, 4H); 1.43-1.80 (m, 13H);
1.87-1.94 (m, IH); 1.95-2.04 (m, 2H); 2.18-2.28 (m, IH); 2.44 (s, 3H); 2.66-2.73 (m, 2H);
2.80-2.87 (m, IH); 2.90-3.00 (m, 2H); 3.14-3.27 (m, 3H); 3.75-3.84 (m, 2H); 4.41-4.50 (m, IH); 7.10-7.21 (m, 5H); 7.29-7.33 (m, IH); 7.47 (t, J = 5.8 Hz, IH); 7.75 (s, IH); 7.84 (d, J
= 8.6 Hz, IH); 7.87-7.91 (m, IH); 8.19 (s, IH); 8.83 (s, IH).
Example 139
6-Methyl-benzo[b]tbiophene-2-carboxylic acid [ 1 -(2-phenyl- li?- {[ 1 -(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide MS m/z: 645.5 (M+H4). HPLC (method D): Rt = 13.02 min.
IH-NMR (DMSO-d6). • (amongst the others): 0.97-1.12 (m, 4H); 1.42-1.73 (m, 12H);
1.74-1.81 (m, IH); 1.87-1.94 (m, IH); 2.17-2.28 (m, IH); 2.45 (s, 3H); 2.67-2.73 (m, 2H);
2.79-2.87 (m, IH); 2.88-2.99 (m, 2H); 3.31-3.20 (m, IH); 3.76-3.84 (m, 2H); 4.42-4.49 (m,
IH); 7.10-7.21 (m, 5H); 7.28 (d, J = 8.2 Hz, IH); 7.47 (t, J = 5.6Hz, IH); 7.78-7.88 (m, 3H); 8.22 (d, J = 1.9 Hz, IH); 8.22 (s, IH); 8.80 (s, IH).
Example 140
Benzofuran-2-carboxylic acid [ 1 -(2-phenyl- 1 - { [ li?-(tetrahydro-pyran-4-ylmethyl)- piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
Example 141 6-Fluoro-benzo[b]thiophene-2-carboxylic acid [l-(2-phenyl-l-{[li?-(tetrahydro-pyran-4- ylmemyl)-piperidin-4-ylmemyl]-carbamoyl}-emylcarbamoyl)-cyclopentyl]-amide
MS m/z: 649.3 (M+H4). HPLC (method D): Rt = 12.51 min. IH-NMR (DMSO-d6). • (amongst the others): 0.97-1.12 (m, 4H); 1.42-1.73 (m, 12H);
1.74-1.81 (m, IH); 1.87-1.94 (m, IH); 2.17-2.28 (m, IH); 2.45 (s, 3H); 2.67-2.73 (m, 2H);
2.79-2.87 (m, IH); 2.88-3.00 (m, 2H); 3.31-3.20 (m, IH); 3.76-3.84 (m, 2H); 4.42-4.49 (m,
IH); 7.10-7.21 (m, 5H); 7.34 (m, IH); 7.47 (t, J = 5.8Hz, IH); 7.84 (d, J = 8.6, IH); 7.95- 7.98 (m, IH); 8.00-8.04 (m, IH); 8.27 (s, IH); 8.89 (s, IH).
Example 142
1-Methyl-lH-indole -2-carboxylic acid [l-(2-phenyl-l-{[li?-(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
Example 143 7-Chloro-l -methyl- IH-indole -2-carboxylic acid [li?-(2-phenyl-l-{[l-(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
Example 144
5-CUoro-3-me yl-benzofuran-2-carboxylic acid [ li?-(2-phenyl- 1 - {[ 1 -(tetrahydro-pyran-
4-ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide Example 145
6-Diethylamino-benzofuran-2-carboxylic acid [ 1 -(2-phenyl- 1 - { [ 1 R-(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
MS m/z: 686.4 (M+Η ). ΗPLC (method D): Rt = 8.76 min.
Example 146 5-Methoxy-benzofuran-2-carboxylic acid [l-(2-phenyl-l-{[li?-(tetrahydro- pyran-4-ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
MS m/z: 645.5 (M+Η ). ΗPLC (method D): Rt = 11.98 min.
Example 147
5-Diethylamino-benzofuran-2-carboxylic acid [ 1 -(2-phenyl- 1 - { [ li?-(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide MS m/z: 686.6 (M+Η4). ΗPLC (method D): Rt = 8.58 min.
Example 148
3 ,5 ,6-Trimethyl-benzofuran-2-carboxylic acid [ 1 -(2-phenyl- 1 - { [ li?-(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
Example 149 Naphthalene-2-carboxylic acid [l-(2-phenyl-l-{[li?-(tetrahydro-pyran-4-ylmethyl)- piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
MS m/z: 639.5 (M+Η4). ΗPLC (method D): Rt = 13.14 min. Example 150
5 -Bromo-naphthalene-2-carboxylic acid [ 1 -(2-phenyl- 1 - { [ lR-(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmemyl]-carbamoyl}-emylcarbamoyl)-cyclopentyl]-amide
MS m/z: 703.4 (M+H4, monoisotopic). HPLC (method D): Rt = 13.53 min. Example 151
Naphthalene-2-carboxylic acid [ 1 -(2-phenyl- li?- { [ 1 -(tetrahydro-pyran-4-ylmethyl)- piperidin-4-ylmethyl]-carbamoyl}-efhylcarbamoyl)-cyclopentyl]-amide
MS m/z: 625.5 (M+H4). HPLC (method D) Rt = 12.29 min.
IH-NMR (DMSO-d6). δ (amongst the others): 0.94-1.07 (m, 4H); 1.43-1.72 (m, 12H); 1.76-1.83 (m, IH); 1.90-2.00 (m, 3H); 2.25-2.34 (m, IH); 2.55-2.63 (m, 2H); 2.82-2.90 (m,
2H); 2.94-3.01 (m, IH); 3.74-3.83 (m, 2H); 3.91 (s, 3H); 4.42-4.49 (m, IH); 7.10-7.21 (m,
5H); 7.23-7.27 (m, IH); 7.52 (t, J = 5.7 Hz, IH); 7.58-7.67 (m, 2H); 7.80 (d, J = 8.6, IH);
7.95-8.06 (m, 4H); 8.53 (s, IH); 8.78 (s, IH).
By analogous procedure to that described in Example 117, the following compounds have moreover been prepared:
Example 152
Benzo[b]thiophene-2-carboxylic acid [ 1 -(2-phenyl- 1 (R)- { [ 1 -(tetrahydro-pyran-4- ylmethyl)-azetidin-3-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide, by using ethyl 3-azetidincarboxylate in place of ethyl 4-piperidincarboxylate. MS (m/z): 603.3 (MH4). HPLC (method A): Rt = 3.63 min.
Example 153
6-Bromo-naphthalene-2-carboxylic acid [ 1 -( 1 (R)- { [ 1 -(4-methyl-tetrahydro-pyran-4- ylmethyl)-piperimn-4-ylmethyl]-carbamoyl}-2-phenyl-ethylcarbamoyl)-cyclopentyl]- amide, by using C-[l-(4-Me yl-tefrahydro-pyran-4-ylmethyl)-piperid -4-yl]-methylamine prepared as described in Example 117a).
MS (m/z): 617.4 (MH4, isotopic pattern of Br). HPLC (method A): Rt = 4.01 min.
Example 154
6-Bromo-naphthalene-2-carboxylic acid [ 1 -( 1 (R)- { [ 1 -(5 -ethyl-[ 1 ,3 ] dioxan-5-ylmethyl)- piperidin-4-ylmethyl]-carbamoyl}-2-phenyl-ethylcarbamoyl)-cyclopentyl] -amide, by using 5-ethyl-[l,3]dioxane-5 carboxylic acid in place of 4-tefrahydropyrancarboxylic acid. Example 155 6-Bromo-naphthalene-2-carboxylic acid [ 1 -( 1 (R)- { [4-methyl- 1 -(4-methyl-tetrahydro- pyran-4-ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-2-phenyl-ethylcarbamoyl)- cyclopentyl] -amide, by using C-[4-methyl-l-(4-memyl-tetrahydro-pyran-4-ylmethyl)-piperidin-4-yl]- methylamine prepared as described in Example 117a).
Example 156 6-Bromo-naphthalene-2-carboxylic acid [ 1 -( 1 (R)- { [4-methyl- 1 -(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-2-phenyl-ethylcarbamoyl)-cyclopentyl]- amide, by using C-[4-methyl-l-(tefrahydro-pyran-4-ylmethyl)-piperidin-4-yl]-methylamine prepared as described in Example 117a).
MS (m/z): 717.4 (MH4, isotopic pattern of Br). HPLC (method A): Rt = 4.16 min.
HPLC methods Mobile phase: A = H2O + 0.1 %TFA; B = MeCN +0.1 % TFA
METHOD A
Column: Zorbax™ SB-18, 3.5 μm, lOOA (50 x 4.6 mm)
Gradient: from A/B = 95/5 to A/B = 5/95 in 6.5 min +1 min isocratic
Flow rate: 3 ml/min λ=220, 270 nm.
METHOD B
Column: Platinum™ RP-18, 3 μm, lOOA (33 x 7 mm)
Gradient: from A/B = 95/5 to A/B = 5/95 in 6.5 min +1 min isocratic
Flow rate: 3 ml/min λ=220, 270 nm.
METHOD C
Column: Jupiter™ C18, 5 μm (250 x 4.6 mm)
Gradient: from A/B = 85/15 to A/B = 5/95 in 20 min
Flow rate: 1 ml/min λ=210 nm.
METHOD D
Column: Symmetry™ 300 C18, 5 μm (250 x 4.6 mm) Gradient: from A/B = 85/15 to A/B = 5/95 in 20 min
Flow rate: 1 ml min λ-210 nm.
METHOD E Column: Protein & Peptide Vydac™ CI 8 (250 x 4.6 mm)
Gradient: from A/B = 80/20 to A/B = 20/80 in 25 min + A/B = 20/80 for 10 min
Flow rate: 1 ml/min λ=230 nm.
METHOD F Column: Inertsil ODS-3 (GL Sciences), 3 μm (50 x 3 mm)
(250 x 4.6 mm)
Gradient: from A/B = 80/20 to A/B = 30/70 in 9 min
Flow rate: 0.8 ml/min λ=230 nm. List of Abbreviations
In the present description the following abbreviations have been used:
Ac5c, aminocyclopentanecarboxylic;Ac6c, aminocyclohexanecarboxylic; AcOEt, ethyl acetate; Boc, N-tert-butyloxycarbonyl;BSA,N,O-bis(trimethylsilyl)acetamide; DCM, dichloromethane; DIPEA, N,N-diisopropylethylamine; DMF, N,N-dimefhylformamide; EDC, l-ethyl-3-(3-dimeth iaminopropyl)carbodiimide hydrochloride; EtOAc, ethyl acetate; HOBt, 1-hydroxybenzotriazole; TEA, triethylamine; TEMPO, 2,2,6,6-tetramethyl-
1-piperidinyloxy; TFA, trifluoroacetic acid; THF, tetrahydrofuran; TMSC1, trimethylsilylchloride; Z, N-benzyloxycarbonyl.
The evaluation of the antagonist activity on NK-2 receptors has been assessed by binding and functional tests according to that already described in literature in relation to NK-2 antagonists.
In particular, the affinity of the present compounds for the human NK-2 receptor has been assessed by a binding test using Chinese hamster ovary (CHO) cell membranes transfected with NK-2 receptor of human ileum together with [125I]NKA (Amersham, aspecific activity 2000 Ci/mmol) radiobinder at the concentration of 100 pM in competition studies. The test substances have been tested within a concentration range from 0.01 nM to 10 nM. At the end of the incubation time (30 min, 20°C) the samples have been filtered and radioactivity has been determined using a gamma-counter.
The data shown in the following Table I have been obtained for some compounds of general formula (I) and refer to the affinity values of human NK-2 receptor:
TABLE I
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
The present compounds of formula (I) can be handled according to the common pharmacopoeial techniques in order to prepare formulations suitable for oral, intranasal, parentheral, sublingual, inhalatory, transdermic, local or rectal use according to the data known in literature for this kind of products; these formulations comprise oral formulations, such as tablets, capsules, powders, granulated preparations, and oral solutions or suspensions, formulations for sublingual admimstration, for intranasal administration, aerosol formulations, implantations, formulations for subcutaneous, intramuscular, intravenous^ intraocular .and rectal administration. The effective, doses, are 0.1 to 50 mg/kg of body weight. For humans the effective dose may preferably range from 0.5 to 4000 mg/day, in particular from 2.5 to 1000 mg according to the age of patients and to the type of treatment.
The treatment is performed by administering to the patient the required amount 1 to 4 times-per-day for periods of time up to 2 weeks or in any case until remission of symptoms; for chronic pathologies, admimstration can be prolonged for significantly longer periods of time according to the physician judgement.
Thanks to their high antagonist activity to tachykinins NK-2 receptor, the present compounds are useful in the treatment of diseases in which Neurokinine A plays a pathogenetic role, and namely in the following pathologies: - chronic obstructive respiratory pathologies, such as asthma and allergic rhinitis, cough, bronchitis; - ophtalmic pathologies, such as conjunctivitis or vitreoretinopathy; - skin problems, such as allergic and contact dermatitis, atopic dermatitis, eczema, itch, psoriasis, burns, in particular solar burns;
- intestinal disorders, such as irritable colon, ulcerous colitis, Crohn disease, diarrhoea;
- gastric diseases, such as nausea or emesis; - urinary pathologies, such as prostatitis, spinal reflex bladder, urinary incontinence, cystitis, urethritis, nephritis, erectile dysfunctions;
- tumoral pathologies, autoimmunitary diseases or diseases associated to AIDS;
- pathologies of the nervous central system, such as anxiety, depression, schizophreny, dementia, epilepsy, Parkinson's syndrome, Alzheimer's diseases, drugs and alcohol addiction, alcoholism, Huntington's chorea, neurodegenerative diseases and somatic disorders, such as stress;
- treatment of pain, in particular visceralgia, neuritis, neuralgia;
- cardiovascular diseases, such as hypertension, edemas, thrombosis, angina, vascular spasmus; - inflammatory, such as arthritis, rheumatoid arthritis.

Claims

1) Linear compounds of general formula (I) comprising an alfa-alfa-disubstituted amino acid and at least an amino group capable of giving basic characteristics to the compounds
Figure imgf000061_0001
wherein:
XI is a group selected from -NR6-CO-, -CO- and -NR6-CS-
Rl is an aryl or aryl-alkyl or aryl-ethylene group containing from 7 to 12 carbon atoms, wherein aryl indicates a group selected from the group consisting of pyridine, pyrrol, thiophene, benzene, naphthalene, imidazol, diphenyl, phenyl-thiophene, and it can be possibly substituted by one or more groups independently chosen from the group consisting of halogen, C1-C6 alkyl possibly substituted by not more than three fluorine atoms (such as a trifluoromethylic group), C1-C6 alkyloxy possibly substituted by not more than three fluorine atoms (such as a trifluoromethoxylic group), OH, -NHRIO, - N(R10)2, -SRIO, -CONHR10,- -COR-10, -COOR1Θ, -R9GOOR10, -OR COOR10, - R9COR10, -CONHR10, -R9CONHR10, -NHCORIO, and -nitro, wherein RIO is H or a linear or branched C1-C6 alkyl chain, and R9 is a linear or branched C1-C6 alkylene chain; or the radical:
Figure imgf000061_0002
possibly substituted by one or more substituents independently chosen from halogen, Cl- C6 alkyl possibly substituted by not more than three fluorine atoms (such as a trifluoromethylic group), C1-C6 alkyloxy possibly substituted by not more than three fluorine atoms (such as a trifluoromethoxylic group), -OH, -NHRIO, -N(R10)2, -SRIO, - CONHR10, -COR10, -COOR10, -R9COOR10, -OR9COOR10, -R9COR10, -CONHRIO, - R9CONHR10, -NHCORIO, and -nitro, wherein RIO is H or a linear or branched C1-C6 alkyl chain, and R9 is a linear or branched C1-C6 alkylene chain, and wherein D = O, S, CH2, O-CH2 or N-R7, wherein R7 is selected from the group consisting of H, a linear or branched C1-C6 alkyl chain, and acyl radical R8-CO, wherein R8 is selected from the group consisting of H and linear or branched C1-C6 alkyl chain;
R6 is selected from the group consisting of H and linear or branched C1-C6 alkyl chain; A and B are independently selected from the group consisting of linear or branched C1-C6 alkyl chain, aryl or arylalkyl chain wherein the aryl portion is selected from the group consisting of benzothiophene, indol, pyridine, pyrrol, benzofurane, thiophene, benzene, naphthalene, imidazol, diphenyl, and it can be possibly substituted by one or more substituents independently chosen from halogen, C1-C6 alkyl chain possibly substituted by not more than three fluorine atoms (such as a trifluoromethylic group), C1-C6 alkyloxy possibly substituted by not more than three fluorine atoms (such as a trifluoromethoxylic group), -OH, -NHRIO, -N(R10)2, -SRIO, -CONHR10, -COR10, -COOR10, -R9COOR10, - OR9COOR10, -R9COR10, -CONHR10, -R9CONHR10, -NHCORIO, and -nitro, wherein RIO is H or a linear or branched C1-C6 alkyl chain, and R9 is a linear or branched C1-C6 alkylene group, or A and B, together with the carbon atom to which they are bound, may form a group having general formula (II):
Figure imgf000062_0001
wherein the broken line indicates a possible double bond; n and m can independently be 0, 1 or 2; R13 and R14 are independently selected from the group consisting of H, C1-C6 alkyl chain, or they can be linked to form an aromatic group selected from the group consisting of benzothiophene, indol, pyridine, pyrrol, benzofurane, thiophene, benzene, naphthalene, imidazol, and biphenyl, which can be possibly substituted by one or more substituents independently selected from halogen, C1-C6 alkyl possibly substituted by not more than three fluorine atoms (such as trifluoromethylic group), C1-C6 alkyloxy chain possibly substituted by not more than three fluorine atoms (such as trifluoromethoxylic group), -OH, -NHRIO, -N(R10)2, -SRIO, -CONHR10, -COR10, -COOR10, -R9COOR10, - OR9COOR10, -R9COR10, -CONHR10, -R9CONHR10, -NHCORIO, and -nitro, wherein RIO is H or linear or branched C1-C6 alkyl chain, and R9 is a linear or branched C1-C6 alkylene chain;
X2 is selected from the group consisting of -CONR6- and -CH2NR6-, wherein R6 is as described above; R2 is selected from the group consisting of an aryl-alkyl or aryl radical wherein the aryl portion is selected from the group consisting of benzothiophene, indol, pyridine, pyrrol, benzofurane, thiophene, benzene, naphthalene, imidazol, and biphenyl, and it can be possibly substituted by one or more substituents independently selected from halogen, Cl- C6 alkyl possibly substituted by not more than three fluorine atoms (such as a trifluoromethylic group), C1-C6 alkyloxy possibly substituted by not more than three fluorine atoms (such as a trifluoromethoxylic group), -OH, -NHRIO, -N(R10)2, -SRIO, - CONHR10, -COR10, -COOR10, -R9COOR10, -OR9COOR10, -R9COR10, -CONHR10, - R9CONHR10, -NHCORIO, and -nitro, wherein RIO is H or a linear or branched C1-C6 alkyl chain, and R9 is a linear or branched C1-C6 alkylene chain, R3 includes at least a basic amino group, and it is represented by the general formula: ~" 4 " ^3" R5 wherein R4 is selected from the group consisting of:
- C1-C6 alkylene, C5-C8 cycloalkylene,
- an aliphatic heterocycle containing at least one atom selected from N, S and O, and possibly substituted by one or two C1-C6 alkyl groups or -COR15 group, in which R15 is selected from the group consisting of -NR11R12 and -ORll, wherein Rl l and R12, independently from each other, are H or a linear or branched C1-C6 alkyl group;
- aryl-alkyl or aryl wherein the aryl portion is selected from the group consisting of benzothiophene, indol, pyridine, pyrrol, benzofurane, thiophene, benzene, naphthalene, imidazol, and biphenyl, and it can be possibly substituted by one or more substituents independently selected from halogen, C1-C6 alkyl possibly substituted by not more than three fluorine atoms (such as a trifluoromethylic group), C1-C6 alkyloxy possibly substituted by not more than three fluorine atoms (such as a trifluoromethoxylic group), - OH, -NHRIO, -N(R10)2, -SRIO, -CONHR10, -COR10, -COOR10, -R9COOR10, - OR9COOR10, -R9COR10, -CONHR10, -R9CONHR10, -NHCORIO, and -nitro, wherein RIO is H or a linear or branched C1-C6 alkyl group, and R9 is a linear or branched C1-C6 alkylene group, X3 is a single bond or it is selcted from the group consisting of -CH2-, -CH2-CH2-, -CO-, - OCH2-CH2O-, -O- , -NH-CO-CH2-, and -NH-CO-; or -R4-X3- taken together are a group -CO-CH2- R5 is: an aliphatic heterocycle selected from the group consisting of pyrrolidine, piperidine, moφholine, chinuclidine, diazepan, tetrahydropyran, l,4-dioxa-8-azaspiro[4,5]decane, possibly substituted by one or more substituents selected from the group consisting of Cl- C6 alkyl, hydroxymethyl, -OH, cyanomethyl, and C1-C6 alkyloxy;
- an azetidine possibly substituted by a group -(CH2)n-R17, wherein R17 is selected from the group consisting of moφholine, piperidine, pyrrolidine, tetrahydropyran, and tefrahydrothiopyran;
- a piperidine possibly C-substituted by a C1-C6 alkyl chain, substituted by a group X5- R18 wherein X5 is a bond or a group -C(R11)(R12)-, -CO-, -COCH2-, -CH2CH2-, and R18 is selected from the group consisting of moφholine, piperidine, pyrrolidine, tetrahydropyran, tetrahydrotiopyran, cyclohexane, dioxane, l,4-dioxa-spiro(4,5)decyl and an aromatic selected from the group consisting of thiophene, pyridine, furane, pyrrol, thiadiazole, thiazole, and phenyl possibly substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl possibly substituted by not more than three fluorine atoms, C1-C6 alkyloxy possibly substituted by not more than three fluorine atoms, -OH, -NHRIO, -N(R10)2, and -SRIO wherein RIO, Rll and R12 are selected from H and linear or branched CI -C6 alkyl chain;
- a piperazine possibly C-substituted by one or two C1-C6 alkyl groups, and possibly N- substituted by a group chosen from -SO2NRl lR12,-(CH2)2O(CH2)2OH, -CH2CN, or by the group -X4-R16 wherein X4 is a bond or it is selected from the group consisting of -CO-, - CH2-, -CONR6-, -COCH2- and -CO-NR6-CH2-, and R16 is selected from the group consisting of pyirolidine, moφholine, tetrahydropyran, tetrahydrofurane, dioxane, thiophene, pyridine, phenyl, naphthyl, diphenyl, pyrazol, oxazol, isoxazol and thiadiazol, possibly substituted by one or more groups selected from halogen, C1-C6 alkyl, C1-C6 alkyloxy, OH; and R6, Rl 1 and R12 are as defined above;
- an amino group selected from the group consisting of -NR11R12, -NH(CH2)m- NR11R12, amino-tetrahydropyran, furylmethylamino, -NH(CH2)2O(CH2)2OH, wherein m ranges from 3 to 6, and Rl 1 and R12 are as defined above
- an amino-cycloalkyl group possibly substituted on the ring by a group selected from OH, and NR11R12, wherein Rl 1 and R12 are as defined above,
-a cycloalkyl group possibly substituted on the ring by a group selected from NR11R12, wherein Rl 1 and R12 are as defined above; - an aryl group selected from the group consisting of thiophene, pyridine, furane or phenyl possibly substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkyloxy, and OH; the 'retro-inverted' compounds of the formula (I) compounds as above defined, in which one or more amidic bonds are inverted; the pharmaceutically acceptable salts of the compounds of general formula (I) as above defined, with organic or inorganic acids selected from the group consisting of hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, trifluoroacetic acid,oxalic acid, malonic acid, maleic acid, fumaric acid, succinic acid, tartaric acid and citric acid; and the diastereoisomers and enantiomers of the compounds of formula (I) as above defined, or mixtures thereof.
2. The compounds of formula (I) according to claim 1, wherein the aminoacidic residue of general formula (III)
Figure imgf000065_0001
is selected from the group consisting of aminoacidic residues of • α, -disubstituted glycine-type selected from the group consisting of 1-aminocyclohexane-l -carboxylic acid (Ac6c), 1 -aminocyclopentane- 1 -carboxylic acid (Ac5c), l-aminocyclopent-3-ene-l- carboxylic acid (Ac5c), 1-aminoisobutyrric acid, 1-aminoindane-l -carboxylic acid (1-Aic), 2-aminoindane-2-carboxylic acid (2-Aic), 2-aminotetraline-2-carboxylic acid (2-Atc), 2- ' methyl-2-ethylglycine, 2-methyl-2-isopropylglycine, 2-methyl-2-n-propylglycine, 2- . methyl-2-(2-butyl) glycine, 2-methyl-2-isobutylglycine, 2-methyl-phenylalanine; and the other groups are as defined in claim 1. 3. The compounds of formula (I) according to claim 1, wherein: - XI is a CO group;
Rl is an aryl or aryl-efhylene group containing from 7 to 12 carbon atoms, wherein aryl is a group selected from benzene, naphthalene, and biphenyl possibly substituted by one or more groups independently selected from halogen, C1-C6 alkyl possibly substituted by not more than three fluorine atoms (such as a trifluoromethylic group), C1-C6 alkyloxy possibly substituted by not more than three fluorine atoms (such as a trifluoromethoxylic group), -OH, -NHRIO, -N(R10)2, -SRIO, -CONHR10, -COR10, -COOR10, -R9COOR10, - OR9COOR10, -R9COR10, -CONHR10, -R9CONHR10, -NHCORIO, and -nitro, wherein RIO is H or a linear or branched C1-C6 alkyl chain, and R9 is a linear or branched C1-C6 alkylene; or it is the following radical
Figure imgf000066_0001
possibly substituted by one or more substituents independently selected from halogen, Cl- C6 alkyl possibly substituted by not more than three fluorine atoms (such as trifluoromethylic group), C1-C6 alkyloxy possibly substituted by not more than three fluorine atoms (such as trifluoromethoxylic group), -OH, -NHRIO, -N(R10)2, -SRIO, - CONHR10, -COR10, -COOR10, -R9COOR10, -OR9COOR10, -R9COR10, -CONHR10, - R9CONHR10, -NHCORIO, and -nitro, wherein RIO is H or linear or branched C1-C6 alkyl chain, and R9 is a linear or branched C1-C6 alkylene chain, and wherein D = O, S or N-R7„wherein R7 is selected from the group consisting of H, linear or branched C1-C6 alkyl chain, acyl radical R8-CO, wherein R8 is selected from the group consisting of H and linear or branched C1-C6 alkyl chain;
- R6 is selected from the group consisting of H and linear or branched C1-C6 alkyl; - the amino acidic residue of general formula (III)
Figure imgf000067_0001
is an α,α-disubstituted glycine-type residue selected from the group consisting of 1- aminocyclohexane-1 -carboxylic (Ac6c), 1 -aminocyclopentane- 1 -carboxylic acid (Ac5c), 1-aminoindane-l -carboxylic acid (1-Aic), l-aminocyclopentan-3-ene 1- carboxylic acid (Ac5c), 2-methyl-phenylalanine, 2-methyl-2-ethyl-glycine,
R2 is a phenylmethyl group possibly substituted on the phenyl portion by one or two groups independently selected from the group cosisting of halogen, C1-C6 alkyl, C1-C6 alkyloxy, and OH;
- X2 is selected from -CONR6- and -CH2NR6;
R3 includes at least one basic amino group and it is the following group:
— R4 - X3- R5 wherein - R4 is selected from the group consisting of a group -(CH2)..-, wherein n ranges from 1 to 3, a C5-C8 cycloalkylene group and an aliphatio heterocycle selected from piperidine, pyrrolidine or piperazine possibly substituted by one or two C1-C6 alkyl chains; - X3 is a bond or it is selected from the group consisting of -CO-, -CH2-, -CH2-CH2-, -CO- CH2-, and -NH-CO-; - R5 is selected from the group consisting of: a) an aliphatic heterocycle selected from piperidine, pyrrolidine, moφholine, diazepan, tetrahydropyran, tetrahydrothiopyran, and l,4-dioxa-8-azaspiro[4,5]decane, possibly substituted by one or two groups selected from C1-C6 alkyl, hydroxymethyl, cyanomethyl, C1-C6 alkyloxy, and OH; b) an azetidine possibly substituted by a -(CH2)n-R1 group wherein R17 is selected from the group consisting of moφholine, piperidine, pyrrolidine, tetrahydropyran, and tetrahydrothiopyran; c) a piperidine, possibly C-substituted by a C1-C6 alkyl chain, substituted by a group X5- R18, wherein X5 is a bond or it is selected from the group consisting of -C(R11)(R12)-, - CO-, -CH2CH2-, and -COCH2-; and R18 is selected from the group consisting of furane, moφholine, pyrrole, thiophene, tetrahydropyran, tetrahydrothiopyran, pyrrolidine, cyclohexane, cyclopentane, 1-3-dioxane, thiazole and l,4-dioxa-spiro(4,5)decyl, possibly substituted by one or more groups selected from halogen, C1-C6 alkyl, C1-C6 alkyloxy, - OH, -NHRIO, -N(R10)2, and -SRIO, wherein RIO, Rl 1 and R12 are selected from H and linear or branched C1-C6 alkyl; d) a piperazine possibly C-substituted by one or two C1-C6 alkyl groups and possibly N- substituted by a group selected from -(CH2)2O(CH2)2OH, -CH2CN and a group X4-R16, wherein X4 is a bond or it is selected from the group consisting of -CH2-,-CH2-CH2-, and -COCH2-, and R16 is selected from the group consisting of pyridine, thiophene, tetrahydropyran, moφholine, tetrahydrofurane, and 1,
3-dioxane; e) an amino group selected from -NR11R12 and -NH-(CH2)m-NRllR12 wherein Rll, R12 and m are as defined above; f) an amino-cycloalkyl possibly substituted on the ring by a group selected from OH and - NR11R12, or a cycloalkyl possibly substituted by a group NR11R12, wherein Rll and
R12 are as defined above; g) an heteroaromatic selected from pyridine and thiazole.
4. The compounds of general formula (I) according to claim 3, wherein: XI is a -CO- group; Rl is an aromatic group selected from the group consisting of biphenyl, pnenyi-etnyiene, naphthyl, phenyl-thiophene, benzothiophene, benzofurane, and indole possibly N- substituted by a C1-C6 alkyl group, which can be possibly substituted by one, two or three groups independently selected from the group consisting of halogen, C1-C6 alkyl possibly substituted by not more than three fluorine atoms, C1-C6 alkyloxy, OH, NHRIO, and N(R10)2, wherein Rl 0 is selected from H and C 1 -C6 alkyl; the amino acidic residue of general formula (III) is selected from the group consisting of 1- aminocyclohexane-1 -carboxylic acid (Ac6c), 1 -aminocyclopentane- 1 -carboxylic acid (Ac5c), 1-aminoindane-l -carboxylic acid (1-Aic), l-aminocyclopentan-3-ene 1- carboxylic acid (Ac5c), 2-methyl-phenylalanine, and 2-methyϊ-2-ethyl-glycine; R6 is H;
R2 is a phenyl-methyl group, having the phenyl group possibly substituted by a C1-C6 alkyl group; X2 is selected from -CONH- and CH2NH-;
R3 includes at least one basic amino group having the following formula:
— R4 - X3- R5 wherein: - R4 is selected from the group consisting of a group -(CH2)n- wherein n ranges from 1 to
3, a C5-C8 cycloalkylene group selected from cyclopentylene and cyclohexylene, and an aliphatic heterocycle selected from piperidine, pyrrolidine and • piperazine possibly substituted by one or two C1-C6 alkyl groups;
- X3 is a bond or it is a group selected from -CO-, -CH2-, -CH2-CH2-, and -NH-CO-; - R5 is selected from: a) an aliphatic heterocycle selected from the group consisting of piperidine, pyrrolidine, moφholine, diazepan, tetrahydropyran, and l,4-dioxa-8-azaspiro[4,5]decane, possibly substituted by one or two groups selected from C1-C6 alkyl, C1-C6 alkyloxy, OH, and cyanomethyl; b) an azetidine substituted by a group -(CH2)n-Rl 7, wherein Rl 7 is tetrahydropyran; c) a piperidine possibly C-substituted by a C1-C6 alkyl group, and substituted by a group X5-R18 wherein X5 is a bond or it is selected from the group consisting of -C(R11)(R12)-, -CO-, -CH2CH2-, and -COCH2-, and R18 is a group selected from thiophene, tetrahydropyran, tetrahydrothiopyran, pyrrolidine, cyclohexane, cyclopentane, and 1-3- dioxane, possibly substituted by one or more groups selected from C1-C6 alkyl, -NHRIO, and -N(R10)2, wherein RIO, Rll and R12 are selected from H and linear or branched Cl- C6 alkyl; d) a piperazine possibly C-substituted by one or two C1-C6 alkyl group, and possibly N- substituted by a group selected from -CH2CN and X4-R16, wherein X4 is a bond or it is selected from -CH2- and -COCH2-, and R16 is selected from the group consisting of pyridine, thiophene, tetrahydropyran, moφholine, tetrahydrofurane, and 1,3-dioxane; e) an amino group selected from -NR11R12 and -NH-(CH2)m-NRl lR12, wherein Rll, R12 and m are as defined above; f) an amino-cyclohexane or a cyclohexane possibly substituted on the ring by the group - NR11 Rl 2, wherein Rl 1 and Rl 2 are as defined above; g) an heteroaromatic group represented by pyridine.
5. The compounds of general formula (I) according to claim 4, wherein: XI is a -CO- group;
Rl is an aromatic group selected from the group consisting of phenyl-ethylene, naphthyl, benzothiophene, and benzofurane, possibly substituted by one, two or three groups independently selected from halogen, C1-C6 alkyl possibly substituted by not more than three fluorine atoms, C1-C6 alkyloxy, OH, NHRIO, and N(R10)2 wherein RIO is selected from H and C1-C6 alkyl; the amino acidic residue of general formula (III) is selected from 1-aminocyclohexane-l- carboxylic acid (Ac6c), and 1 -aminocyclopentane- 1 -carboxylic acid (Ac5c);
R6 is H; R2 is phenyl-methyl;
X2 is -CONH-;
R3 includes at least one basic amino group and it is the following group:
— R4 - X3- R5 wherein - R4 is selected from -(CH2)n- wherein n ranges from 1 to 3, and piperidine possibly substituted by a C1-C6 alkyl group;
X3 is a bond or it is a group selected from -CO- and -CH2-;
R5 is selected from: a) an aliphatic heterocycle selected from piperidine and tetrahydropyran, possibly substituted by one or more C1-C6 alkyl groups; b) a piperidine possibly C-substituted by a C1-C6 alkyl group, substituted by a group X5- R18 wherein X5 is a bond or it is a group selected from -C(R11)(R12)- and -CO-, and R18 is a group selected from tetrahydropyran, cyclohexane and 1-3-dioxane, possibly substituted by one or more groups selected from C1-C6 alkyl, -NHRIO, and -N(R10)2, wherein RIO, Rl 1 and R12 are selected from H and linear or branched C1-C6 alkyl; c) a piperazine possibly C-substituted by one or two C1-C6 alkyl groups, and possibly N- substituted by a group X4-R16 wherein X4 is -CH2-, and R16 is selected from tetrahydropyran and 1,3 -dioxane.
6. The compounds of general formula (I) according to claim 4, wherein the said compounds are defined by the following formulas:
Nα|^α enzo[b]fhiophenyl-2-ylcarbonyl)-l-aminocyclopentane-l-carbonyl]-D- phenylalanine-N-[3(moφholin-4-yl)propyl]amide (lR,3S)-acid-NΥ{NαpSTα(benzo[b]tbiophen-2-yl-carbonyl)-l-aminocyclopentan-l-carboxy]-
D-phenylalanil}-3-aminocyclopentan-l-carboxylic-N-[(lS,2S)-2-aminocyclohexyl] amide
N^^pS^ i hen^-ylcarboxy)- 1 -aminocyclopentan-1 -carboxy]-D-phenylalanil} -(1 R,3 S)-
3-aminocyclopentane-l-carboxylic-acid-N-((lS,2S)-2-aminocyclohexyl)amide trifluoroacetate salt
N7{Nαp f0l(N-(methyl)indol-2-ylcarboxy)-l-aminocyclopentan-l-carboxy]-D- phenylalanyl}-(lR,3S)-3-aminocyclopentane-l-carboxylic-acid-N-((lS,2S)-2-amino cyclohexyl)amide trifluoroacetate salt
Nγ{Nα[Nα[4-(methyl)cynnamoyl]- 1 -aminocyclopentan- 1 -carboxy]-D-phenylalanyl} - (lR,3S)-3-aminocyclopentane-l-carboxylic-acid-N-((lS,2S)-2-aminocyclohexyl)amide trifluoroacetate salt
Nγ{Nα[Nα(benzofuran-2-ylcarboxy)- 1 -aminocyclopentan- 1 -carboxy] -D-phenylalanyl} -
(lR,3S)-3-aminocyclopentane-l-carboxylic-acid-N-((lS,2S)-2-aminocyclohexyl) amide trifluoroacetate salt Nα[Nα(4-(methyl)cinnamoyl)-(R,S) 1 -aminoindane- 1 -carboxy] -D-phenylalanine amide-N-
[(lS,3R)-3-(moφholin-4-ylmethyl)cyclopentyl]
Nγ{Nα[Nα(benzo[b]thiophen-2-ylcarbonyl)- 1 -aminocyclopentan- 1 -carboxy]-D- phenylalanyl} -( 1 R,3 S)-3 -aminocyclopentane- 1 -carboxylic-acid-N-(( 1 S ,2S)-2- dimethylaminocyclohexyl)amide hydrochloride salt Nγ{Nα[Nα(benzo[b]thiophen-2-ylcarbonyl)- 1 -aminocyclopentan- 1 -carboxy]-D-4-methyl- phenylalanyl} -( 1 R,3 S)-3 -aminocyclopentane- 1 -carboxylic-acid-N-( 1 S ,2S)-2-dimethyl aminocyclohexyl)amide hydrochloride salt
Nγ{Nα[Nα(4-methyl-cinnamoyl)- 1 -aminocyclopentan- 1 -carboxy] -D-phenylalanyl} -
( 1 R,3 S)-3 -aminocyclopentane- 1 -carboxylic-acid-N-(( 1 S ,2S)-2- dimethylaminocyclohexyl)amide hydrochloride salt
Nγ{NαpNf (benzofuran-2-ylcarboxy)- 1 -aminocyclopentan- 1 -carboxy]-D-phenylalanyl} -
(lR,3S)-3-aminocyclopentane-l-carboxylic-acid-N-((lS,2S)-2- dimethylaminocyclohexyl)amide hydrochloride salt
NY{Nα[N0t(biphen-4-ylcarbonyl)- 1 -aminocyclopentan- 1 -carboxy] -D-phenylalanyl} - (lR,3S)-3-aminocyclopentane-l-carboxylic-acid-N-((lS,2S)-2- dimethylaminocyclohexyl)amide hydrochloride salt Nγ{NαrNα(N-(methyl)indol-2-ylcarboxy)-l-aminocyclopentan-l-carboxy]-D- phenylalanyl}-(lR,3S)-3-aminocyclopentane-l-carboxylic-acid-N-((lS,2S)-2- dimethylaminocyclohexyl)amide hydrochloride salt
NΥ{Nα[Nα(benzo[b]thiophen-2-ylcarbonyl)-(R)- -methyl-α-ethylglycyl]-D- phenylalanyl}-(lR,3S)-3-amino cyclopentane- 1 -carboxylic-acid-N-((l S,2S)-2- aminocyclohexyl) amide trifluoroacetate salt
Nγ{Nα[Nα(4-methylcinnamoyl)-(R)-α-methyl-α-ethylglycyl]-D-ρhenylalanyl}-(lR,3S)-3- amino cyclopentane- 1 -carboxylic-acid-N-((l S,2S)-2-aminocyclohexyl) amide trifluoroacetate salt NΥ{Nα[Nα(biphenyl-4-carboxy)-l-aminocyclopentan-l-carboxy]-R-3(4(methyl) phenyl)alanyl}-(lR,3S)-3-aminocyclopentane-l-carboxylic-acid-N-((lS,2S)-2- aminocyclohexyl)amide hydrochloride salt
Nγ{Nα|^α(N-(methyl)indol-2-ylcarboxy)-l-aminocyclopentan-l-carboxy]-R-3-(4- methyl)phenyl)alanyl} -( 1 R,3 S)-3-aminocyclopentane- 1 -carboxylic-acid-N-(( 1 S ,2S)-2- aminocyclohexyl)amide hydrochloride salt
Nγ{NαrjNα(4-(memyl)cynnamoyl)-l-aminocyclopentan-l-carboxy]-R-3[4- methyl)phenyl]alanyl}-(lR,3S)-3-aminocyclopentane-l-carboxylic-acid-N-((lS,2S)-2- aminocyclohexyl)amide hydrochloride salt
Nαp^α(benzo[b]tMophen=2^yl-carbonyl)^t-aminocyclohexan4^arboxy]-D-phenylalaniner N- {3-[bis(n-butyl)amino]propyl} amide
Nα[Nα(benzo[b]thiophen-2-yl-carbonyl)-l-aminocyclohexan-l-carboxy]-D-phenylalanine-
N-[3(moφholin -4-yl)propyl]amide acid-3-cz-f-NΥ{Nα[^α(berιzo[b]ιWophen-2-ylcarbonyl)-l-aminocyclohexan-l-carboxy]-D- phenylalanil}aminocyclohexan-l-carboxylic -N-((lR,2S)-2-aminocyclohexyl)amide Nγ{NαpSIα(benzo[b]thiophen-2-ylcarbonyl)-l-aminocyclohexan-l-carboxy]-D- phenylalanyl}-3-cw-aminocyclohexan-l-carboxylic-acid-N-(5-aminopentyl)-amide trifluoroacetate salt
Nα[N α(benzo[b]fhiophen-2-ylcarbonyl)- 1 -(R)-amino-indane- 1 -carboxy] -D-phenylalanine-
N-[3(moφholin-4-yl)propyl ]amide Nα[Nα enzo[b]thiophen-2-ylcarbonyl)- 1 -aminocyclopentane- 1 -carboxy]-L- phenylalanine-N-[3(moφholin-4-yl)propyl ]amide (lR,3S) acid-3-Nγ{Nα| fα(benzo[b]tlιiόphen-2-ylcarbonyl)-l-aminocyclohexan-l- carboxy] -D-phenylalanil} aminocyclopentane- 1 -carboxylic-N-(l S ,2R)-2-aminocyclohexyl) amide acid-3-cis-Nγ{Nα|^α(benzo[b]tMophen-2-ylcarbonyl)-l-aminocyclopentano-l-carboxy]-L- phenylalanil} aminocyclohexan-1 -carboxylic -N-(2-cis-aminocyclohexyl) amide NΥ{Nα[^α(benzo[b]thiophen-2-ylcarbonyl)-l-aminocyclohexan-l-carboxy]-D- phenylalanil} -(L-(4R)amino-proline-N-(lR,2R)-aminocyclohexyl) amide acid-3- cis-Nγ{NαrjNα(benzo[b]tln'ophen-2-ylcarbonyl)-l-aminocyclohexan-l-carboxy]-D- phenylalanil}-aminocyclohexan-l-carboxylic- -N-[(lS,2S)-2-aminocyclohexyl]amide acid-3-cis-Nγ{Nα|T->fα(benzo[b]tlήophen-2-ylcarbonyl)-l-aminocyclopentan-l-carboxy]-D- phenylalamT}aminocyclohexan-l-carboxylic-N-[(lS,2R)-2-dimethylaminocyclohexyl] amide acid-3-cis-NΥ{Nα|^ (benzo[b]thiophen-2-ylcarbonyl)- 1 -aminocyclopentan- 1 -carboxy]-D- phenylalanil } aminocyclohexan- 1 -carboxylic-N- [(IS ,2R)-aminocyclohexyl] amide acido-3-cis-NΥ{NαpNα(benzo[b]tWophen-2-ylcarbonyl)-l-aminocyclopentan-l-carboxy]- D-phenylalamT}aminocyclohexan-l-carboxylic-N-[(lS,2S)-aminocyclohexyl] amide Nαr Sfα(benzo[b]thiophen-2-ylcarbonyl)- 1 -aminocyclopentano- 1 -carboxy]-D-phenylalanina amide-N-[(lS,3R)-3-(4-(methyl)piperazin-l-yl)methyl)cyclopentyl]
Figure imgf000073_0001
amide-N-[(l S,3R)-3-(4-(methyl)piperazin- 1 -yl)carbonyl)cyclopentane
NαrjNα(benzo[b]tln^phen-2-ylcarbonyl)-D-α-methylphenylalanil]-D-phenylalanina-N-[3- (moφholin-4-yl)propyl] amide acid-3-cis-Nα[Nα(benzo[b]ιhiophen-2-ylcarbonyl)-l-aminocyclohexan-l-carboxy]-D- phenylalanil } aminocyclohexan- 1 -carboxylic -N-(( 1 R,2S)-2-methylaminocyclohexyl)amide Nα|^ enzo[b]tlιiophen-2-ylcarbonyl)-l-aminocyclopentan-l-carboxy]-D-phenylalanil}- L-(4R)amino-prolina-N-(-2-cis-aminocyclohexyl) amide
(1 R,3 S) acid-3-Nγ{Nα[Nα(benzo[b]thiophen-2-ylcarbonyl)- 1 -aminocyclopentan- 1 - carbox^y]-D-phenylalarιil}amiribcyclopentane-l-carboxylic-N-(2-cis- aminocyclohexyl)amide (lS,3R)-l-N{N |Nrα(benzo[b]tl ophen-2-ylcarbonyl)-l-arninocyclopentan-l-carboxy]-D- phenylalanil} -3- { [ 1 S-((2S)-aminocyclohexyl)amino]methyl} amino cyclopentane acid-3-cis-N{Nα|^ (benzo[b]thiophen-2-ylcarbonyl)-l-aminocyclopentan-l-carboxy]-D- phenylalanil} aminocyclohexan-l-carboxylic-N-((lR,2S)-2-dimethylaminocyclohexyl) amide
(1 R,3 S) acid-3-N {Nα[Ηα enzo[b]ιWophen-2-ylcarbonyl)- 1 -aminocyclohexan- 1 -carboxy]- D-phenylalanil}aminocyclopehtan-l-carboxylic-N-((lR,2R)2-aminocyclohexyl) amide
Biphenyl-4-carboxylic acid, {l-[l-(3-moφholin-4-yl-propylcarbamoyl)-2-(R)-phenyl- ethylcarbamoyl] -cyclopentyl} -amide
Benzofuran-2-carboxylic acid, { 1 -[ 1 -(3-moφholin-4-yl-propylcarbamoyl)-2-(R)-phenyl- ethylcarbamoyl]-cyclopentyl}-amide Benzo[b]thiophene-2-carboxylic acid, methyl- {1-[1 -(3-moφholin-4-yl-propylcarbamoyl)-
2(R)-phenyl-ethylcarbamoyl]-cyclohexyl}-amide l-[3-(3,4-dichlorophenyl)-acryloylamino]-cyclopentanecarboxylic acid, [l-(3-moφholin-
4-yl-propylcarbamoyl)-2-(R)-phenyl-ethyl]-amide
Benzo[b]thiophene-2-carboxylic acid { 1 -[ li?-(3-moφholin-4-yl-propylcarbamoyl)-2- phenyl-ethylcarbamoyl]-cyclopent-3-enyl}-amide
1 -Methyl- lH-indole-2-carboxylico acido, { 1 -[ 1 -(3 -moφholin-4-yl-propylcarbamoyl)-2-
(R)-phenyl-ethylcarbamoyl] -cyclopentyl} -amide
Benzo[b]thiophene-2-carboxylic acid (l-{l-[3-(2,6-dimethyl-moφholin-4-yl)- propylcarbamoyl]-2-(R)-phenyl-ethylcarbamoyl}-cyclohexyl)-amide lH-indole-2-carboxylic acid, {l-[l-(3-moφholin-4-yl-propylcarbamoyl)-2-(R)-phenyl- efhylcarbamoyl]-cyclopentyl} -amide l-[3-(3,4-dibromophenyl)-acryloylamino]-cyclopentanecarboxylic acid [l-(3-moφholin-4- yl-propylcarbamoyl)-2-(R)-phenyl-ethyl]-amide
5-phenyl-thiophene-2-carboxylic acid, { 1 -[ 1 -(3-moφholin-4-yl-propylcarbamoyl)-2-(R)- phenyl-ethylcarbamoyl]-cyclopentyl}-amide
Benzo[b]thiophene-2-carboxylic acid, (1 - { 1 (R)- [3 -(4-methyl-[ 1 ,4] diazepan- 1 -yl)- propylcarbamoyl]-2-phenylethyl carbamoyl}-cyclopentyl)-amide TFA salt
Benzo b]tluophene-2-carboxylic acid (l-{l(R)-[3-(4-memoxy-piperidin-l-yl)- propylcarbamoyl]-2-phenyl-ethylcarbamoyl}-cyclopentyl)-amide TFA salt Benzo[b]thiophene-2-carboxylic acid (l-{l-(R)-[3-(4-hydroxy-piperidin-l-yl)- propylcarbamoyl]-2-phenylethyl carbamoyl} -cyclopentyl)-amide. Benzo[b]thiophene-2-carboxylic acid (1 :- { 1 (R)-[3-(l ,4-dioxa-8-aza-spiro[4.5]dec-8-yl)- propylcarbamoyl] -2-phenyl-ethylcarbamoyl} -cyclopentyl)-amide TFA salt Benzo[b]tMophene-2-carboxylic acid (l-{l(R)-[3-(3,5-ct"5-dimemylpiperazin-l-yl)-3-oxo- propylcarbamoyl]-2-phenyl-ethylcarbamoyl}-cyclopentyl)-amide TFA salt Benzo[b]fhiophene-2-carboxylic acid (l-{l(R)-[3-oxo-3-(4-pyridin-2-yl-piperazin-l-yl)- propylcarbamoyl]-2-phenyl-ethylcarbamoyl}-cyclopentyl)-amide 6-Bromo-naphthalene-2-carboxylic acid (1 - { 1 (R)-[3-oxo-3-(4-pyridin-2-yl-piperazin- 1 - yl)-propylcarbamoyl]-2-phenyl-ethylcarbamoyl} -cyclopentyl)-amide TFA salt 6-Bromo-benzo[b]tMophene-2-carboxylic acid (l-{l(R)-[3-oxo-3-(4-pyridin-2-yl- piperazin-l-yl)-propylcarbamoyl]-2-phenyl-ethylcarbamoyl}-cyclopentyl)-amide
Benzo[b]thiophene-2-carboxylic acid [l-(l(R)-{3-oxo-3-[4-(tefrahydro-pyran-4-ylmethyl)- piperazin- 1 -yl]-propylcarbamoyl} -2-phenyl-ethylcarbamoyl)-cyclopentyl]-amide TFA salt Benzo[b]thiophene-2-carboxylic acid [l-(l(R)-{3-oxo-3-[4-(tetrahydro-pyran-4-yl)- piperazin-l-yl]-propylcarbamoyl}-2-phenyl-ethylcarbamoyl)-cyclopentyl]-amide TFA salt Benzo[b]fhiophene-2-carboxylic acid (l-{l(R)-[3-(4-[l,3]dioxan-5-ylmethyl-piperazin-l- yl)-3-oxo-propylcarbamoyl]-2-phenyl-ethylcarbamoyl}-cyclopentyl)-amide TFA salt Benzo[b]thiophene-2-carboxylic acid [ 1 -(1 (R)- {[ 1 -(1 -amino-cyclopentanecarbonyl)- piperidin-4-ylmethyl]-carbamoyl}-2-phenyl-ethylcarbamoyl)-cyclopentyl]-amide Benzo[b]thiophene-2-carboxylic acid [1 -(1 (R)- {3-oxo-3-[4-(tetrahydro-furan-2(R)- ylmethyl)-piperazin- 1 -yl]-prbpylcarbamoyl} -2-phenyl-ethylcarbamoyl)-cyclopentyl]- amide TFA salt
Benzo[b]thiophene-2-carboxylic acid (1 - { 1 (R)-[3-(4-cyanomethyl-piperazin-l-yl)-3-oxo- propylcarbamoyl] -2-phenyl-ethylcarbamoyl} -cyclopentyl)-amide Benzo[b]thiophene-2-carboxylic acid { 1 -[2-phenyl- 1 (R)-(l -pyridin-2-ylmethyl-piperidin- 4-ylcarbamoyl)-ethylcarbamoyl]-cyclopentyl} -amide TFA salt.
Benzo[b]thiophene-2-carboxylic acid [ 1 -(2-phenyl- 1 (R)- { 1 -[2-(tetrahydro-pyran-4-yl)- emyl]-piperidin-4-ylcarbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide TFA salt 6-Bromo-naphthalene-2-carboxylic acid (l-{l(R)-[(l-ethyl-piperidin-4-ylmethyl)- carbamoyl]-2-phenyl-ethylcarbamoyl}-cyclopentyl)-ah ide Benzo[b]thiophene-2-carboxylic acid {l-[2-phenyl-l(R)-({l-[2-(tetrahydro-pyran-4-yl)- ethyl]-piperidin-4-ylmethyl}-carbamoyl)-efhylcarbamoyl]-cyclopentyl}-amide Benzo[b]thiophene-2-carboxylic acid (1 - { 1 (R)-[(l -cyclohexylmethyl-piperidin-4- ylmethyl)-carbamoyl]-2-phenyl-efhylcarbamoyl}-cyclopentyl)-amide Benzo[b]thiophene-2-carboxylic acid [ 1 -(2-phenyl- 1 (R)- {[1 -(tetrahydro-thiopyran-4-yl)- piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide TFA salt Benzo[b]thiophene-2-carboxylic acid [ 1 -(2-phenyl- l(R)-{[l-(tetrahydro-thiopyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide 1 -((E)-3 -_ -Tolyl-acryloylamino)-cyclopentanecarboxylic acid {2-phenyl- 1 (R)-[( 1 - tlu^phen-2-ylmemyl-piperidin-4-ylmethyl)-carbamoyl]-ethyl} -amide TFA salt 6-Bromo-naphthalene-2-carboxylic acid ( 1 - {2-phenyl- 1 (R)-[2-( 1 -pyrrolidin-2(S)- ylmethyl-piperidin-4-yl)-ethylcarbamoyl]-ethylcarbamoyl}-cyclopentyl)-amide TFA salt 6-Bromo-naphthalene-2-carboxylic acid (l-{2-phenyl-l(R)-[(piperidin-4-ylmethyl)- carbamoyl]-ethylcarbamoyl}-cyclopentyl)-amide
1 -(3-JD-Tolyl-acryloylamino)-cyclopentanecarboxylic acid (2-phenyl- 1 (R)- {2-[ 1 - (tefrahydro-pyran-4-ylmethyl)-piperidin-4-yl]-ethylcarbamoyl} -ethyl)-amide TFA salt Benzo[b]thiophene-2-carboxylic acid (l-{l(R)-[2-(l-cyanomethyl-piperidin-4-yl)- ethylcarbamoyl]-2-phenyl-ethylcarbamoyl}-cyclopentyl)-amide TFA salt Benzo[b]thiophene-2-carboxylic acid (1 - { 1 (R)-[(l -[ 1 ,3]dioxan-5-ylmethyl-piperidin-4- ylmethyl)-carbamoyl]-2-phenyl-ethylcarbamόyl} -cyclopentyl)-amide TFA salt Benzo[b]thiophene-2-carboxylic acid (l-{l(R)-[(l-[l,3]dioxan-2-ylmethyl-piperidin-4- ylmethyl)-carbamoyl] -2-phenyl-ethylcarbamoyl } -cyclopentyl)-amide
5-Chloro-benzofuran-2-carboxylic acid [ 1 -(2-phenyl- 1 (R)- {[ 1 -(tetrahydro-pyran-4-yl)- piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
5 -Chloro-benzofuran-2-carboxylic acid [ 1 -(2-phenyl- 1 (R)- { [ 1 -(tetrahydro-thiopyran-4-yl)- piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide Benzo[b]fhiophene-2-carboxylic acid [l-(l(R)-benzyl-2-{2-[l-(thiophen-2-yl-acetyl)- piperidin-4-yl]-ethylamino} -ethylcarbamoyl)-cyclopentyl]-amide TFA salt Benzo[b]thiophene-2-carboxylic acid [1-(1(R)-{[1-(1 -amino-cyclohexanecarbonyl)- piperidin-4-ylmefhyl]-carbamoyl} -2-phenyl-ethylcarbamoyl)-cyclopentyl]-amide TFA salt 6-Bromo-naphthalene-2-carboxylic acid [l-(2-phenyl-r(R)-{2-[l-(pyrrolidine-2(S)- carbonyl)-piperidin-4-yl]-emylcarbamoyl}-ethylcarbamoyl)-cyclopentyl]-arnide 6-Bromo-naphthalene-2-carboxylic acid [ 1 -(2-phenyl- 1 (R)- {2-[ 1 -(pyrrolidine-2(R)- carbonyl)-piperidin-4-yl]-ethylcarbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide Benzo[b]thiophene-2-carboxylic acid [l-(2-phenyl-l(R)-{2-[4-(thiophen-2-yl-acetyl)- piperazin-l-yl]-ethylcarbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide.
5-CUoro-benzofuran-2-carboxylic acid {l-[lR-(3-moφholin-4-yl-propylcarbamoyl)-2- phenyl-ethylcarbamoyl] -cyclopentyl} -amide 5-Chloro-benzo[b]thiophene-2-carboxylic acid {l-[lR-(3-moφholin-4-yl- propylcarbamoyl)-2-phenyl-ethylcarbamoyl]-cyclopentyl}-amide
5-Bromo-benzofuran-2-carboxylic acid {l-[lR-(3-moφholin-4-yl-propylcarbamoyl)-2- phenyl-ethylcarbamoyl]-cyclopentyl}-amide
6-Chloro-benzo[b]thiophene-2-carboxylic acid {l-[li?-(3-moφholin-4-yl- propylcarbamoyl)-2-phenyl-ethylcarbamoyl]-cyclopentyl} -amide
6-Methoxy-benzo[b]thiophene-2-carboxylic acid {l-[li?-(3-moφholin-4-yl- propylcarbamoyl)-2-phenyl-ethylcarbamoyl]-cyclopentyl}-amide
4-Chloro-benzo[b]thiophene-2-carboxylic acid {l-[lR-(3-moφholin-4-yl- propylcarbamoyl)-2-phenyl-ethylcarbamoyl]-cyclopentyl}-amide 6-Bromo-benzo[b]fhiophene-2-carboxylic acid {l-[lR-(3-moφholin-4-yl- propylcarbamoyl)-2-phenyl-ethylcarbamoyl]-cyclopentyl}-amide
6-Bromo-benzo[b]thiophene-2-carboxylic acid { 1 -[lR-(3-moφholin-4-yl- propylcarbamoyl)-2-phenyl-ethylcarbamoyl]-cyclohexyl}-amide
5-Fluoro-l-methyl-lH-indole-2-carboxylic acid {l-[li?-(3-moφholin-4-yl-l propylcarbamoyl)-2-phenyl-ethylcarbamoyl]-cyclopentyl}-amide
6-Chloro-l-methyl-lH-indole-2-carboxylic acid {l-[li?-(3-moφholin-4-yl- propylcarbamoyl)-2-phenyl-ethylcarbamoyl]-cyclopentyl}-amide
7-Methyl-benzo[b]thiophene-2-carboxylic acid {l-[lR-(3-moφholin-4-yl- propylcarbamoyl)-2-phenyl-ethylcarbamoyl]-cyclopentyl}-amide 5-Memyl-benzofuran-2-carboxylic acid {l-[lR-(3-moφholin-4-yl-propylcarbamoyl)-2- phenyl-ethylcarbamoyl]-cyclopentyl}-amide l,5-Dimethyl-lH-indole-2-carboxylic acid {l-[li? -(3-moφholin-4-yl-propylcarbamoyl)-2- phenyl-ethylcarbamoyl]-cyclopentyl}-amide
6-Amino-benzo[b]thiophene-2-carboxylic acid {l-[li? -(3-moφholin-4-yl- proρylcarbamoyl)-2-ρhenyl-ethylcarbamoyl]-cyclopentyl} -amide
6,7-Dichloro-benzo[b]thiophene-2-carboxylic acid {l-[li? -(3-moφholin-4-yl- propylcarbamoyl)-2-phenyl-ethylcarbamoyl] -cyclopentyl} -amide 5-te^Butyl-benzofuran-2-carboxylic acid [l-(2-phenyl-lR-{[l-(tetrahydro-pyran-4- ylmemyl)-piperidin-4-ylmemyl]-carbamoyl}-emylcarbamoyl)-cyclopentyl]-amide 6-Iodo-benzo[b]thiophene-2-carboxylic acid [ 1 -(2-phenyl- li?- { [ 1 -(tetrahydro-pyran-4- ylmemyl)-piperimn-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide 7-Bromo-benzo[b]fhiophene-2-carboxylic acid [ 1 -(2-phenyl- li?- { [ 1 -(tetrahydro-pyran-4- ylmemyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide 7-Iodo-benzo[b]thiophene-2-carboxylic acid [1 -(2-phenyl- 1R- {[1 -(tetrahydro-pyran-4- ylmemyl)-piperimn-4-ylmemyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide 7-Methyl-benzo[b]thiophene-2-carboxylic acid [1 -(2-phenyl- 1R- {[1 -(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
7-Trifluoromethyl-benzo[b]thiophene-2-carboxylic acid [l-(2-phenyl-li?-{[l-(tetrahydro- pyran-4-ylmethyl)-piperidm-4-ylmethyl]-carbamoyl}-e ylcarbamoyl)-cyclopentyl]-amide 7-CUoro-benzo[b]thiophene-2-carboxylic acid [l-(2-phenyl-lR-{[l-(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide Benzofuran-2-carboxylic acid [ 1 -(2-phenyl- 1 - { [ li?-(tetrahydro-pyran-4-ylmethyl)- piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide 1 -Methyl- IH-indole -2-carboxylic acid [l-(2-phenyl-l-{[li?-(tetrahydro-pyran-4- ylmemyl)-ρiperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide 7-Chloro-l -methyl- IH-indole -2-carboxylic acid [lR-(2-phenyl-l-{[l-(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
5 -Chloro-3-methyl-benzofuran-2-carboxylic acid [ li?-(2-phenyl- 1 - { [ 1 -(tetrahydro-pyran- 4-ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide 5-Me oxy-benzofuran-2-carboxylic acid [l-(2-phenyl-l-{[lR-(tetrahydro-pyran-4- ylmemyl)-piperi(hn-4-ylmemyl]-carbamoyl}-emylcarbamoyl)-cyclopentyl]-amide 3,5,6-Trime yl-benzofuran-2-carboxylic acid [l-(2-phenyl-l-{[li?-(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide 5-Bromo-naphthalene-2-carboxylic acid [l-(2-phenyl-l-{[li?-(tetrahydro-pyran-4- ylmemyl)-piperimn-4-ylmemyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide Naphmalene-2-carboxylic acid [l-(2-phenyl-lR-{[l-(tefrahydrb-pyfan-4-ylmemyl)- piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
Benzo[b]thiophene-2-carboxylic acid [l-(2-phenyl-l(R)-{[l-(tetrahydro-pyran-4- ylmethyl)-azetidin-3-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide,
7. The compounds of general formula (I) according to claims 4 and 5, wherein the said compounds are defined by the following formulas:
Benzo[b]thiophene-2-carboxylic acid (1 - {2-phenyl- 1 (R)-[ 1 -(tetrahydro-pyran-4-ylmethyl)- piperidin-4-ylcarbamoyl]-ethylcarbamoyl}-cyclopentyl)-amide TFA salt Benzo[b]thiophene-2-carboxylic acid [ 1 -(1 (R)- {2-[(l -amino-cyclohexanecarbonyl)- amino]-ethylcarbamoyl}-2-phenyl-emylcarbamoyl)-cyclopentyl]-amide 6-Bromo-benzo[b]thiophene-2-carboxylic acid [ 1 -(2-phenyl- 1 (R)- { [ 1 -(tetrahydro-pyran-4- ylmethyl)-piperidm-4-ylmemyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide TFA salt Benzo[b]thiophene-2-carboxylic acid (l-{l-(R)-[(l-isopropyl-piperidin-4-ylmethyl)- carbamoyl]-2-phenyl-ethylcarbamoyl}-cyclopentyl)-amide Benzo[b]thiophene-2-carboxylic acid [ 1 -(2-phenyl- 1 (R)- { [ 1 -(tetrahydro-pyran-4- ylmemyl)-piperidm-4-ylme yl]-carbamoyl}-emylcarbamoyl)-cyclopentyl]-amide 6-Bromo-naphthalene-2-carboxylic acid [ 1 -(2-phenyl- 1 (R)- { [ 1 -(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide Benzo[b]thiophene-2-carboxylic acid [l-(2-phenyl-l(R)-{[l-(tetrahydro-pyran-4-yl)- piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide 1 -(3 -E-J -Tolyl-acryloylamino)-cyclopentanecarboxylic acid (2-phenyl- 1 (R)- { [ 1 - (tefrahydro-pyran-4-ylme yl)-piperimn-4-ylmemyl]-carbamoyl}-ethyl)-amide TFA salt Benzo[b]thiophene-2-carboxylic acid [l-(2-phenyl-l(R)-{2-[l-(tetrahydro-pyran-4- ylmemyl)-piperidin-4-yl]-emylcarbamoyl}-emylcarbamoyl)-cyclopentyl]-amideTFA salt Benzo[b]fhiophene-2-carboxylic acid [ 1 -(2-phenyl- 1 (R)- {2-[ 1 -(tetrahydro-pyran-4-yl)- piperidin-4-yl]-ethylcarbamoyl}-eιhylcarbamoyl)-cyclopentyl]-amideTFA salt 6-Bromo-naphthalene-2-carboxylic acid [ 1 -(2-phenyl- 1 (R)- { [ 1 -(tetrahydro-pyran-4-yl)- piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
6-Bromo-naphthalene-2-carboxylic acid (l-{l(R)-[(l-[l,3]dioxan-5-ylmethyl-piperidin-4- ylmefhyl)-carbamoyl]-2-phenyl-ethylcarbamoyl}-cyclopentyl)-amide 5-Chloro-berιzofuran-2-carboxylic acid (l-{l(R)-[(l-[l,3]dioxan-5-ylmemyl-piperidin-4- ylmemyl)-carbamoyl]-2-phenyl-ethylcarbamoyl}-cyclopentyl)-amide ■ — 6-Bromo-naphthalene-2-carboxylic acid [l-(l(R)-{[l-(l-amino-cyclohexanecarbonyl)- piperidm-4-ylmethyl]-carbamoyl}-2-phenyl-ethylcarbamoyl)-cyclopentyl]-amide 6-Iodo-naphthalene-2-carboxylic acid [l-(2-phenyl-lR-{[l-(tefrahydro-pyran-4-ylmethyl)- piperidin-4-ylmethyl] -carbamoyl} -efhylcarbamoyl)-cyclopentyl]-amide 6-Methoxy-naphthalene-2-carboxylic acid [ 1 -(2-phenyl- li?- { [ 1 -(tetrahydro-pyran-4- ylmethyl)-piperidm-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide 6-Bromo-benzofuran-2-carboxylic acid [l-(2-phenyl-li?-{[l-(tetrahydro-pyran-4- ylmethyl)-piperidm-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide 6-CUoro-berιzofuran-2-carboxylic acid [l-(2-phenyl-li?-{[l-(tetrahydro-pyran-4- • ylmethyl)-piperimn-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide 5-Fluoro-benzofuran-2-carboxylic acid [l-(2-phenyl-li?-{[l-(tetrahydro-pyran-4- ylmemyl)-piperidin-4-ylmethyl]-carbamoyl}-emylcarbamoyl)-cyclopentyl]-amide 5-Chloro-benzofuran-2-carboxylic acid [ 1 -(2-phenyl- li?- { [ 1 -(tetrahydro-pyran-4- ylmethyl)-piperidm-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide 5-Bromo-benzofuran-2-carboxylic acid [l-(2-phenyl-li?-{[l-(tetrahydro-pyran-4- ylmemyl)-piperidin-4-ylmemyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide 7-tert-Butyl-benzofuran-2-carboxylic acid [1 -(2-phenyl- li?-{[l -(tetrahydro-pyran-4- ylmemyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide 6-Me yl-berizofuran-2-carboxylic acid [ 1 -(2-phenyl- 1R- { [ 1 -(tetrahydro-pyran-4- ylmemyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide 5-Metfryl-berιzofuran-2-carboxylic acid [l-(2-phenyl-li?-{[l-(tetrahydro-pyran-4- ylmemyl)-piperimn-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
5-Iodo-benzofuran-2-carboxylic acid [ 1 -(2-phenyl- li?- { [ 1 -(tetrahydro-pyran-4-ylmethyl)- piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide 6-Chloro-benzo[b]thiophene-2-carboxylic acid [l-(2-phenyl-lR-{[l-(tetrahydro-pyran-4- ylmethyl)-piperimn-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide 6-Trifluoromethyl-benzo[b]thiophene-2-carboxylic acid [l-(2-phenyl-lR-{[l-(tetrahydro- pyran-4-ylmethyl)-piperidin-4-ylmefhyl] -carbamoyl } -ethylcarbamoyl)-cyclopentyl] -amide 6-Methoxy-benzo[b]tMophene-2-carboxylic acid [l-(2-phenyl-lR-{[l-(tefrahydro-pyran-4- ylmefhyl)-piperidin-4-ylmethyl]-carbamoyl} -ethylcarbamoyl)-cyclopentyl]-amide. 5-Methyl-benzo[b]thiophene-2-carboxylic acid [1 -(2-phenyl- lR-{ [ l-(tetrahydro-pyran-4- ylmefhyl)-piperidin-4-ylmethyl] -carbamoyl } -ethylcarbamoyl)-cyclopentyl] -amide
6-Methyl-benzo[b]thiophene-2-carboxylic acid [l-(2-phenyl-li?-{[l-(tetrahydro-pyran-4- ylme yl)-piperidm-47ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide 6-Fluoro-benzo[b]thiophene-2-carboxylic acid [ 1 -(2-phenyl- 1 - {[ li?-(tetrahydro-pyran-4- ylmethyl)-piperidm-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide 6-Diethylamino-benzofuran-2-carboxylic acid [l-(2-phenyl-l-{[lR-(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl} -ethylcarbamoyl)-cyclopentyl]-amide 5-Diethylamino-benzofuran-2-carboxylic acid [l-(2-phenyl-l-{[lR-(tetrahydro-pyran-4- ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
Naphthalene-2-carboxylic acid [ 1 -(2-phenyl- 1 - { [ 1 R-(tetrahydro-pyran-4-ylmethyl)- piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide
6-Bromo-naphthalene-2-carboxylic acid [ 1 -(1 (R)- { [ 1 -(4-methyl-tetrahydro-pyran-4- ylmemyl)-piperidm-4-ylmemyl]-carbamoyl}-2-phenyl-ethylcarbamoyl)-cyclopentyl]- amide
6-Bromo-naphthaleneτ2-carboxylic acid [l-(l(R)-{[l^(5-ethyl-[l,3]dioxan-5-ylmethyl)- piperidm-4-ylmemyl]-carbamoyl}-2-phenyl-e ylcarbamoyl)-cyclopentyl]-amide,
6-Bromo-naphthalene-2-carboxylic acid [ 1 -(1 (R)- { [4-methyl- 1 -(4-methyl-tetrahydro- pyran-4-ylmemyl)-piperidin-4-ylmethyl]-carbamoyl}-2-phenyl-ethylcarbamoyl)- cyclopentyl] -amide,
6-Bromo-naphthalene-2-carboxylic acid [ 1 ^(1 (R)- { [4-methyl- 1 -(tetrahydro-pyran-4- ylmemyl)-piperidm-4-ylmethyl]-carbamoyl}-2-phenyl-ethylcarbamoyl)-cyclopentyl]- amide.
8. Compounds defined by the following formulas: benzo[b]thiophene-2-carboxylic acid, [l-(l-aminomethyl-2-(R)-phenyl-ethylcarbamoyl)- cyclohexyl] -amide benzo[b]thiophene-2-carboxylic acid { 1 -[2-phenyl-l (R)-(piperidin-4-ylcarbamoyl)- ethylcarbamoyl]-cyclopentyl} -amide benzo[b]thiophene-2-carboxylic acid (l-{2-phenyl-l(R)-[(piperidin-4-yl-methyl)- carbamoyl]-ethylcarbamoyl}-cyclopentyl)-amide benzo[b]thiophene-2-carboxylic acid {l-[2-phenyl-l(R)-(2-piperidin-4-yl- ethylcarbamoyl)-ethylcarbamoyl]-cyclopentyl} -amide TFA salt benzo[b]thiophene-2-carboxylic acid [ 1 -(2-phenyl- r(R)-{2-[4-(tetrahydro-pyran-4- ylmethyl)-ρiperazin-l -yl]-ethylcarbamoyl} -ethylcarbamoyl)-cyclopentyl]-amide TFA salt
C-[l-(tefr ydro-pyran-4-ylmethyl)-piperidin-4-yl]-methylamine in form of free amines or salts thereof with hydrochloric acid, sulphuric acid or trifluoroacetic acid.
9. Use of the compounds of general formula (I) according to claims 1 - 7 for the preparation of pharmaceutical formulations useful in the treatment of pathologies associated to the stimulation of NK-2 receptor.
10. Use of the compounds of general formula (I) according to claim 9, for the preparation of pharmaceutical formulations useful in the treatment of respiratory pathologies, such as asthma and allergic rhinitis; ophthalmic diseases, such as conjunctivitis, skin diseases, such as allergic and contact dermatitis, and psoriasis, intestinal disorders, such as irritable colon, ulcerous colitis and Chron disease, gastric diseases, urinary diseases, such as cystitis and incontinence, erectile dysfunctions, diseases of the nervous central system, such as anxiety, depression and schizophreny, tumoural pathologies, autoimmumtary diseases or diseases related to AIDS, cardiovascular pathologies, neuritis, neuralgia and treatment of pain, visceralgia, inflammatory processes, such as osteoarthritis or rheumatoid arthritis.
11. Pharmaceutical formulations comprising as the active principle at least one compound of general formula (I) according to claims 1-7, or mixtures thereof.
12. The pharmaceutical formulations according to claim 11, further comprising pharmaceutically acceptable diluents and excipients.
13. The pharmaceutical formulations according to claims 11 and 12, for the treatment of respiratory pathologies, such as asthma and allergic rhinitis; ophthalmic diseases, such as conjunctivitis, skin diseases, such as allergic and contact dermatitis, and psoriasis, intestinal disorders, such as irritable colon, ulcerous colitis and Chron disease, gastric diseases, urinary diseases, such as cystitis and incontinence, erectile dysfunctions, diseases of the nervous central system, such as anxiety, depression and schizophreny, tumoural pathologies, autoimmunitary diseases or diseases related to AIDS, cardiovascular pathologies, neuritis, neuralgia and treatment of pain, visceralgia, inflammatory processes, such as osteoarthritis or rheumatoid arthritis..
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006045820A1 (en) * 2004-10-27 2006-05-04 Laboratori Guidotti S.P.A. Pharmaceutical compositions based on nk2 antagonists for pediatric use
JP2007537180A (en) * 2004-05-13 2007-12-20 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Novel substituted thiophenecarboxamides, methods for their preparation and their use as drugs
ITMI20090897A1 (en) * 2009-05-21 2010-11-22 Malesci Sas PROCESS FOR THE PREPARATION OF IBODUTANT (MEN15596) AND RELATIVE INTERMEDIATES
US11897871B1 (en) 2021-06-14 2024-02-13 Scorpion Therapeutics, Inc. Methods for treating cancer

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4012239B2 (en) * 2006-01-11 2007-11-21 生化学工業株式会社 Oxazolone derivatives
US20080227823A1 (en) * 2007-03-12 2008-09-18 Hassan Pajouhesh Amide derivatives as calcium channel blockers
JP5929483B2 (en) 2011-05-10 2016-06-08 住友化学株式会社 How to promote plant growth
CA2839699A1 (en) 2011-06-24 2012-12-27 Amgen Inc. Trpm8 antagonists and their use in treatments
MX2013015058A (en) 2011-06-24 2014-01-20 Amgen Inc Trpm8 antagonists and their use in treatments.
EP2671575A1 (en) * 2012-06-04 2013-12-11 Universität Regensburg Ras inhibitors
US8952009B2 (en) 2012-08-06 2015-02-10 Amgen Inc. Chroman derivatives as TRPM8 inhibitors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995019966A1 (en) * 1994-01-19 1995-07-27 A. Menarini Industrie Farmaceutiche Riunite S.R.L. Tachykinins antagonists
WO2000014109A1 (en) * 1998-09-08 2000-03-16 Menarini Ricerche S.P.A. Basic products having antagonistic activity on the nk-1 receptor and their use in pharmaceutical compositions

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3711335A1 (en) * 1987-04-03 1988-10-20 Merck Patent Gmbh AMINO ACID DERIVATIVES
US5164372A (en) 1989-04-28 1992-11-17 Fujisawa Pharmaceutical Company, Ltd. Peptide compounds having substance p antagonism, processes for preparation thereof and pharmaceutical composition comprising the same
NZ255721A (en) 1992-08-13 1997-06-24 Warner Lambert Co Hetarylmethoxy carbonyl substituted tryptophan amides, esters, analogues and pharmaceutical compositions thereof
IL112778A0 (en) * 1994-03-04 1995-05-26 Merck & Co Inc Substituted heterocycles, their preparation and pharmaceutical compositions containing them
JPH10501228A (en) * 1994-06-06 1998-02-03 ワーナー−ランバート・コンパニー Tachykinin (NK1) receptor antagonist
US5483070A (en) * 1994-08-02 1996-01-09 Packard Instrument Company Scintillation counter
IT1291776B1 (en) 1997-02-07 1999-01-21 Menarini Ricerche Spa MONOCYCLIC COMPOUNDS WITH FOUR BIFUNCTIONAL RESIDUES, HAVING NK-2 ANTAGONIST ACTION
IT1291823B1 (en) 1997-04-08 1999-01-21 Menarini Ricerche Spa PSEUDO-PEPTIDE COMPOUNDS, THEIR PREPARATION AND USE IN PHARMACEUTICAL FORMULATIONS
AU729995B2 (en) * 1997-06-30 2001-02-22 Nippon Kayaku Kabushiki Kaisha Novel naphthyridine derivatives or salts thereof
AU8875798A (en) * 1997-08-29 1999-03-22 Proteus Molecular Design Ltd Meta-benzamidine derivatives as serin protease inhibitors
US6740682B2 (en) * 1997-08-29 2004-05-25 Tularik Limited Meta-benzamidine derivatives as serine protease inhibitors
DE60022508T2 (en) * 1999-06-14 2006-06-08 Eli Lilly And Co., Indianapolis INHIBITORS OF SERIN PROTEASES
IT1307809B1 (en) 1999-10-21 2001-11-19 Menarini Ricerche Spa BASIC MONOCYCLIC COMPOUNDS WITH NK-2 ANTAGONIST ACTION, MANUFACTURING PROCESSES AND FORMULATIONS CONTAINING THEM.
GB0030305D0 (en) * 2000-12-13 2001-01-24 Lilly Co Eli Compounds
GB0030303D0 (en) * 2000-12-13 2001-01-24 Lilly Co Eli Compounds
US20050038692A1 (en) 2003-08-14 2005-02-17 Kane John Michael System and method for facilitating centralized candidate selection and monitoring subject participation in clinical trial studies

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995019966A1 (en) * 1994-01-19 1995-07-27 A. Menarini Industrie Farmaceutiche Riunite S.R.L. Tachykinins antagonists
WO2000014109A1 (en) * 1998-09-08 2000-03-16 Menarini Ricerche S.P.A. Basic products having antagonistic activity on the nk-1 receptor and their use in pharmaceutical compositions

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BODEN P ET AL: "USE OF A DIPEPTIDE CHEMICAL LIBRARY IN THE DEVELOPMENT OF NON-PEPTIDE TACHYKININ NK3 RECEPTOR SELECTIVE ANTAGONISTS" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 39, no. 8, 12 April 1996 (1996-04-12), pages 1664-1675, XP000575827 ISSN: 0022-2623 *
BOYLE S ET AL: "RATIONAL DESIGN OF HIGH AFFINITY TACHYKININ NK1 RECEPTOR ANTAGONISTS" BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER SCIENCE LTD, GB, vol. 2, no. 5, 1994, pages 357-370, XP000917251 ISSN: 0968-0896 *
BOYLE S ET AL: "RATIONAL DESIGN OF HIGH AFFINITY TACHYKININ NK2 RECEPTOR ANTAGONISTS" BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER SCIENCE LTD, GB, vol. 2, no. 2, 1994, pages 101-113, XP008004494 ISSN: 0968-0896 cited in the application *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007537180A (en) * 2004-05-13 2007-12-20 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Novel substituted thiophenecarboxamides, methods for their preparation and their use as drugs
WO2006045820A1 (en) * 2004-10-27 2006-05-04 Laboratori Guidotti S.P.A. Pharmaceutical compositions based on nk2 antagonists for pediatric use
JP2008517977A (en) * 2004-10-27 2008-05-29 ラボラトリ グイドッティ ソシエタ ペル アチオニ Formulations based on pediatric NK2 antagonists
EA012264B1 (en) * 2004-10-27 2009-08-28 Лаборатори Гуидотти С.П.А. Pharmaceutical compositions based on nk2 antagonists for pediatric use
US7727955B2 (en) 2004-10-27 2010-06-01 Laboratori Guidotti S.P.A. Pharmaceutical compositions based on NK2 antagonists for pediatric use
NO338586B1 (en) * 2004-10-27 2016-09-12 Laboratori Guidotti Spa Use of tachykinin antagonist for the preparation of pharmaceutical formulations, oral pharmaceutical composition for pediatric use, and food product comprising said pharmaceutical composition
JP2012527410A (en) * 2009-05-21 2012-11-08 マレシ イスティトゥート ファルマコビオロジコ ソシエタ ペル アチオニ Process for the preparation of IBODUTANT (MEN 15596) and related intermediates
KR20120023675A (en) * 2009-05-21 2012-03-13 마레시 이스티튜토 파르마코바이올로지코 에스.피.에이. Process for the preparation of ibodutant (men15596) and related intermediates
WO2010133306A1 (en) * 2009-05-21 2010-11-25 Malesci Istituto Farmacobiologico S.P.A. Process for the preparation of ibodutant (men15596) and related intermediates
US8431684B2 (en) 2009-05-21 2013-04-30 Malesci Istituto Farmacobiologico S.P.A. Process for the preparation of ibodutant (MEN15596) and related intermediates
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AU2010251514B2 (en) * 2009-05-21 2014-06-12 Malesci Istituto Farmacobiologico S.P.A. Process for the preparation of ibodutant (MEN15596) and related intermediates
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