Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/04—Linear peptides containing only normal peptide links
  • C07K7/22—Tachykinins, e.g. Eledoisins, Substance P; Related peptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/14—Antitussive agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
  • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• the present invention refers to compound of general formula (I)
• X1. X2. X3. X4, same or different, are a group chosen among: -CONR-, -NRCO-, -CH2-NR-, -NR-CH2- where R is H , C1-.3 alkyl, benzyl; f, m, same or different, are a number chosen among 0,1 and 2; Ri and R2, same or different, are a group:
• r 0, 1 , 2 and Ar is an aromatic group chosen among: benzene, naphthalene, thiophene, benzothiophene, pyridine, quinoline, indole, furan, benzofuran, thiazole, benzothiazole, imidazole, benzoimidazole, possibly substituted with up to 2 substituents chosen among C1-3 alkyl, haloalkyl, C1-.3 alkyloxy, C2-4 amino-alkyloxy, halogens, OH, NH2, CN, NR6R7, where Re ed R7, same or different, are H or C1-.3 alkyl, R3 is a group chosen among the following groups:
• Rg is a methanesulfonyl, tosyl, tetrahydropyranyl, tetrahydrothiopyranyl possibly mono or di-substituted by oxygen on the S atom, piperidyl possibly substituted on the N-atom by a C1-3 alkyl, C1-3 acyl, aminosulfonyl, methanesulfonyl; or a group (CH2)g-R-
• R11 is H, C1-3 alkyl; h is 0,1 ,2,3; and R12 is chosen among: morpholine, pyrrolidine possibly substituted with an hydroxy or an hydroxymethyl, piperidine possibly substituted with a group hydroxy, carboxyamido or aminosulfonyl, piperazine possibly substituted on the N-atom by C1-3 alkyl, triazole, tetrazole, 5-mercapto-tetrazole, furan, thiophene, thiomorpholine possibly mono or di-oxygenated on the S-atom, amino- cyclohexane possibly substituted by an hydroxy group.
• R 13 is morpholine or piperazine possibly substituted with a C 2 . 6 alkyl containing one or more ether or hydroxy groups.
• the NK2 receptor of tachykinins is widely present in the peripheral nervous system in mammals.
• One of the various effects of the selective stimulation of the NK2 receptor is the contraction of smooth muscles. Therefore the antagonists of the NK2 receptor are agents capable of controlling the excessive contraction of smooth muscles in all those pathologic condition where the release of tachykinins contributes to the genesis of the corresponding pathological disorder. More particularly the broncospastic component of asthma, cough, pulmonary irritations, intestinal spasms or local spasms in bladder and ureter in the case of cystitis, infections and kidney colics can be considered conditions where the administration of NK2 antagonists is appropriated (E.M. Kudlacz et al. Eur. J. Pharmacol., 1993 36, 17-25).
• Cyclic compounds in particular cyclic hexapeptides, cyclic (AT. McKnight et al.
• WO9834949 it is described how compounds having lower molecular weight, monoyclic, containing only four bi-functional residues linked among each other by a peptide or pseudopeptide bond present pharmacological activity similar or higher than that of known compounds and moreover show a high selectivity for the human NK2 receptor.
• the present invention makes available new monocyclic compounds of general formula (I) as above defined containing four residues linked to each other by a peptide or pseudopetide bond having an antagonistic action on the NK2 receptor.
• the present invention refers also to the pharmaceutically acceptable salts of the above said compounds, to processes for their preparation and to pharmaceutical compositions containing them.
• the present invention refers also to the corresponding enatiomers and the mixture of diastereoisomers.
• Preferred compounds according to the present invention are those wherein in formula (I): f is 1 m is 0 X1. *2 > X3. X4, same or different are a group -CONR- and -NRCO-, R is H or methyl
• Ri and R2 same or different, are::
• Ar is an aromatic group chosen among benzene, pyridine, indole, possibly substituted up to two residues with substituents chosen among: Ci_3 alkyl and haloalkyl, C1-.3 alkyloxy, C2-4 amino alkyloxy, halogens, OH, NH2, CN, NR6R7, where R6 and R7 t same or different, are H or C1-3 alkyl; R3 is a group chosen among:
• Ari is an aromatic group chosen among: alfa naphthyl, beta naphthyl, phenyl, phenyl substituted up to two residues chosen among C1-.3 alkyl and haloalkyl, C1-3 alkyloxy, halogens, OH, NH2,
• R5 is H
• R4 is a group chosen among:
• R ⁇ is H or C-
• R11 is H, C1-3 alkyl; h is 0,1 ,2,3; and R12 is chosen among: morpholine, pyrrolidine possibly substituted with an hydroxy or hydroxymethyl, piperidine possibly substituted with a group hydroxy ! carboxyamido or aminosulfonyl, piperazine possibly substituted on the N-atom by C1-.3 alkyl, triazole, tetrazole, 5-mercapto-tetrazole, furan, thiophene, thiomorpholine possibly mono or di-oxygenated on the S-atom, amino- cylohexane possibly substituted by an hydroxy group.
• R13 is a group chosen among morpholine and piperazine possibly substituted by a C2-6 alkyl containing one or more ether or hydroxy groups.
• - R is H; - R1 is the lateral chain of triptophane;
• R2 is the lateral chain of phenylalanine possibly substituted with up to two residues chosen among: chlorine, fluorine, CF3, OH, CN ; or a group 3-pyridyl- methyl, 4-pyridyl-methyl;
• R3 is benzyl. and the other substituents re as above defined.
• R, R1 , R2, R3, R5, f, m are as above defined and:
• R4 is a group NR8R9 wherein:
• R8 is H or methyl
• R9 is a group chosen among: : 4-tetrahydropyranyl, 4-tetraidrothiopyranyl, 1-oxo- tetraidrothiopyran-4-yl, 1 ,1-dioxo-tetrahydrothiopyran-4-yl, N-methyl-4-piperidinyl,
• N-methansulfonvl-4-piperidinvl N-aminosulfonyl-4-piperidinyl, or R8 and R9 together with the N atom to which they are linked represent: N- methyl-piperazinyl, N-acetyl-piperazinyl, piperazinyl, N-methanesulfonyl- piperazinyl.
• R4 represents a group NR ⁇ Rg, where R ⁇ is H and R9 is chosen among: methanesulfonyl, tosyl, a group (CH2)g-R ⁇
• R5, f, m are as previously defined, those wherein: R4 represents a group - N(Rn )CO(CH2)h-Rl 2 wherein R « n is H, h is O oM , and R12 is chosen among. : 1-tetrazolyl, 5-mercapto-tetrazol-1-yl, 1-triazolyl, furanyl, thiophenyl, morpholine, 4-hydroxy-piperidine, 4-carboxyamido-piperidine,
• R4 is a group COR13 wherein R13 is a group chosen among: morpholine and 4- (hydroxyethyloxyethyl)-piperazine.
• phrases of formula (I) are for example the salts with inorganic acids (as hydrochloric, hydrobromic, hydroiodic, sulphuric, nitric, phosphoric) or organic acids (as acetic, propionic, succinic, malonic, citric, tartaric, methanesulfonic, p-toluensulfonic).
• inorganic acids as hydrochloric, hydrobromic, hydroiodic, sulphuric, nitric, phosphoric
• organic acids as acetic, propionic, succinic, malonic, citric, tartaric, methanesulfonic, p-toluensulfonic.
• the compounds of formula (I) containing peptide or pseudopeptide bonds can be obtained by the normal condensation reactions according to known techniques.
• carboxyiic group normally the methods using EDCI.HCI and HOBt or PyBOP and DIEA in DMF are preferred.
• the dicarboxylic precursors containing the R4 group and the diamino precursors containing the R3 group were prepared according to the methods described in literature.
• the compounds of formula (I) as above described are powerful antagonists of NK2 receptor of tachykinins and can be administered as agents capable of controlling the excessive smooth muscular contraction in whatever pathological condition where the release of tachykinins contributes to the pathology.
• the broncospastic component of asthma, cough, pulmonary irritation, the intestinal spasms or local spasms of bladder and ureter during cystitis, infections and kidneys colics can be considered conditions where the administration of compounds of formula (I) as NK2 antagonists, can be appropriate.
• the compounds of formula (I) object of the present invention are useful for the administration to superior animals and humans by parenteral, oral, by inhalation, sublingual administration giving pharmacological effects thanks to their properties.
• parenteral administration intravenous, intramuscular and intradermal
• sterile solutions or lyophilised preparations are used.
• nasal, by inhalation or sublingual administration aqueous solutions, aerosol, powders or capsules are used as appropriate.
• the quantity of active principle administerd with the above said formulations is normally comprised between 0.1 and 10 mg/kg of patient body weight.
• reaction mixture was left under stirring for a night at room, added with AcOEt ( 80 ml ), washed with HCI 1 N ( 3 x 30 ml ), Na2C03 5% ( 3 x 30 ml ) and H2O ( 30 ml ).
• the organic phase was evaporated under vacuum at 30°C, giving 1.8 g of ivory colored solid residue.
• reaction mixture was left under stirring at room temeprature for 4 h.After evaporation of the solvent (under vacuum) the residue was treated with KHSO4 aq. 5% giving a solid which was filtered, washed with NaHCO3 aq. 5%, water, and thereafter dried the product was crystallized from ethanol giving 850 mg of the desired compound as a white solid.
• the compound is prepared as in example 1 but using as reagent 1-methyl-4- piperidone.
• the compound is prepared according to Example 1 but using as reagent tetrahydro-thiopyran-4-one.
• the compound is prepared as in example 1 but using as reagent 1 ,1-dioxo- tetrahydro-thiopyran-4-one.
• the obtained solid (790 mg) is suspended in dichlorometane (6.5 ml). The suspension is cooled at 0°C, (3.5 ml) is added and the tempearure is raised at room temperature maintaining under stirring for 1 h. The solution is concentrated to dryness and the residue is treated with ethyl ether, under stirring, the formed solid is filtered and washed with ether. After drying the obtained solid (550 mg) is solved in 8 ml of DMF are added to a solution of DMF (6 ml), Boc-Trp-OH (250 mg), HOBt (216 mg), EDCI.HCI (200 mg). DIEA (0.23 ml) is added drop by drop and the solution is stirred for 1 h.
• the solution is concentrated to dryness and the residues treated with water and citric acid, under stirring; the formed solid is filtered and washed with water, NaHCO3 5%, water; 623 mg of a solid compound are obtained.
• the obtained solid is solved in DMF (15 ml); diethylamine (1.5 ml) is added and the solution is stirred for 2 h. The solvent is evaporated and the residue is treated with diethylether under stirring, the formed solid is filtered and washed with diethylether obtaining 220 mg of a solid product.
• the product is solved in 4 ml of DMF and added drop by drop to a solution of Fmoc-D-Asp-(OtBu)-OH (150 mg), HOBt (115 mg), EDCI.HCI (84 mg) in DMF (4 ml).
• the solution is maintained 2 h under stirring, concentrated to dryness and the residue is treated with citric acid 10% and water; the formed solid is filtered, washed with water, NaHCO3 al 5%, water and dried, 340 mg of a solid product are obtained.
• the obtained product is suspended in dichloromethane, ethanediol (0.035 ml) and, at 0°C, TFA (4 ml). The temperature is brought to room temperature under stirring for 1 h.
• the solution is dried and the residue is treated with diethylether under stirring, the formed solid is filtered and washed with diethylether. After drying 280 mg of solid product are obtained.
• the product is solved in 30 ml of DMF, HOBt (185 mg) and EDCI.HCI (160 mg) are added and the solution is maintained under stirring for 5 h and then left staying for one night.
• the solution is concentrated and the residue is treated with citric acid 10% and water, the formed solid is filtered. Washed with water, NaHCO3 5%, water and dried giving 220 mg of a solid product.
• the obtained solid is solved in DMF (10 ml); added with diethylamine (1.0 diethylether under stirring, the formed solid is filtered, washed with diethylether giving 157 mg of a solid product.
• the obtained product is solved in methanol (13 ml) and added with acetic acid (0.26 ml), tetrahydro-4H-pyran-4-one (80 mg) and sodium cianoborohydride (55 mg) in the given order.
• the solution is concentrated and purified by preparative HPLC (Method P3).
• EXAMPLE 12 cyclo ⁇ Suc[1 -(R)-(4-tetrahydropyranyl)amino]-Trp-Phe(4-CF3)-[(R)- NH-CH(CH2-C6H5)-CH2NH] ⁇
• the compound is prepared according to Example 1 but using as reagent N-Boc iminodiacetaldheyde, carrying on the reaction for 16 h and removing the protective group N-Boc with TFA in dichloromethane.
• the so obtained product is purified by preparative HPLC (Method P2).
• Example 17 The compound described in Example 17 was solved in anhydrous DMF treated with TEA and methanesulfonyl chloride. After 3 h under stirring at room temperature the mixture is purified by preparative HPLC (Method P6).
• EXAMPLE 21 cyclo ⁇ -Suc[1-(S)-methanesulfonylamino]-Trp-Phe-[(R)-NH- CH(CH2C6H5)-CH2-NH] ⁇ (compound of general formula I wherein C-R4 has S-configuration, R4 is methanesulfonylamino and the other substituens are as described in compound A)
• reaction mixture is concentrated under vacuum, diluted with ethylacetate and washed with an aqueous solution of citric acid (10%), water, saturated solution of NaHCO ⁇ and water in the given order. After drying on Na2SO4 and evaporation of the solvent the product is isolated by preparative HPLC.
• the compound is prepared according to the procedure of Example 1 but using as reagent 2-furaldheyde.
• the so obtained crude was purified by prepartive HPLC
• R4 has S-configuration and the other substituents are as described for Compound A)
• EXAMPLE 31 cyclo ⁇ Suc[1-(S)-(2-tetrazol-1-yl)acetylamino]-Trp-Phe-[(R)-NH- CH(CH2-C6H5)-CH2NH] ⁇ (compound of general formula I wherein C-R4 has S-configuration, R4 is (2- tetrazol-1-yl)acetylamino and the other substituents are as described for Compound A) As starting compound the isomer of compound A having S-configuration at C-R4 is used.
• EXAMPLE 38 cyclo ⁇ Suc[1 -(R)-2-(4-hydroxy-piperidin-1 -yl)acetylamino]-Trp-Phe- [(R)-NH-CH(CH2-C6H5)-CH2NH] ⁇
• EXAMPLE 45 cyclo ⁇ Suc[1-(R)-2-(1-oxo-thiomorpholin-4-yl)acetylamino]-Trp-Phe- [(R)-NH-CH(CH2-C6H5)-CH2NH] ⁇ (compound of general formula I wherein R4 is 2-(1-oxo-thiomorpholin-4- yl)acetylamino and the other substituents are as described for Compound A)
• the compound was prepared according to EXAMPLE 29 but using as reagent 2- (1 -oxo-thiomorpholin-4-yl)acetic acid.
• EXAMPLE 48 cyclo ⁇ Suc[1 -(4-hydroxyethyloxyethyl-piperazin-1 -yl)carbonyl]-Trp-
• Method P3 Column: Vydac RP18 20 ⁇ , 22 x 250 mm
• PyBOP benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate
• TEA triethylamine
• TFA trifluoroacetic acid
• DMF N,N-dimethylformamide
• NKA neurokinin A
• HOBt 1- hydroxybenzotriazole
• rt retention time
• THF tetrahydrofuran.
• the compounds described in the present invention act as antagonists on the NK2 receptor of tachykinins
• the biological activity was tested in three different functional tests in vitro using rabbit pulmonary arteria (RPA), hamster trachea (HT) and rat urinary bladder (RUB) according to the methods described by Maggi CA. et al. Br. J. Pharmacol. 1990, 100, 588, D'Orleans-Juste P. et al. Eur. J. Pharmacol. 1986, 125, 37 e Maggi CA. et al. J. Pharmacol. Exp. Ther. 246, 308, 1988.
• RPA rabbit pulmonary arteria
• HT hamster trachea
• RAB rat urinary bladder
• the affinity of the compounds for the human NK2 receptor was evaluated in a test of binding using membranes of CHO (Chinese hamster ovary) cells transfected with the NK-2 receptor of human ileum and the radioligand [ 125 I]NKA (Amersham, specific activity 2000 Ci/mmol) at the concentration of 100 pM in studies of competition.
• the examined compounds were tested in a range of concentration comprised between 0.01 nM and 10mM. After incubation (30 min., 20°C) the samples were filtered and the radioactivity was determined using a gama-counter.
• the data collected by functional studies are expressed as pA 2 (Arunlakshana O. and Schild H.O., Br. J. Pharmacol. Chemother.

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