EP0590152A1 - Peptides mit tachykininantagonistischer wirkung - Google Patents

Peptides mit tachykininantagonistischer wirkung

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Publication number
EP0590152A1
EP0590152A1 EP92913210A EP92913210A EP0590152A1 EP 0590152 A1 EP0590152 A1 EP 0590152A1 EP 92913210 A EP92913210 A EP 92913210A EP 92913210 A EP92913210 A EP 92913210A EP 0590152 A1 EP0590152 A1 EP 0590152A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
compound
carboxy
formula
group
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP92913210A
Other languages
English (en)
French (fr)
Inventor
Masaaki 4-12 Nakasakurazuka 5-Chome Matsuo
Daijiro 20-11 Kindacho 2-Chome Hagiwara
Hiroshi 86 Jodojinishidacho Sakyo-Ku Miyake
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fujisawa Pharmaceutical Co Ltd
Original Assignee
Fujisawa Pharmaceutical Co Ltd
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Filing date
Publication date
Application filed by Fujisawa Pharmaceutical Co Ltd filed Critical Fujisawa Pharmaceutical Co Ltd
Publication of EP0590152A1 publication Critical patent/EP0590152A1/de
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
    • C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to new peptide
  • tachykinin antagonism especially substance P antagonism, neurokinin A antagonism, neurokinin .B antagonism, and the like, to processes for preparation thereof, to pharmaceutical composition comprising the same, and to a use of the same as a medicament.
  • One object of the present invention is to provide new and useful peptide compounds and pharmaceutically
  • tachykinin antagonism especially substance P antagonism, neurokinin A antagonism,
  • neurokinin B antagonism and the like.
  • Another object of the present invention is to provide processes for the preparation of said peptide compounds and salts thereof.
  • a further object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, said peptide compounds and
  • Still further object of the present invention is to provide a use of said peptide compound or a
  • tachykinin antagonist especially substance P antagonist, neurokinin A antagonist or neurokinin B antagonist, useful for treating or preventing tachykinin mediated diseases, for example, respiratory diseases such as asthma, bronchitis, rhinitis, cough, expectoration, and the like; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact
  • dermatitis atopic dermatitis, urticaria, and other eczematoid dermatitis, and the like
  • inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and the like
  • pains or aches e.g., migraine, headache, toothache, cancerous pain, back pain, etc.
  • the like in human being or animals e.g., migraine, headache, toothache, cancerous pain, back pain, etc.
  • the object compounds of the present invention can be represented by the following general formula (I).
  • R 1 is lower alkyl, aryl, ar(lower)alkyl
  • Z is O, S or NH
  • R 2 is hydrogen or lower alkyl
  • R 3 is hydrogen or suitable substituent
  • R 4 is lower alkyl which may have suitable
  • R 5 is ar( lower)alkyl which may have suitable
  • R 4 and R 5 are linked together to form
  • A is an amino acid residue which may have
  • Y is bond, lower alkylene, lower alkenylene
  • R 1 is aryl, or a group of the formula :
  • Z is O or N-R 6 a ,
  • R 6 a is hydrogen or lower
  • R 2 is hydrogen
  • R 4 is lower alkyl which may have suitable
  • R 5 is ar(lower)alkyl which may have suitable substituent(s),
  • A is group of the formula :
  • R 7 is hydoxy or lower alkoxy
  • Y is bond or lower alkenylene
  • R 3 is suitable substituent.
  • the new peptide compounds (I) can be prepared by processes which are illustrated in the following schemes.
  • R 1 , R 2 , R 3 , R 4 , R 5 , A, X and Y are each as defined above,
  • R 4 a is protected carboxy (lower) alkyl
  • R 4 b is carboxy (lower) alkyl
  • R 6 b is protected carboxy (lower) alkyl or
  • R 6 c is carboxy (lower) alkyl or
  • R 6 b is amino (lower) alkyl
  • R 6 e is guanidino (lower) alkyl
  • R 8 is hydrogen or halogen
  • a 1 is an amino acid residue containing an amino
  • a 2 is an amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid residue containing a protected amino acid
  • a 3 is an amino acid residue containing a sulfonyloxy which has a suitable substituent
  • a 4 is an amino acid residue containing an azido
  • a 5 is an amino acid residue containing an amino
  • Ma is an alkaline metal.
  • amino acid, peptides, protective groups, condensing agents, etc. are indicated by the abbreviations according to the IUPAC-IUB (Commission on Biological Nomenclature) which are in common use in the field of art.
  • amino acids and their residues when shown by such abbreviations are meant to be L-configured compounds and residues.
  • Suitable pharmaceutically acceptable salts of the starting and object compound are conventional non-toxic salt and include an acid addition salt such as an organic acid salt (e.g. acetate, trifluoroacetate, maleate. tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acid salt (e.g.
  • an organic acid salt e.g. acetate, trifluoroacetate, maleate. tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.
  • an inorganic acid salt e.g.
  • hydrochloride hydrobromide, hydriodide, sulfate, nitrate, phosphate, etc.
  • a salt with an amino acid e.g.
  • arginine aspartic acid, glutamic acid, etc.
  • a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt,
  • dicyclohexylamine salt N,N'-dibenzylethylenediamine salt, etc.), or the like.
  • Suitable “lower alkyl” may include a straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like, in which the most preferred one is methyl.
  • Suitable "aryl” and the aryl moiety of “arylamino” may include phenyl, tolyl, xylyl, mesityl, cumenyl, naphtyl, and the like, in which the preferred one is
  • Suitable "ar(lower)alkyl” may include mono- or di- or triphenyK lower) alkyl (e.g. trityl, benzhydryl, benzyl, phenethy1, etc.), and the like.
  • Suitable "lower alkylene” is one having 1 to 6 carbon atom(s) and may include methylene, ethylene, trimethylene, propylene, tetramethylene, methyltrimethylene,
  • hexamethylene and the like, in which the preferred one is methylene, ethylene or trimethylene.
  • Suitable "lower alkenylene” is one having 2 to 6 carbon atom(s) and may include vinylene, propenylene, and the like, in which the preferred one is vinylene.
  • Suitable “lower alkylimino” may include methylimino, ethylimino, and the like.
  • an amino acid residue means a bivalent residue derived from an amino acid, and such amino acid may be glycine (Gly), D- or L- alanine (Ala), ⁇ -alanine ( ⁇ Ala), D- or L- valine (Val), D- or L- leucine (Leu), D- or L- isoleucine (lie), D- or L- serine (Ser), D- or L- threonine (Thr), D- or L- cysteine (Cys), D- or L- methionine (Met) , D- or L- phenylalanine (Phe) , D- or L-tryptophan (Trp), D- or L- tyrosine (Tyr), D- or L- proline (Pro), D- or L- didehydroproline ( ⁇ Pro) such as 3 ,4-didehydroproline ( ⁇ ( 3 , 4)Pro) , D- or L- hydroxyproline (Pro(OH
  • carbamoyl lower alkanoyl (e.g., formyl, acetyl, etc.), lower alkoxycarbonyl (e.g.,t-butoxycarbonyl, etc.), trihalo(lower) alkoxycarbonyl (e.g.
  • alkylsulfonyl e.g., mesyl ethylsulfonyl, etc.
  • lower alkoxalyl e.g., methoxyalyl, ethoxyalyl, etc.
  • arylsulfonyl e.g., phenylsulfonyl, tolylsulfonyl, etc.
  • haloar( lower) alkoxycarbonyl e.g., o-chlorobenzyloxy- carbonyl, etc.
  • carboxy(lower)alkanoyl e.g.,
  • alkoxycarbonyl- ⁇ -alanyl e.g.,
  • N,N-di(lower) alkylamino(lower)alkanoyl e.g., N,N-di(lower) alkylamino(lower)alkanoyl
  • amino(lower)alkanoyl e.g., aminoacetyl, aminopropionyl, etc.
  • N-ar(lower)alkoxycarbonylamino(lower)alkanoyl e.g, N-benzyloxycarbonylaminoacetyl, etc.
  • threonyl N-lower alkoxycarbonylthreonyl (e.g. N-t-butoxycarbonylthreonyl, etc.)
  • N-lower alkanoylthreonyl e.g., N-acetylthreonyl, etc.
  • alkoxycarbonylamino(lower)alkanoyl e.g.,
  • carboxymethyl, etc. protected carboxy (lower) alkyl such as esterified carboxy (lower) alkyl (e.g.
  • morpholino glycino amide, threonino amide, N'-glutamino N-lower alkylamide (e.g., N'-glutamino N-t-butylamide, etc.), di ⁇ lower)alkylamino (e.g.
  • Suitable “carboxy(lower)alkyl” may include
  • Suitable "protected carboxy(lower)alkyl” means the above-mentioned carboxy(lower)alkyl, in which the carboxy group is protected by a conventional protective group such as esterified carboxy group.
  • Preferred example of the ester moiety thereof may include lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, tert-butyl ester, etc.), and the like.
  • suitable substituent(s)" may include carbamoyl(lower)alkyl (e.g., carbamoylmethyl, carbamoylethyl, carbamoylpropyl, etc.), carbamoyl(lower)alkyl having suitable
  • substituent(s) such as lower alkylcarbamoyl(lower)alkyl (e.g., methylcarbamoylmethyl, ethylcarbamoylmethyl, etc.), amino(lower)alkylcarbamoyl(lower)alkyl (e.g.,
  • aminomethylcarbamoylmethyl aminoethylcarbamoylmethyl, etc.
  • lower alkylamino(lower)alkylcarbamoyl(lower)alkyl e.g., dimethylaminomethylcarbamoylmethyl
  • substituent(s) may include a conventional group, which is used in the field of art such as lower alkyl,
  • lower alkylamino(lower)alkyl e.g. dimethylaminomethyl, dimethylaminoethyl, etc.
  • hydroxy(lower)alkyl e.g., hydroxymethyl, hydroxyethyl, etc.
  • hydroxy(lower)alkyl such as acyloxy(lower)alkyl (e.g.
  • halo(lower)alkyl e.g.
  • pyrrolidinyl(lower)alkyl e.g. pyrrolidin-1-ylethyl, etc.
  • pyrrolidin-1-ylethyl e.g. pyrrolidin-1-ylethyl, etc.
  • Suitable "an amino acid residue containing an amino, a hydroxy and/or a carboxy" may include a bivalent residue of an amino acid such as Pro(40H), Ser, Thr, Tyr, and the like.
  • protected amino, a protected hydroxy and/or a protected carboxy means the above-mentioned group, in which the amino, hydroxy and/or carboxy is protected by a
  • arylsulfonyl e.g., phenylsulfonyl, tolylsulfonyl, etc.
  • lower alkoxycarbonyl(lower)alkyl e.g., methoxycarbonylmethyl, ethoxycarbonylmethyl, etc.
  • Suitable “pyridyKlower)alkyl” may include 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, and the like.
  • Suitable group of the formula : in which R 4 and R 5 are linked together to form benzene-condensed lower alkylene, may include 1-indolinyl, 2-isoindolinyl,
  • Suitable "hydroxy(lower)alkyl” may include
  • Suitable "protected hydroxy(lower)alkyl” means the above-mentioned hydroxy(lower)alky1, in which the hydroxy group is protected by a conventional protective group such as acyl (e.g. acetyl, etc.), and may include
  • Suitable "amino protective group” may be a
  • acyl such as lower alkanoyl (e.g. formyl, acetyl,
  • propionyl butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.
  • lower alkoxycarbonyl e.g.
  • alkanesulfonyl e.g. methanesulfonyl, ethanesulfonyl, etc. and the like.
  • Suitable “carboxy(lower)alkoxy” may include
  • Suitable "protected carboxy(lower)alkoxy” means the above-mentioned carboxy(lower)alkoxy, in which the carboxy group is protected by a conventional protective group such as esterified carboxy group.
  • Preferred example of the ester moiety thereof may include lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, tert-butyl ester, etc. and the like.
  • Suitable "lower alkoxy” may include straight or branched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, hexyloxy, and the like.
  • sulfonyloxy which has a suitable substituent means a bivalent residue derived, from an amino acid containing sulfonyloxy which has a suitable substituent, in which "sulfonyloxy which has a suitable substituent" may include lower alkylsulfonyloxy (e.g., methylsulfonyloxy,
  • arylsulfonyloxy e.g., phenylsulfonyloxy, tolylsulfonyloxy, etc.
  • arylsulfonyloxy e.g., phenylsulfonyloxy, tolylsulfonyloxy, etc.
  • Suitable "an amino acid residue containing an azido" may include a bivalent residue of an amino acid such as Pro( 4N 3 ) , and the like.
  • Suitable "an amino acid residue containing an amino” may include a bivalent residue of an amino acid such as Pro(4NH 2 ), and the like.
  • Suitable “amino (lower) alkyl” may include aminomethyl, aminoethyl, aminopropyl, and the like.
  • Suitable "protected amino(lower) alkyl” means the above-mentioned amino (lower) alkyl, in which the amino group is protected by a conventional protective group such as acylamino group.
  • Preferred example of the acyl moiety thereof may include lower alkoxycarbonyl (e.g.
  • Suitable “guanidino (lower) alkyl” may include
  • Suitable "halogen” may include chloro, fluoro,
  • Suitable "alkaline metal” may include sodium,
  • Suitable substituent on R moiety may include a.
  • lower alkyl which may have suitable substituent(s), amino protective group, each as defined above, hydroxy, halogen (e.g. fluoro, chloro, etc.), lower alkoxy (e.g. methoxy, butoxy, etc.),
  • N,N-di(lower)alkylamino e.g. dimethylamino, etc.
  • lower alkoxycarbonyl e.g. methoxycarbonyl, t-butoxycarbonyl, etc.
  • lower alkyleneamino(lower)alkyl e.g. pyrrolidin-1-ylethyl, etc.
  • Suitable substituent on R 3 moiety may include a conventional group, which is used in the field of amino acid and peptide chemistry, such as lower alkyl which may have suitable substituent(s), carboxy(lower)alkoxy, protected carboxy(lower)alkoxy, each as defined above, halogen (e.g. fluoro, chloro, etc.), lower alkoxy (e.g. methoxy, butoxy, etc.), nitro, amino, protected amino, in which amino protective group is as defined above, and the like.
  • R 1 , R 2 , R 3 , R 4 , R 5 , A and Y are as follows.
  • R' is di(lower) alkoxyphenyl, mono-or di-or triphenyl- (lower) alkyl which may have lower alkoxy, indolinyl, pyridyl, or a group of the formula :
  • R 6 is lower alkyl, di (lower)alkylamino-
  • R 8 is hydrogen or halogen
  • R 2 is hydrogen or lower alkyl
  • R 3 is lower alkyl or halogen
  • R 4 is lower alkyl, carboxy(lower)alkyl or esterified
  • R 5 is mono-or di-or triphenyl(lower)alkyl or pyridyl(lower)-alkyl, A is a bivalent residue derived from an amino acid
  • substituents such as hydroxyproline, glycine, serine, methionine, lysine, histidine, glutamine, thioproline and aminoproline, whose side chains may be substituted by the substituent selected from the group consisting of lower alkoxycarbonyl, carboxy(lower)alkyl,
  • Y is bond, lower alkylene, lower alkenylene or lower alkylimino.
  • R 1 , R 2 , R 3 , R 4 , R 5 , A and Y are as follows.
  • R' is a group of the formula :
  • R 6 is lower alkyl
  • R 8 is hydrogen
  • R 2 is hydrogen
  • R 3 is lower alkyl or halogen
  • R 4 is lower alkyl
  • R 5 is phenyl(lower)alkyl
  • A is hydroxyproline
  • R 1 , R 2 , R 3 , R 4 , R 5 , A and Y are bond. Also, the preferred embodiments of R 1 , R 2 , R 3 , R 4 , R 5 , A and Y are as follows.
  • R 1 is di(lower)alkoxyphenyl, mono-or di-or triphemyl (lower)- alkyl which may have lower alkoxy, indolinyl, pyridyl, or a group of the formula :
  • R 6 is lower alkyl, di(lower)alkylamino- (lower)alkyl, pyrrolidinyl(lower)alkyl, carboxy(lower)alkyl, esterified carboxy- (lower)alkyl, amino(lower) alkyl, guanidino(lower)alkyl, pyridyl (lower)alkyl or acylamino(lower)alkyl, and
  • R 8 is hydrogen or halogen
  • R 2 is hydrogen or lower alkyl
  • R 3 is hydrogen
  • R 4 is lower alkyl, carboxy(lower)alkyl or esterified
  • R 5 is mono-or di-or triphenyl(lower)alkyl
  • A is a bivalent residue derived from an amino acid
  • hydroxyproline which may have suitable substituent such as glycine, serine, methionine, lysine, histidine, glutamine, thioproline and
  • aminoproline whose side chains may be substituted by the substituent selected from the group consisting of lower alkoxycarbonyl, carboxy( lower)alkyl, esterified carboxy(lower)alkyl and lower alkylsulfonyl, and
  • Y is bond, lower alkylene, lower alkenylene or lower
  • R 1 , R 2 , R 3 , R 4 , R 5 , A and Y are as follows.
  • R 1 is di(lower)alkoxy ⁇ henyl, mono-or di-or triphemyl (lower)- alkyl which may have lower alkoxy, indolinyl, pyridyl, or a group of the formula :
  • R 6 is di(lower)alkylamino(lower)alkyl
  • pyrrolidinyl(lower)alkyl carboxy(lower)alkyl, esterified carboxy(lower)alkyl, amino(lower)- alkyl, guanidino(lower)alkyl, pyridyl(lower)- alkyl or acylamino(lower)alkyl, and R 8 is hydrogen or halogen,
  • R a is hydrogen or lower alkyl
  • R 3 is hydrogen
  • R 4 is lower alkyl, carboxy(lower)alkyl or esterified
  • R 5 is mono-or di-or triphenyl(lower)alkyl
  • A is a bivalent residue derived from hydroxyproline which
  • Y is bond, lower alkylene, lower alkenylene or lower
  • the object compound (I) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the amino group or a salt thereof with the compound (III) or its reactive derivative at the carboxy group or a salt thereof.
  • Suitable reactive derivative at the amino group of the compound (II) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (II) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as bis(trimethylsilyl)acetamide, mono(trimethylsyliy acetamide, bis( trimethylsilyl)urea or the like; a derivative formed by reaction of the compound (II) with phosphorus trichloride or phosgene, and the like.
  • Suitable salts of the compound (II) and its reactive derivative can be referred to the ones as exemplified for the compound (I).
  • Suitable reactive derivative at the carboxy group of the compound (III) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like.
  • Suitable examples of the reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride within acid such as substituted phosphoric acid [e.g.
  • halogenated phosphoric acid, etc. dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [e.g. methanesulfonic acid, etc.], aliphatic carboxylic acid [e.g. acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylic acid [e.g. benzoic acid, etc.]; a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole,
  • dimethylpyrazole triazole or tetrazole
  • an activated ester e.g. cyanomethyl ester, rnethoxymethyl ester, dimethyliminomethyl 3 2 ester, vinyl ester,
  • N-hydroxy compound e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide,
  • N-hydroxyphthalimide 1-hydroxy-1H-benzotriazole, etc.]
  • These reactive derivatives can optionally be selected from them according to the kind of the
  • Suitable salts of the compound (III) and its reactive derivative may be a base salt such as an alkali metal salt [e.g. sodium salt, potassium salt, etc.], an alkaline earth metal salt [e.g. calcium salt, magnesium salt, etc.], an ammonium salt, an organic base salt [e.g.
  • trimethylamine salt triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt,
  • the reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform. methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform. methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile,
  • a conventional condensing agent such as N,N' -dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide;
  • N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide N,N' -diethylcarbodiimide, N,N'-diisopropylcarbodiimide; N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;
  • 1-alkoxy-l-chloroethylene 1-alkoxy-l-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus
  • triphenylphosphine 2-ethyl-7-hydroxybenzisoxazolium salt
  • reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine,
  • N-(lower)alkylmorpholine N,N-di(lower)alkylbenzylamine, or the like.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
  • the object compound (I) or a salt thereof can be prepared by reacting the compound (IV) or its reactive derivative at the amino group or a salt thereof with the compound (V) or its reactive derivative at the carboxy group or a salt thereof.
  • Suitable salts of the compound (IV) and its reactive derivative can be referred to the ones as exemplified for the compound (II).
  • Suitable salts of the compound (V) and its reactive derivative can be referred to the ones as exemplified for the compound (III).
  • This reaction can be carried out in substantially the same manner as Process 1, and therefore the reaction mode and reaction conditions [e.g. reactive derivatives, solvents, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 1.
  • reaction mode and reaction conditions e.g. reactive derivatives, solvents, reaction temperature, etc.
  • the object compound (I-b) or a salt thereof can be prepared by subjecting the compound (I-a) or a salt thereof to elimination reaction of the amino, hydroxy and/or carboxy protective group.
  • Suitable base may include, for example, an inorganic base such as alkali metal hydroxide (e.g. sodium
  • alkaline earth metal hydroxide e.g. magnesium hydroxide, calcium
  • alkali metal carbonate e.g. sodium carbonate, potassium carbonate, etc.
  • alkaline earth metal carbonate e.g. magnesium carbonate, calcium
  • alkali metal bicarbonate e.g. sodium bicarbonate, potassium bicarbonate, etc.
  • alkali metal acetate e.g. sodium acetate, potassium acetate, etc.
  • alkaline earth metal phosphate e.g. magnesium phosphate, calcium phosphate, etc.
  • alkali metal hydrogen phosphate e.g. disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.
  • an organic base such as trialkylamine (e.g. trimethylaminev triethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine,
  • Suitable acid may include an organic acid (e.g.
  • formic acid acetic acid, propionic acid, etc.
  • an inorganic acid e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc.
  • the present hydrolysis is usually carried out in an organic solvent, water, or a mixed solvent thereof.
  • the reaction temperature is not critical, and it may suitably be selected in accordance with the kind of the carboxyprotective group and the elimination method.
  • the elimination using Lewis acid is carried out by reacting the compound (I-a) or a salt thereof with Lewis acid such as boron trihalide (e.g. boron trichloride, boron trifluoride, etc.), titanium tetrahalide (e.g. titanium tetrachloride, titanium tetrabromide, etc.), tin tetrahalide (e.g. tin tetrachloride, tin tetrabromide, etc.), aluminum halide (e.g. aluminum chloride, aluminum bromide, etc.), trihaloacetic acid (e.g. trichloroacetic acid, trifluoroacetic acid, etc.) or the like.
  • Lewis acid such as boron trihalide (e.g. boron trichloride, boron trifluoride, etc.), titanium tetrahalide (e.g. titanium tetrachloride, titanium tetrabromide,
  • This elimination reaction is preferably carried out in the presence of cation trapping agents (e.g. anisole, phenol, etc.) and is usually carried out in a solvent such as nitroalkane (e.g. nitromethane, nitroethane, etc.), alkylene halide (e.g. methylene chloride, ethylene chloride, etc.), diethyl ether, carbon disulfide or any other solvent which does not adversely affect the cation trapping agents (e.g. anisole, phenol, etc.) and is usually carried out in a solvent such as nitroalkane (e.g. nitromethane, nitroethane, etc.), alkylene halide (e.g. methylene chloride, ethylene chloride, etc.), diethyl ether, carbon disulfide or any other solvent which does not adversely affect the nitroalkane (e.g. nitromethane, nitroethane, etc.), alkylene halide (e.
  • the reduction elimination can be applied preferably for elimination of the protective group such as
  • halo(lower)alkyl e.g. 2-iodoethyl, 2,2,2-trichloroethyl, etc.
  • ar(lower)alkyl e.g. benzyl, etc.
  • the reduction method applicable for the elimination reacting may include, for example, reduction by using a combination of a metal (e.g. zinc , zinc amalgam, etc. ) or a salt of chromium compound (e.g. chromous chloride, chromous acetate, etc.) and an organic or an inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid, etc.); and conventional catalytic reduction in the
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling, at ambient temperature or under warming.
  • the object compound (I-d) or a salt thereof can be prepared by subjecting the compound (I-C) or a salt thereof to elimination reaction of the carboxy or amino, protective group.
  • This reaction can be carried out in substantially the same manner as Process 3, and therefore the reaction mode and reaction conditions [e.g. bases, acids, reducing agents, catalysts, solvents, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 3.
  • reaction mode and reaction conditions e.g. bases, acids, reducing agents, catalysts, solvents, reaction temperature, etc.
  • the object compound (1-3. or a salt thereof can be prepared by subjecting the compound (I-b) or its reactive derivative at the amino, hydroxy and/or carboxy group or a salt thereof to introduction reaction of the amino, hydroxy and/or carboxy protective group.
  • reaction can be carried out in substantially the same manner as Process 1, and therefore the reaction mode and reaction conditions [e.g. solvents, reaction
  • the present reaction includes, within its scope, the case that the amino group on R 1 is reacted during the reaction or at the post-treating step of the present process.
  • the compound (I-f) or a salt thereof can be prepared by reactin ⁇ the compound ( I-e) or a salt thereof with the compound (VI).
  • the reaction is usually carried out in a conventional solvent such as dimethyl sulfoxide or any other solvent which does not adversely influence the reaction.
  • the object compound (I-g) or a salt thereof can be prepared by subjecting the compound (I-f) or a salt thereof to hydrogenation. This reaction is usually carried out in the presence of triphenylphosphine, palladium on carbon, or the like.
  • the reaction is usually carried out in a conventional solvent such as alcohol (e.g., methanol, ethanol, etc.), or any other solvent which does not adversely influence the reaction.
  • a conventional solvent such as alcohol (e.g., methanol, ethanol, etc.), or any other solvent which does not adversely influence the reaction.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the object compound (I-i) or a salt thereof can be prepared by subjecting the compound (I-h) or a salt thereof to elimination reaction of the carboxy protective group.
  • This reaction can be carried out in substantially the same manner as Process 3, and therefore the reaction mode and reaction conditions [e.g. bases, acids, reducing agents, catalysts, solvents, reaction temperature, etc.] of this reaction are. to be referred to those as explained in Process 3.
  • reaction mode and reaction conditions e.g. bases, acids, reducing agents, catalysts, solvents, reaction temperature, etc.
  • the object compound (I-k) or a salt thereof can be prepared by subjecting the compound (I-f) or a salt thereof to introduction reaction of amidino group.
  • This reaction is usually carried out in the presence of introducing agent of amidino group such as
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, or the like.
  • the compound (I) and the other compounds may include one or more stereoisomers due to asymmetric carbon atoms, and all of such isomers and mixture thereof are included within the scope of this invention.
  • the object compounds (I) and pharmaceutically acceptable salt thereof have pharmacological activities such as tachykinin antagonism, especially substance P antagonism, neurokinin A antagonism or neurokinin B antagonism, and therefore are useful for treating or preventing tachykinin mediated diseases, particularly substance P mediated diseases, for example, respiratory diseases such as asthma, bronchitis rhinitis, cough, expectoration, and the like; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like;
  • cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis, and the like; inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and the like; pains or aches (e.g. migraine, headache, toothache, cancerous pain, back pain, etc.); and the like.
  • object compounds (I) of the present invention are useful for treating or preventing ophthalmic diseases such as glaucoma, uveitis, and the like; gastrointestinal diseases such as ulcer, ulcerative colitis, irritable bowel syndrome, food
  • inflammatory diseases such as nephritis, and the like
  • circulatory diseases such as hypertension, angina pectoris, cardiac failure
  • thrombosis and the like; epilepsy; spastic paralysis; pollakiuria; dementia; Alzheimer's diseases;
  • the compounds (I) and pharmaceutically acceptable salts thereof of the present invention can be used in a form of pharmaceutical
  • compositions may be capsules, tablets, dragees, granules, solution, suspension, emulsion, or the like. If desired, there may be included in these preparation, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.
  • the dosage of the compounds (I) will vary depending upon the age and condition of the patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg,
  • 100 mg, 250 mg, 500 mg and 1000 mg of the compound (I) may be effective for treating asthma and the like.
  • amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.
  • pellets were resuspended in buffer (5 mM Tris-HCl pH 7.5), homogenized with a teflon homogenizer and centrifuged (14000 xg, 20 min) to yield pellets which were referred to as crude membrane fractions.
  • the obtained pallets were stored at -70°C until use.
  • reaction mixture was extracted with ethyl acetate, and the organic layer was washed successively with water, and aqueous sodium hydrogencarbonate solution, 0.5N hydrochloric acid, water and an aqueous sodium
  • the object compound was obtained according to a similar manner to to that of Preparation 13.
  • the object compound was obtained according to a similar manner to to that of Preparation 25.
  • the object compound was obtained according to a similar manner to to that of Preparation 17.
  • the object compound was obtained according to a similar manner to to that of Preparation 29.
  • the object compound was obtained according to a similar manner to to that of Preparation 30 and used to the next reaction without purification.
  • the object compound was obtained according to a similar manner to to that of Preparation 5.
  • the object compound was obtained according to a similar manner to to that of Preparation 28 and used to the next reaction without purification.
  • the object compound was obtained according to a similar manner to to that of Preparation 29.
  • the object compound was obtained according to a similar manner to to that of Preparation 13.
  • the object compound was obtained according to a similar manner to to that of Preparation 17.
  • reaction mixture was poured into water (150 ml) and the pH was adjusted to 8 with sodium hydrogen carbonate solution.
  • the product was extracted with ethyl acetate and the organic layer was washed sodium hydrogen carbonate
  • reaction mixture was extracted with ethyl acetate and the organic layer was washed successively with an aqueous sodium hydrogencarbonate solution, water, 0.5N hydrochloric acid, water, and an aqueous sodium chloride solution, and dried over magnesium sulfate.
  • reaction mixture was washed successively with water, diluted sodium hydrogencarbonate solution, 0.5N hydrochloric acid and brine, and dried over magnesium sulfate. After evaporation, the crude material was purifried on a silica-gel column (80g) eluting with a mixed solvent of chloroform and methanol(from 98:8 to 96.5:3.5) to give
  • Example 10 The object compounds were obtained according to a similar manner to to that of Example 10.
  • the object compound was obtained according to a similar manner to to that of Preparation 19.
  • the object compound was obtained according to a
  • the object compound was obtained according to a

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EP92913210A 1991-06-19 1992-06-18 Peptides mit tachykininantagonistischer wirkung Withdrawn EP0590152A1 (de)

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