GB1564317A - Dipeptide derivatives - Google Patents

Dipeptide derivatives Download PDF

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Publication number
GB1564317A
GB1564317A GB26662/76A GB2666276A GB1564317A GB 1564317 A GB1564317 A GB 1564317A GB 26662/76 A GB26662/76 A GB 26662/76A GB 2666276 A GB2666276 A GB 2666276A GB 1564317 A GB1564317 A GB 1564317A
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alanyl
proline
manufactured
anilide
process according
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GB26662/76A
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Roche Products Ltd
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Roche Products Ltd
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Priority to GB26662/76A priority Critical patent/GB1564317A/en
Priority to CH704377A priority patent/CH627735A5/en
Priority to US05/804,680 priority patent/US4187216A/en
Priority to PH19860A priority patent/PH14141A/en
Priority to ZA00773634A priority patent/ZA773634B/en
Priority to IL52337A priority patent/IL52337A/en
Priority to CA280,942A priority patent/CA1092097A/en
Priority to NZ184428A priority patent/NZ184428A/en
Priority to AU26243/77A priority patent/AU510722B2/en
Priority to IE1254/77A priority patent/IE45517B1/en
Priority to IT24908/77A priority patent/IT1080679B/en
Priority to SE7707339A priority patent/SE7707339L/en
Priority to NL7706967A priority patent/NL7706967A/en
Priority to FR7719277A priority patent/FR2360561A1/en
Priority to JP7394677A priority patent/JPS532417A/en
Priority to AT448177A priority patent/AT355742B/en
Priority to BE178738A priority patent/BE856064A/en
Priority to LU77603A priority patent/LU77603A1/xx
Priority to DK283177A priority patent/DK283177A/en
Priority to DE19772728593 priority patent/DE2728593A1/en
Priority to AT0300379A priority patent/AT363205B/en
Priority to AT0300479A priority patent/AT363626B/en
Priority to AT0300579A priority patent/AT363206B/en
Publication of GB1564317A publication Critical patent/GB1564317A/en
Priority to CH388481A priority patent/CH628873A5/en
Priority to CH388581A priority patent/CH628874A5/en
Priority to CH388381A priority patent/CH628616A5/en
Expired legal-status Critical Current

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    • 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
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • 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
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Description

(54) DIPEPTIDE DERIVATIVES (71) We, ROCHE PRODUCTS LIMITED, a British Company of Broad water Road, Welwyn Garden City, Hertford shire, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention relates to dipeptide derivatives. More particularly, the invention is concerned with dipeptide derivatives, a process for the manufacture thereof and pharmaceutical preparations containing same.
The dipaptide derivatives provided by the present invention have the following general formula
wherein R represents a phenyl, substituted phenyl, lower cycloalkyl or n-(CI--C,)- alkyl group; R1 and R2 each represent a hydrogen atom or a methyl group, with the proviso that R' and R2 do not simultaneously represent a hydrogen atom, or R1 and R2 together represent a trimethylene group; R3 represents an acyl group derived from a carboxylic acid, a sulphonic acid or a sul phinic acid; and the asterisk denotes that the configuration at the carbon atom so marked is L when R1 represents other than a hydrogen atom.
The acyl group denoted by R3 in formula I can represent, for example, an alkanoyl, halo-alkanoyl, nitro-alkanoyl, cyano-alkanoyl, cycloalkylcarbonyl, cycloalkyl-alkanoyl, aroyl, aryl-alkanoyl, alkoxycarbonyl, aryloxycarbonyl, aryl-alkoxycarbonyl, arylsulphonyl, alkylsul phonyl, cydoalkylsulphonyl, cycloalkylsul pbinyl, cycloalkyl - alkylsulphonyl or cyclo alkyl-alkylsulphinyl group. ~ The substituted-phenyl group denoted by R in formula I is a phenyl group carrying one or more substituents, preferably selected from halogen (i.e. fluorine, chlorine, bromine or iodine), lower alkyl, lower alkoxy and nitro.
Examples of such substituted-phenyl groups are 4 - methoxyphenyl, 4 - nitrophenyl and 2,4-dichlorophenyl. The term "lower cycle; alkyl" used in relation to R means a monocyclic cycloalkyl group containing from 3 to 8 carbon atoms, i.e. cydopropyl, cydobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclo octyl. Of the ( Ce ) etCWC6)-alkyl groups denoted by R (i.e. n-butyl, pentyl and ehexyl), the n-pentyl group is preferred. The term "alkanoyl" means an alkanoyl group derived from a straight-chain or branched-chain alkanoic acid, preferably a lower alkanoyl group such as acetyl, propionyl, butyryl, isobutyryl, valeroyl or pivaloyl. The term "halo-alkanoyl" means an alkanoyl group which carries one or more halogen atoms. The halo-alkanoyl group is preferably a halo-(lower alkanoyl) group such as monochloroacetyl, dichloroacetyl or, especially, trifluoroacetyl. The term "nitro-alkanoyl" means an alkanoyl group carrying a nitro group, preferably a nitro (lower alkanoyl) group such as nitroacetyl.
The term "cyano-alkanoyl" means an alkanoyl group carrying a cyano group, preferably a cyano-(lower alkanoyl) group such as cyanoacetyl. The term "cycloalkylcarbonyl" means a group of the formula R'-CO- in which R5 represents a lower cydoalkyl group as hereinbefore defined (such cycloalkylcarbonyl groups being referred to hereinafter as lower cycloalkylcarbonyl groups such as cyclopentylcarbonyl or cyctohexylcarbonyl or an ali phatic bridged and/or condensed ring system which may be substituted by oxo or hydroxy (e.g. adamantylcarbonyl). The term "cycloalkyl-alkanoyl" means an alkanoyl group in which one of the hydrogen atoms has been replaced by the group R5 hereinbefore (e.g.
adamantylacetyl). The term "aroyl" means an aroyl group (e.g. benzoyl) which may carry one or more substituents selected from halogen, lower alkyl, lower alkoxy, nitro, amino and lower alkanoylamino. The term "aryl-alkanoyl" means an alkanoyl group in which one of the hydrogen atoms has been replaced by an aryl group, the term "aryl" meaning an aryl group (e.g. phenyl) optionally carrying one or more substituents selected from halogen, lower alkyl, lower alkoxy, nitro, amino and lower alkanoylamino. The preferred aryl-alkanoyl groups are the aryl-(lower alkanoyl) groups such as the phenacetyl, phenylpropionyl and like groups.
The term "alkoxycarbonyl" means a straightchain or branched-chain alkoxycarbonyl group, preferably a lower alkoxycarbonyl group such as methoxycarbonyl or ethoxycarbonyl. The term "aryloxycarbonyl" means an aryloxycarbonyl group in which the aryl group is ds defined earlier. The term t'aryl-alkoxy- carbonyl" means an alkoxycarbonyl group in which one of the hydrogen atoms has been replaced by an aryl group as defined earlier, preferably an aryl-(lower alkoxycarbonyl) group such as the benzyloxycarbdnyl group.
The term "arylsulphonyl" means an aryl sniphonyl group in which the aryl group is as defined earlier. For example, the arylsulphonyl group may be the benzenesulphonyl group or a naphthalenesulphonylgroup (e.g.
1-naphthalenesulphonyl) or a benzenesulphonyl group carrying one or more substituents which may be present on the aforementioned aryl group (e.g. ptoluenesulphonyl, 4-chloro benzenesulphonyl, 4 - aminobenzenesulphonyl, 4 - acetylaminobenzenesulphonyl, 4-methoxybenzenesulphonyl or mesitylenesulphonyl).
The alkylsulphonyl group is preferably a lower alkylsulphonyl group such as methylsulphonyl etc. The term "cycloalkylsulphonyl" means a group of the formula R5-SO2- in which R5 has the significance given earlier, examples of such groups being adamantylsulphonyl (e.g.
1 - adamantylsulphonyl), camphorsulphonyl (e.g. D - 10 - camphorsulphonyl) etc. The term "cycloalkylsulphinyl" means a group of the formula R5-SO- in which R5 has the significance given earlier, examples of such groups being adamantylsulphinyl such as 1adamantylsulphinyl. The term "cycloalkylalkylsulphonyl" means an alkylsulphonyl group which carries a substituent R5 hereinbefore ,ie.g. isobornylmethylsulphonyl) and the term cycloalkyl-alkylsulphinyl" means an alkyl sllphinyl group which carries a substituent R1 hereinbefore (e.g. bornylmethylsulphinyl).
The terms "lower alkanoyl", "lower alkyl" and "lower alkoxy" as used herein, alone or in combination as the contex may require, mean that such groups contain up to 6 carbon atoms. (This definition does not apply to "lower cycloalkyl" used in relation to R.) Examples of lower alkyl and lower alkoxy groups which, like the lower alkanoyl groups, can be straight-chain or branched-chain, are methyl, ethyl, propyl and isopropyl, and methoxy, ethoxy, propoxy and isopropoxy, respectively.
In one particular embodiment of the present invention, R3 represents the trifluoroacetyl group or a lower alkanoyl, lower cycloalkyl- carbonyl, benzoyl, phenyl- (lower alkanoyl), lower alkoxycarbonyl, phenoxycarbonyl, phenyl- (lower alkoxycarbonyl), benzene sulphonyl, naphthalenesulphonyl or lower alkylsulphonyl group, the benzoyl, phenoxy carbonyl and benzenesulphonyl groups and the phenyl portion of the phenyl-(lower alkanoyl) and phenyl-(lower alkoxycarbonyl) groups optionally carrying one or more substituents selected from halogen, lower alkyl, lower alkoxy and nitro.
In another particular embodiment of the present invention, R3 represents a lower alkanoyl, lower cyctoalkylcarbonyl, benzoyl, phenyl-(lower alkanoyl), lower alkoxy carbonyl, phenoxycarbonyl or phenyl-(lower alkoxycarbonyl) group, the benzoyl and phenoxycarbonyl groups and the phenyl portion of the phenyl-(lower alkanoyl) and phenyl (lower alkoxycarbonyl) groups optionally carrying one or more substituents selected from halogen, lower alkyl, lower alkoxy and nitro.
One preferred class of dipeptide derivatives provided by the present invention comprises those in which R1 represents a hydrogen atom and R2 represents a methyl group or Rl and R2 together represent a trimethylene group.
Another preferred class of dipeptide deriva tives provided by the invention comprises those in which R3 represents an alkanoyl group, especially a lower alkanoyl group and particu larly propionyl, an aroyl group, especially benzoyl, an aryl-alkoxycarbonyl group, espe cially an aryl-(lower alkoxycarbonyl) group and particularly benzyloxycarbonyli or an aryl sulphonyl group, especially ptoluenesulphonyl.
Other preferred values for R3 are the cyclo alkylsulphonyl, cyctoalkylsulphinyl, cycloalkyl alkylsulphonyl and cyctoalkyl-alkylsulphinyl groups. When R represents a substituted phenyl group, this is preferably a 4-methoxy phenyl, 4-nitrophenyl or 2,4-dichlorophenyl group. When R represents a lower cyctoalkyl group, this is preferably a cyctoalkyl group containing from 5 to 8 carbon atoms.
Examples of dipeptide derivatives of formula I are: N - benzyloxycarbonyl - L - alanyl proline anilide, N - benzyloxycarbonyl - L - alanyl proline 2,4-Dichloroanilide, N - benzyloxycarbonyl - L - alanyl proline 4-nitroanilide, N - benzyloxycarbonyl - L - alanyl proline 4-methoxyanilide, N-acetyl-L-alanyl-L-proline anilide, N-propionyl-L-alanyl-L-proline anilide, N-benzoyl-L-alanyl-L-proline anilide, N-pivaloyl-L-alanyl-L-proline anilide, N-hexanoyl-L-alanyl-L-proline anilide, N - trifluoroacetyl - L - alanyl - L- proline anilide, N - cyanoacetyl - L - alanyl - L - proline anilide, N - ( 1 - adamantylcarbonyl) - L - alanyl L-proline anilide, N - (1 - adamantylacetyl) - L - alanyl L-proline anilide, N - (p - toluenesulphonyl) - L - alanyl L-proline anilide, N - benzenesulphonyl - L - alanyl proline anilide, N - (4 - nitrobenzenesulphonyl) alanyl-L-proline anilide, N - (1 - naphthalenesulphonyl) alanyl-L-proline anilide, N - (1 - adamantylsulphinyl) - L - alanyl L-proline aniline, N - (1 - adamantylsulphonyl) alanyl-L-proline anilide, N - (D - 10 - camphorsulphonyl) alanyl-L-proline anilide, N - (4 - acetylaminobenzenesulphonyl) L-alanyl-L-proline anilide, N - (4 - methoxybenzenesulphonyl) alanyl-L-proline anilide, N - mesitylenesulphonyl - L - alanyl - proline anilide, N - propionyl - L - alanyl - L - proline 2,4dichloroanilide N - propionyl - L - alanyl - L - proline 4-nitroanilide, N - propionyl - L - alanyl - L - proline 4-methoxyanilide, N - benzyloxycarbonyl - L - alanyl proline cyclopentylamide, N-benzyloxycarbonyl - L - alanyl proline cyclohexylamide, N - benzyloxycarbonyl - L - alanyl proline cycioheptylamide, N - benzyloxycarbonyl - L - alanyl proline cyclooctylamide, N - propionyl - L - alanyl- L- proline cyclopentylamide, N - propionyl - L - alanyl - L - proline cyclohexylamide, N - (p - toluenesulphonyl) - L - alanyl L-proline cyclohexylamide, N - propionyl - L - alanyl - L - proline cycloheptylamide, N propionyl - L - alanyl - L - proline cyclooctylamide, N - benzyloxycarbonyl - L - alanyl alanine anilide, N-propionyl-L-alanyl-L-alanine anilide, N-benzoyl-L-alanyl-L-alanine anilide, N - benzyloxycarbonyl - L - alanyl alanine cyclohexylamide, N - propionyl - L - alanyl - L - alanine cyclohexylamide, N - benzyloxycarbonyl - L - alanyl proline n-pentylamide and N - propionyl - L - alanyl- L - proline n-pentylamide.
According to the process provided by the present invention, the dipeptide derivatives aforesaid are manufactured by (a) condensing an amide of the general formula
wherein R, R1, R2 and the asterisk have the significance given earlier, with an Nprotected-L-alanine of the general formula
wherein R represents a protecting group or (b) amidating a carboxylic acid of the general formula
wherein R1, R2, R4 and the asterisk have the significance given earlier, and, in either case and where required, cleaving off the protecting group denoted by R4 and introducing a group denoted by R3 hereinbefore and, if desired, oxidising a resulting dipeptide derivative of formula I in which R3 represents an acyl group derived from a sulphinic acid to give a corresponding dipeptide derivative of formula I in which Ra represents an acyl group derived from a sulphonic acid.
The protecting group denoted by R4 in the N-protected-L-alanine starting materials of formula III and the carboxylic acid starting materials of formula IV can be any protecting group known per se in peptide chemistry.
Thus, for example, R4 can represent the trifluoroacetyl or ptoluenesulphonyl group or a lower alkoxycarbonyl group (e.g. tert.butoxycarbonyl), an aryloxycarbonyl group (e.g.
phenoxycarbonyl) or an aryl- (lower alkoxy carbonyl) group (e.g. benzyloxycarbonyl).
may also represent, for example, a formyl, trityl, 2-(biphenylyl)-isopropyloxycarbonyl or phthaloyl group. In a preferred embodiment of this invention, R4 represents an aryl-(lower alkoxycarbonyl) group, especially the benzyloxycarbonyl group.
The condensation of an amide of formula II with an N-protected-L-alanine of formula III in accordance with embodiment (a) of the present process can be carried out according to methods which are known per se in peptide chemistry; for example, according to the mixed anhydride, azide, activated ester or acid chloride method.
For example, an amide of formula II can be condensed with an N-protected-L-alanine of formula III in which the carboxyl group is present in the form of a mixed anhydride residue formed with an inorganic or organic acid. Suitably, such an N-protected-L-alanine carrying a free carboxyl function is treated with a tertiary base such as a tri(lower alkyl)amine (e.g. triethylamine) or N-ethylmorpholine in an inert organic solvent (e.g. tetrahydrofuran, 1,2-dimethoxyethane, dichloromethane, toluene, petroleum ether or mixtures thereof) and the salt obtained is reacted with a chloroformate (e.g. ethyl chloroformate or isobutyl chloroformate) at a low temperature.
The mixed anhydride obtained is then conveniently condensed in sitg with an amide of formula II.
Again, for example, an amide of formula II can be condensed with an N-protected-Lalanine in which the carboxyl group is in the form of an acid azide. This condensation is expediently carried out in the presence of an inert organic solvent such as dimethylformamide or ethyl acetate at a low temperature.
Yet again, for example, an amide of formula II can be condensed with an N-protected-Lalanine in which the carboxyl group is in the form of an active ester group (e.g. the pnitrophenyl, 2,4,5-trichiorophenyl, N-hydroxysuccinimide or hydroxybenztriazole ester group). This condensation is suitably carried out in an inert organic solvent such as dimethylformamide or tetrahydrofuran.
Further, for example, an amide of formula II can be condensed with an N-protected-L alanine in the presence of dicZclohexylcarbo- diimide. This condensation is expediently car ried out in the presence of an inert organic solvent (e.g. dimethylformamide or methylene chloride) at a low temperature (e.g. Oo C).
Still further, for example, an amide of formula II can be condensed with an N protected-L-alanine in which the carboxyl group is in the form of an acid chloride. It is preferred to carry out this condensation in the presence of a base (e.g. an alkali metal hydroxide such as sodium hydroxide) and at a low temperature (e.g. OOC).
The amidation of a carboxylic acid of formula IV in accordance with embodiment (b) of the present process can be carried out according to methods known per se. Thus, for example, a carboxylic acid of formula IV in which R2 represents a methyl group or R1 and R2 together represent a trimethylene group can be converted in the manner described earlier in connection with the condensation of an amide of formula II with an N-protected L-alanine of formula III into an acid azide, activated ester, mixed anhydride or acid chloride as the case may require and can then be reacted with an appropriate amine yielding the group denoted by R hereinbefore. Alternatively, a carboxylic acid of formula IV in which R2 represents a methyl group or R1 and R2 together represent a trimethylene group can be amidated in the presence of dicyclohexylcarbodiimide. In the amidation of a carboxylic acid of formula IV in which R2 represents a hydrogen atom, care must be taken that no racemisation occurs. This latter amidation can suitably be carried out according to the acid azide or N-hydroxysuccinimide/dicydohexylcarbodiimide method.
The condensation of an amide of formula II with an N-protected-L-alanine of formula III or the amidation of a carboxylic acid of formula IV yields a compound of the general formula
wherein R, R1, R2, R4 and the asterisk have the significance given earlier.
It will be appreciated that compounds of formula V in which the protecting group denoted by R4 is the trifluoroacetyl or p toluenesulphonyl group or a lower alkoxycarbonyl, aryloxycarbonyl or aryl- (lower alkoxycarbonyl) group correspond to dipeptide derivatives of formula I in which R3 has any of these values. Those compounds of formula V which are not covered by formula I, and which are novel, also form part of the invention.
The protecting group denoted by R4 can be cleaved off from a compound of formula V according to known methods. For example, the cleavage of the trifluoroacetyl group can be carried out by treatment with an appropriate base (e.g. an alkali metal hydroxide such as sodium hydroxide). The ptoluenesulphonyl group can be cleaved off by treatment with an alkali metal (e.g. sodium) in liquid ammonia. The cleavage of a lower alkoxycarbonyl, aryloxycarbonyl or aryl-(lower alkoxycarbonyl) group or the 2-(biphenylyl)isopropyloxycarbonyl group can be carried out by hydrolysis (e.g. by treatment with hydrogen bromide in glacial acetic acid). An aryl-(lower alkoxycarbonyl) group can also be cleaved off by hydrogenolysis (e.g. in the presence of palladium-on-charcoal or platinum oxide).
The tert.butoxycarbonyl or 2-(biphenylyl)-isopropyloxycarbonyl group may also be cleaved off using hydrogen chloride in dioxan or trifluoroacetic acid.
The cleavage of the protecting group denoted by R4 from a compound of formula V yields a compound of the general formula
wherein R, R1, R2 and the asterisk have the significance given earlier, which may be isolated if desired, suitably in the form of a hydrohalide salt such as the hydrobromide, and then converted into a dipeptide derivative of formula I by the introduction of the group R3 according to methods known per se or which may be converted in situ into a dipeptide derivative of formula I in the same manner. The compounds of general formula VI, and their hydrohalides, also form part of the invention.
The introduction of a group denoted by R3 into a compound of formula VI is carried out in accordance with methods which are known per se.
Thus, for example, in one method, a compound of formula VI can be treated with an appropriate acid chloride (e.g. an alkanoic acid chloride such as pivaloyl chloride, a cycS alkane carboxylic acid chloride such as cyclohexane carboxylic acid chloride, a cycloalkylalkanoic acid chloride such as adamantylacetyl chloride, an aroic acid chloride such as benzoyl chloride, an aryl-alkanoic acid chloride such as phenacetyl chloride, an arylsulphonic acid chloride such as ptoluenesulphonyl chloride, benzenesulphonyl chloride, 4-nitrobenzenesulphonyl chloride or l-naphthalenesulphonyl chloride, an alkanesulphonic acid chloride such as methanesulphonyl chloride, a cycloalkanesuiphinyl chloride such as adamantanesulphinyl chloride) in the presence of a base (e.g. an alkali metal hydroxide such as sodium hydroxide or a tertiary amine such as triethylamine or pyridine). This treatment is advantageously carried out at about room temperature. It is advantageous to carry out this treatment in the presence of an inert organic solvent such as a halogenated hydrocarbon (e.g. methylene chloride) when an alkali metal hydroxide is used as the base.
When a tertiary amine is used as the base, it can be present in excess and can thereby also serve as a solvent.
In another method, for example, a compound of formula VI can be treated with an appropriate acid anhydride (e.g. a haloalkanoic acid anhydride such as trifluoroacetic anhydride or an alkanoic acid anhydride such as propionic anhydride, isobutyric anhydride or ovaleric anhydride) in the presence of a base, preferably a tertiary amine and, in particular, pyridine. It is expedient to carry out this treatment at about room temperature. An excess of the tertiary amine can be present and can thereby also serve as a solvent. This treatment can, however, also be carried out :n the presence of an appropriate inert organic solvent.
In a further method, for example, a compound of formula VI can be treated with an appropriate chloroformate in the presence of N-ethylmorpholine. Examples of chloroformates which may be used in this method are the alkyl chloroformates, particularly ethyl chloroformate and isobutyl chloroformate. This treatment may be carried out in an inert organic solvent (e.g. tetrahydrofuran) and at a temperature of about room temperature.
In yet a further method, a hydrohalide salt, particularly the hydrobromide salt, of a compound of formula VI can be condensed with an appropriate acid yielding the group denoted by R3 in the presence of a suitable condensing agent such as a carbodiimide (e.g. N,N-di cyclohexylcarbodiimide) in accordance with known procedures. The condensation is carried out in the presence of a tertiary amine (e.g. triethylamine or N-ethylmorpholine) and preferably in the presence of an inert organic solvent such as a chlorinated hydrocarbon (e.g.
methylene chloride). It is expedient to carry out the condensation at about 0 C.
The oxidation of a dipeptide derivative of formula I in which Ra represents an acyl group derived from a sulphinic acid to give a corresponding dipeptide derivative of formula I in which R3 represents an acyl group derived from a sulphonic acid can be carried out in accordance with methods known per se. Suitable oxidising agents which can be used include potassium permanganate in acetone and organic peracids such as peracetic acid and perbenzoic acid. The organic peracid may be formed in situ using hydrogen peroxide and the corresponding organic acid (e.g. hydrogen peroxide and glacial acetic acid). The oxidation is expediently carried out at about room temperature, but in certain circumstances it can be advantageous to warm the oxidation mixture (e.g. up to 650C).
The amide starting materials of formula II can be prepared, for example, by amidating a corresponding N-protected a-amino carboxylic acid in a manner analogous to that described earlier in connection with the amidation of a carboxylic acid of formula IV and subsequently removing the N-protecting group in a manner analogous to that described earlier in connection with the cleavage of the protecting group R4 from a compound of formula VI.
The N-protected-L-alanine starting materials of formula III are known compounds which can be prepared according to conventional methods from L-alanine.
The starting materials of formula IV can be prepared, for example, by condensing an N-protected-L-alanine with a lower alkyl or aryl-(lower alkyl) ester of L-alanine, Lproline, N-methyl-Lalanine or sarcosine in accordance with methods known per se (e.g.
the mixed anhydride, azide, activated ester or acid chloride method described earlier in connection with the condensation of an amide of formula II with an N-protected-L-alanine of formula III) and then hydrolysing a resulting ester to the corresponding carboxylic acid.
The dipeptide derivatives of formula I hereinbefore possess activity as elastase inhibitors.
Thus, for example, the present dipeptide derivatives possess in vitro elastase inhibiting activity against human granulocyte elastase.
This activity can be demonstrated according to the test method of Visser, L. and Blout, E.
R., Biochem. Biophys. Acta 268 (1972) 257, using human granulocyte elastase as the enzyme. The results obtained with representative dipeptide derivatives of formula I in this test are given in Table I hereinafter, the Iso being the concentration in millimoles per litre which gives 50% inhibition of the human granulocyte elastase: TABLE I
Dipeptide derivative N-Hexanoyl-L-alanyl-L-proline ani lide 0.7 N-BenzyloxycaibonylL-al anyl-L-proline cyclohexylamide 1.0 N-Benzyloxycarbonyl-L-alanyl-L-proline n-pentylamide ca 5.0 N-(p-Toluenesulphonyl)-L-alanyl-L-pIoline anilide 0.06 N-(1-Adamantyl carbonyl)-L-alanyl-L-proli ne anilide 0.6 N-(l-Adamantylacetyl)-L-alanyl-L-proline ani ii de 0.08 N-(l-Adamantylsulphonyl)-L-alanyl-L-proline anilide 0.007 Again, for example, the dipeptide derivative of formula I in which R3 represents an acetyl, trifluoroacetyl or propionyl group possess in vitro elastase inhibiting activity against porcine pancreatic elastase. This activity can be demonstrated according to the aforementioned test method using porcine pancreatic elastase as the enzyme. The results obtained with representative dipeptide derivatives are given in Table II hereinafter, the Ki being the inhibitor constant in millimoles per litre: TABLE II
Dipeptide derivative Ki (mmol/litre) N-Propionyl-L-al anyl-L-proline ani Ii de 0.04 N-Propionyl-L-al anyl-L-proline 4-nitroanilide 0.026 N-Propionyl-L-alanyl-L-proline cyclohexylamide 0.02 N-Propionyl-L- al anyl-L-alanine anilide 0.04 N-Tri fluoro acetyl-L-alanyl-L-proline ani lide 0.0014 The in vivo elastase inhibiting activity of dipeptide derivatives of formula I in which R3 represents an acetyl, trifluoroacetyl or propionyl group can be demonstrated, for example, by administering said dipeptide derivatives orally or intraperitoneally to rats in which an oedema has previously been induced in a hind paw by the subcutaneous injection therein of a proteolytic enzyme such as porcine pancreatic elastase. Following such oral or parenteral administration, the size of the oedema is reduced.
The dipeptide derivatives of formula I hereinbefore may be used in the treatment of degenerative diseases associated with the action of elastase-like enzymes such as emphysema and arthritis. They may also be used for the treatment of inflammatory conditions in which elastase-like enzymes act as mediators of inflammation. Further, they may be used as adjuncts to topical antifungal and antibaaterial preparations for the treatment of infections associated with the breakdown of host-elastic tissue.
The dipeptide derivatives of formula I hereinbefore may be used as medicaments in the form of pharmaceutical preparations which contain them in association with a compatible pharmaceutical carrier material. This carrier material ma to 0 C and 2.47 ml (0.019 mol) of N-ethylmorpholine were added. This solution was then combined with the mixed anhydride solution prepared as described in the preceding paragraph, stirred at 0 C for 1 hour and then left to stand at room temperature for 16 hours.
The solvents were removed by evaporation to give a white solid which was recrystallised from ethanol to yield 4.9 g (67%) of Nbenzyloxycarbonyl - L - alanyl - L - alanine anilide of melting point 2190--2210C.
(ii) L - Alanyl - L - alanine anilide hydrobromide.
5.5 g (0.0149 g) of N-benzyloxycarbonyl L-alanyl-L-alanine anilide were dissolved in 30 ml of 4N hydrogen bromide in acetic acid and the solution was stirred at room temperature for 1 hour. 300 ml of dry ether were then added. A white solid separated out and was allowed to settle. The solution was decanted off and the solid washed with two 1SO ml portions of ether. Recrystallisation of the solid from methanol/ethyl acetate yielded 4.1 g (88%) of L-alanyl-L-alanine anilide hydrobromide.
(iii) N - Benzoyl - L - alkyl alanine anilide.
4.1 g (0.013 mol) of L-alanyl-lL-alanine anilide hydrobromide were dissolved in 120 ml of dry pyridine and 3 ml (0.026 mol) of benzoyl chloride were added. The solution was stirred at room temperature for 3 hours and was then evaporated to yield a solid. 50 ml of water were added, the solid was filtered off, washed with 50 ml of water and then recrystallised from ethanol to yield 3.15 g (72%) of N-benzoyl-L-alanyl-L-alanine anilide of melting point 2450-2480C; [a]D2 =+66.6 (c=1.086% in dimethylformamide).
Analysis for C1eH21O,N3 (339.40) Calculated: C: 67.24; H: 6.24; N: 12.38.
Found: C: 67.33; H: 6.30; N: 12.43.
(iv) N - Propionyl - L - alany! - alanine onilide.
3.8 g (0.012 mol) of L-alanyl-L-alanine anilide hydrobromide were dissolved in 80 ml of dry pyridine and 3.4 ml (0.024 mol) of propionic anhydride were added. The solution was stirred at room temperature for 2 hours and then evaporated to give a solid.
This solid was recrystallised from ethanol and then from methanol to yield 1.9 g (54%) of N - propionyl - L - alanyl - L - alanine anilide of melting point 2810-2840C; t]D2a= - 101.10 (c=0.995% in acetic acid).
Example 2.
(A) The preparation of the starting material: (i) N - Beneyloxycarbonyl - L - alanine cyclohexylamide.
11.15 g (0.05 mol) of N-benzyloxycarbonyl L-alanine were dissolved in 75 ml of dry tetrahydrofuran and the mixture was cooled to --10"C. 6.35 ml (0.05 mol) of N-ethylmorpholine were added followed by 6.3 ml of isobutyl chloroformate and the solution obtained was stirred at - 100C for 20 minutes.
A solution of 6.05 ml of cyclohexylamine in 75 ml of tetrahydrofuran was then added and the resulting solution was stirred at OOC. After 30 minutes the mixture solidified and 30 ml of dimethylformamide were added. After stirring for a further 1 hour at OOC, the solvent was removed by evaporation, water was added and the solid filtered off. The solid was washed with 150 ml of 1N hydrochloric acid, 150 ml of water, 150 ml of 5% sodium bicarbonate solution and 150 ml of water and then dried in vacua. Recrystallisation from ethyl acetate yielded 11.7 g (77%) of Nbenzyloxycarbonyl - L - alanine cyclchexyl- amide of melting point 1630-1640C.
Analysis for Ct7H2403N2 (304.39) Calculated: C: 67.08; H: 7.95; N: 9.20.
Found: C: 66.83; H: 7.89; N: 9.14.
(ii) L - Alanine cyclohexylamide hydro bromide.
7.0 g of N - benzyloxycarbonyl alanine cyclohexylamide were treated with hydrogen bromide in acetic acid in an analogous manner to that described in Example 1 (A) (ii). The L-alanine cyclohexylamide was obtained in the form of an oil after working-up the mixture in the manner described in Example 1 (A) (ii).
(B) The process: (i) N - Benzyloxycarbonyl - L - alanyl L-alanine cyclohexylamide.
5.14 g of N-benzyloxycarbonyl-L-alanine were dissolved in 40 ml of dry tetrahydrofuran and the solution was cooled to - 100 C. 2.92 ml of N-ethylmorpholine were added followed by 3.01 ml of isobutyl chloroformate. The solution obtained was then stirred at - l00C for 20 minutes.
The oil obtained according to part (A) (ii) of this Example was dissolved in 40 ml of dry dimethylformamide, the solution was cooled to 0 C and 2.92 ml of N-ethylmorpholine were added. This solution was then combined with the mixed anhydride solution prepared as described in the preceding paragraph. After stirring at 0 C for 15 minutes the mixture solidified and 30 ml of dimethylformamide were added. The product did not dissolve completely and the mixture was left to stand for 72 hours. Water was added to the suspension, the product was filtered off, washed with ether and dried. There were obtained 5.8 g (67%) of N-benzoyloxycarbonyl-Lalanyl-L-alanine cyclohexylamide of melting point 233 0-2340C; [α] D20 =4.5 (c= 0.9512% in dimethylformamide).
Analysis for C,0H2,O4N, (375.47) Calculated: C: 63.98; H: 7.79; N: 11.19.
Found: C: 64.14; H: 7.82; N: 11.51.
(ii) L - Alanyl - L - alanine cyclohexyl amide hydrobromide.
3.0 g of N - benzyloxycarbonyl alanyl-L-alanine cyclohexylamide were treated with hydrogen bromide in acetic acid in a manner analogous to that described in Example 1 (B) (ii) to give L-alanyl-L-alanine cyclohexylamide hydrobromide in the form of an oil.
(iii) N - Propionyl - L - Alanyl alanine cyclohexylamide.
The oil obtained according to part (B) (ii) of this Example was dissolved in 50 ml of dry pyridine and treated with 2.1 ml of pro; pionic anhydride. The mixture was then stirred at room temperature for 2 hours. The mixture was evaporated and the crystalline residue recrystallised from methanol. There were obtained 1.84 g (78%) of N-propionyl-L- alanyl-L-alanine cyclohexylamide of melting point 2990-3000C; [a]DZO=--81.10 (c= 1.0424% in glacial acetic acid).
Analysis for C15H27O3N3 (297.4) Calculated: C: 60.58; H: 9.15; N: 14.13.
Found: C: 60.63; H: 9.15; N: 14.07.
Example 3.
(A) The preparotion of the starting material: N - Benzyloxycarbonyl - L - alanyl proline.
289 g (0.903 mol) of N-benzyloxycarbonyl L-alanine N-hydroxysuccinimide ester were dissolved in 1800 ml of 1,2-dimethoxyethane and to this solution was added a solution of 103.98 g (0.903 mol) of L-proline in 1350 ml of water followed by 267 ml (1.8 mol) of triethylamine. The mixture was stirred for 16 hours at room temperature and then the 1,2-dimethoxyethane was removed by evaporation. The aqueous solution was then extracted twice with 300 ml of ethyl acetate each time and the organic layers were discarded. The remaining solution was acidified to pH 1-2 using concentrated hydrochloric acid and exreacted twice with 900 ml of ethyl acetate each time. The organic layers were combined and washed twice with 400 ml of water each time, then dried over sodium sulphate, filtered and evaporated to an oil. On trituration with 1600 ml of ether, the product crystallised out and was filtered off, washed with ether and dried to yield 193.8 g of N-benzyloxycarbonyl L-alanyl-L-proline of melting point 1240--1250C. A second crop of 27.6 g (melting point 1230--124"C) was obtained by evaporation of the mother liquors, trituration with 300 ml of ether and storage at 40C for 1 hour; total yield 77%; [er]D20=91.2 (c=1.03% in methanol).
Analysis for CieH20O,N2 (320.35) Calculated: C: 60.00; H: 6.29; N: 8.74.
Found: C: 59.91; H: 6.40; N: 8.85.
(B) The process: (i) N - Benzytoxycarbonyl - L - alanyl- L-pro1ine 2,4-dchlorounilide, 3.2 g (0.01 mol) of N-benzyloxycarbonyl L-alanyl-L-proline were dissolved in 50 ml of dry tetrahydrofuran and the solution was cooled to -100C. 1.27 ml (0.01 mol) of N-ethylmorpholine were added followed by 1.31 ml (0.01 mol) of isobutyl chloroformate and the mixture was stirred at - 100C for 20 minutes. 1.62 g (0.01 mol) of 2,4-dichloroaniline were then added to give a dark brown solution which was then stirred at 0 C for 1 hour and left to stand at room temperature for 72 hours. The solution was evaporated, the residue dissolved in 100 ml of chloroform and washed with 80 ml of 1N hydrochloric acid, 80 ml of water and 80 ml of 5% sodium bicarbonate solution. The organic phase was dried over magnesium sulphate and evaporated to give a brown oil. Crystallisation from ethyl acetate/ether gave 2.03 g of N-benzyloxycarbonyl - L - alanyl - L - proline 2,4dichloroanilide of melting point 1360-1370C; [α]D20=--151.1 (c=1.144% in methanol).
A further 1.03 g of melting point 1360--1370C was obtained by evaporating the mother liquor and crystallising the oil obtained from a smaller volume of ethyl acetate/ether. The total yield was 66%.
Analysis for C,2H,,O4NCl, (464.36) Calculated: C: 56.91; H: 5.00; N: 9.05.
Found: C: 56.79; H: 5.02; N: 9.10.
(ii) N - prot yl - L - alanyl L praline 2,4-dichtoroanilide.
2.54 g (0.0055 mol) of N-benzyloxycarbonyl - L - alanyl - L - proline 2,4dichloroanilide were dissolved in 10 ml of 4N hydrogen bromide in acetic acid and the solu tion was stirred for 1 hour to give a dark blue solution. Upon addition of 100 ml of dry ether an oil precipitated. This oil was allowed to settle, the liquids were decanted off and the oil was washed with 100 ml of ether. The oil was then dissolved in 30 ml of dry pyridine and 1.42 ml (0.011 mol) of propionic anhydride were added to the solu tion. The purple-coloured solution was stirred at room temperature for 2 hours and then evaporated. The final traces of pyridine were removed by the addition of 50 ml of toluene and re-evaporation. The residue was dissolved in 100 ml of chloroform and the solution washed with 80 ml of 1N hydrochloric acid, 80 ml of water and 80 ml of 5% sodium bicarbonate solution, dried over magnesium sulphate and evaporated to give an oil. This oil was treated with 40 ml of ethyl acetate and left to stand at 4"C for 16 hours. There was obtained a crystalline solid which was recrystallised from warm ethyl acetate/ petroleum ether to give 0.59 g (28%) of N propionyl - L - alanyl - L - proline 2,4-dichloroanilide of melting point 136.50-1380C; [a]2a= - 174.80 (c= 0.992% in methanol).
Analysis for ClTH2lO3NsCl2 (386.29) Calculated: C: 52.86; H: 5.48; N: 10.88.
Found: C: 52.90; H: 5.67; N: 10.85.
Example 4.
(A) The preparation of the starting matenal: N-Benzyloxycarbonyl - L - alanyl proline.
This compound was prepared as described in Example 3 (A).
(B) The process: (i) N - Benzylolxycarbonyl- L - al- L-proline anilide.
32 g (0.1 mol) of N-benzyloxycarbonyl L-alanyl-L-proline were dissolved in 300 ml of dry tetrahydrofuran and the solution was cooled to -100C. 12.7 ml (0.1 mol) of N ethylmorpholine and 13.1 ml (0.1 mol) of isobutyl chloroformate were added and the solution was stirred for 20 minutes while maintaining the temperature at - 100 C. 9.3 ml of aniline weer then added and the mixture was stirred at 0 C for 1 hour. The mixture was found to be slightly acidic and a further 1 g of N-ethyl-morpholine was added. The solution was then left to stand at room tem perature for 16 hours. The solution was eva ted, there being obtained a white crystal line solid which was treated with 500 ml of ether, filtered, washed and dried to give 31.8 g of N-benzyloxycarbonyl-L-alanyl-L- proline anilide of melting point 139.50-140.50C; [url ] D20= - 125.50 (c= 1.195% in methanol). A second crop (1.4 g; melting point 1380-1390C) was obtained by evaporating the mother liquor to a small volume, when crystallisation took place. The total yield was 81%.
Analysis for C,2H25O, (395.46) Calculated: C: 66.82; H: 6.37; N: 10.62.
Found: C: 66.64; H: 6.50; N: 10.44.
(ii) L - Alanyl L proline anilide hydrob romide.
10 g (0.025 mol) of N-benzyloxycarbonyl L-alanyl-L-proline anilide were dissolved in 50 ml of 4N hydrogen bromide in acetic acid and the solution was stirred at room temperature for 1 hour. 300 ml of dry ether were then added. An oil precipitated out and was allowed to settle. The solution was decanted off and the oil was washed with two 150 ml portions of ether, dissolved in the minimum volume of methanol and treated with an excess of ethyl acetate. The product soon crystallised, there being obtained 7.2 g (83%) of Lalanyl-L-proline anilide hydrobromide of melting point 2110--2140C.
(iii) N- Acetyl -L-alarryl-L- proine anilide.
2 g (0.00585 mol) of L-alanyl-L-proline anilide hydrobromide were dissolved in 40 ml of dry pyridine and 1.1 ml (0.0117 mol) of acetic anhydride were added. The solution was stirred at room temperature for 1 hour and then evaporated. Final traces of pyridine were removed by addition of 20 ml of toluene and re-evaporation. The residue was dissolved in 100 ml of chloroform and the solution washed with 80 ml of saturated sodium chloride solution, dried over magnesium sulphate and evaporated to an oil. This oil crystallised from ethyl acetate/petroleum ether to give 1.64 g (93%) of N - acetyl - L - alanyl proline anilide of melting point 1630-1650C; [cr]n20=-186.2" (c=1.022% in methanol).
Analysis for C1sH21OsN3 (303.36) Calculated: C: 63.35; H: 6.98; N: 13.85.
Found: C: 63.47; H: 7.16; N: 14.06.
(iv) N - Propionyl - L - alan3il proline anilide.
8.7 g (0.022 mol) of N-benzyloxycarbonyl L-alanyl-L-proline anilide were dissolved in 40 ml of 4N hydrogen bromide in acetic acid and the solution was stirred at room temperature for 1 hour. Upon addition of 300 ml of dry ether a white solid separated. It was allowed to settle. The solution was decanted off and the solid washed with two 150 ml portions of ether, dried on a rotary evaporator and dissolved in 120 ml of dry pyridine. 5.73 ml (0.044 mol) of propionic anhydride were added and the mixture was stirred at room temperature for 1 hour and then evaporated. The residue was dissolved in 250 ml of chloroform and the solution washed with 100 ml of 1N hydrochloric acid, 100 ml of water and 100 ml of 5% sodium bicarbonate solution, dried over magnesium sulphate and evaporated to an oil. This oil crystallised from ethyl acetate/ether to yield 3.5 g of N-propionyl-L-alanyl-L-proline anilide. A second crop (1.5 g) was obtained from the mother liquor on allowing same to stand. The two crops were combined and chromatographed on 200 g of silica gel. 2% methanol/chloroform was used for the elution and 15 ml fractions were collected. Fractions 35-90 were combined and evaporated. The residue was recrystallised from ethyl acetate/ petroleum ether to give 3.24 g (46%) of Npropionyl - L - alanyl - L - proline anilide of melting point 1560-1570C; [a]D2,=--188.70 (c=1.034% in methanol).
Analysis for C1,H2,O,N3 (317.39) Calculated: C: 64.33; H: 7.30; N: 13.24.
Found: C: 63.58; H: 7.50; N: 13.07; H2O: 1.25.
Water-free: C: 64.37; H: 7.45; N: 13.23.
(v) N - > ayX - L - alatyl - L - ptiX mrilide.
3 g (0.0076 mol) of N-benzyloxycarbonyl L-alanyl-L-proline anilide were treated with 4N hydrogen bromide in acetic acid in a manner analogous to that described in part (B) (ii) of this Example. The hydrobromide obtained was dissolved in 40 ml of dry pyridine and 1.75 ml (0.0052 mol) of benzoyl chloride were added. The solution was stirred at room temperature for 1 hour and then evaporated to an oil. This oil was dissolved in 120 ml of ethyl acetate and the solution was washed twice with two 80 ml portions of 5% citric acid solution, 80 ml of water, twice with two 80 ml portions of 5% sodium bicarbonate solution and twice with two 80 ml portions of water, dried over sodium sulphate and evaporated. The residue crystallised from ethyl acetate/petroleum ether and was further purified by chromatography on 100 g of silica gel using chloroform for the elution. Crystallisation from ethyl acetateXpetroleum ether yielded 1.3 g (47%) of pure N-benzoyl-D alanyl-L-proline anilide of melting point 980-1020C; [a]D20=--64.4" (c= 1.009 /.
in methanol).
Analysis for C21H2sO3N3 (365.44) Calculated: C: 69.03; H: 6.34; N: 11.50.
Found: C: 68.83; H: 6.22; N: 11.46.
(vi) N - Pivaloyl - L - alanyl proline anilide.
1 g (0.00292 mol) of L-alanyl-L-proline anilide hydrobromide was dissolved in 20 ml of dry pyridine and 0.45 ml (0.00584 mol) of pivaloyl chloride was added. The mixture was stirred at room temperature for 1 hour and then evaporated. Final traces of pyridine were removed by addition of 10 ml of toluene and re-evaporation. The residue was dissolved in 80 ml of chloroform and the solution washed with 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and evaporated to an oil. This oil crystallised from chloroform/petroleum ether to yield 0.8 g (80%) of N-pivaloyl-L-alanine L-proline anilide of melting point 710--740C; [rr]D20=-134" (c=1.062% in methanol).
Analysis for C1,H2,O,N3 (345.45) Calculated: C: 66.06; H: 7.88; N: 12.16.
Found: C: 64.04; H: 7.95; N: 11.88; H2O: 3.37.
Water-free: C: 66.20; H: 7.84; N: 12.28.
(vii) N - Hexanoyl - L - alkyl proltne anilide.
1 g (0.00292 mol) of L-alanyl-L-proline anilide hydrobromide was dissolved in 20 ml of dry pyridine and 1.39 ml (0.00584 mol) of hexanoic anhydride were added. The solution was stirred at room temperature for 1 hour and then evaporated. Final traces of pyridine were removed by addition of 10 ml of toluene and re-evaporation. The residue was dissolved in 80 ml of chloroform and the solution washed with 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and evaporated to an oil. This oil crystallised from ethyl acetate/petroleum ether to give 0.9 g (86%) of N-hexanoyl L-alanyl-L-proline anilide of melting point 1130-1150C; []D20= - 171.80 (c=1.01-1% in methanol).
Analysis for C20H2903N3 (359.47) Calculated: C: 66.83; H: 8.13; N: 11.69.
Found: C: 66.71; H: 7.97; N: 11.88.
(viii) N- Trifluoroacetyl - L - alanyl- L-proline anilide.
1.71 g (0.005 mol) of L-alanyl-L-proline anilide hydrobromide were dissolved in 20 ml of dry pyridine and 1.4 ml (0.01 mol) of trifluoroacetic anhydride were added. The mixture was stirred for 1.5 hours at room temperature and the pyridine was then removed by evaporation. The resulting oil was triturated with toluene, re-evaporated and the residue partitioned between 50 ml of dichloromethane and 50 ml of water. The aqueous layer was reextracted with 40 ml of dichloromethane.
The organic layers were combined, washed in sequence with 80 ml of 1N hydrochloric acid, 80 ml of water and 80 ml of 5% sodium bicarbonate solution, dried over magnesium sulphate and evaporated to a solid. This solid was treated with petroleum ether, filtered off and dried to yield 1.58 g (89%) of N-trifluoroacetyl - L - alanyl - L - proline anilide of melting point 2040--2070C; [α]D20=--134.4 (c=0.98% in glacial acetic acid).
Analysis for C16H1aOaN,F, (357.34) Calculated: C: 53.78; H: 5.08; N: 11.76; F: 15.95.
Found: C: 53.51; H: 5.10; N: 11.58; F: 16.01.
(ix) N - Cyanooocetyt - L - alanyl- protine anilide.
1.7 g (0.005 mol) of L-alanyl-L-proline anilide hydrobromide were dissolved in 50 ml of dichloromethane at OOC. 0.42 g (0.005 mol) of cyanoacetic acid, 0.7 ml (0.005 mol) of triethylamine and 1.1 g of N,N-diryclo hexylcarbodiimide were added and the mixture was stirred at 0 C overnight The solvent was removed by evaporation, the residue suspended in 50 ml of ethyl acetate, the suspension filtered and the filtrate washed with 1N hydrochloric add, water, 5% sodium bicarbonate solution and water, dried over magnesium sulphate and evaporated to give a white solid.
Recrystallisation of this solid from ethyl acetate yielded 0.6 g (37%) of N-cyanoacetyl-Lalanyl-L-proline anilide of melting point 183 --184 C; [α]D20 = -204.6 (c=0.78% in methanol).
Analysis for C17H2003N4 (328.38) Calculated: C: 62.18; H: 6.14; N: 17.06.
Found: C: 61.99; H: 6.17; N: 17.24.
(x) N - (1 - Adamantycarbonyl danyl-L-proline anilide.
3.42 g (0.01 mol) of L-alanyl-L-proline anilide hydrobromide were suspended in 100 ml of dry tetrahydrofuran and the suspension was cooled to 0 C. There were then added 2.8 ml (0.02 mol) of triethylamine followed by 1.72 g (0.001 mol) of 1-adamantoyl chloride. The mixture was stirred at 0 C for 0.5 hour and at room temperature for 2 hours and then evaporated. The residue was ex reacted twice with 40 ml of ethyl acetate each nine. The combined ethyl acetate extracts were washed successively with two 20 ml portions of 1N hydrochloric acid, 20 ml of water, two 20 ml portions of 5% sodium bicarbonate solution and two 20 ml portions of water, dried over magnesium sulphate and evaporated. The residue was crystallised from ether/petroleum ether and further purified by chromatography on 100 g of silica gel using chloroform for the elution. Evaporation of the chloroform eluate and crystallisation of the residue from ether/petroleum ether yielded 1.09 g (24%) of pure N - (1 - adamantylcarbonyl alanyl-L-proline anilide of melting point 1190-1210C; [aJn20=-142.90 (c=l% in methanol).
Analysis for C2,H02O3N, (423.56) Calculated: C: 70.89; H: 7.85; N: 9.92.
Found: C: 70.86; H: 7.92; N: 9.84.
(xi) N - (1 - Adamantylacetyl) alanyl-L-proline anilide.
In a manner analogous to that described in part (x) of this Example, from L-alanyl-Lproline anilide hydrobromide and 1-adamantylacetyl chloride there was obtained in 38% yield (recrystallised from ethyl acetate/ petroleum ether) N - (1 - adamantylacetyl) L-alanyl-L-proline anilide of melting point 111 113 C; [α]D20 = -136.7 (c=0.98% in methanol).
Analysis for C20H3,O2N2 (437.59) Calculated: C: 71.37; H: 8.06; N: 9.60.
Found: C: 71.47; H: 8.05; N: 9.50.
(xii) N - (p - Toltènerutphonyl) alartyl-L-proline aralide.
1.71 g (0.005 mol) of L-alanyl-L-proline anilide hydrobromide were suspended in 20 ml of dichloromethane. To the suspension were added 22 ml of 0.5N sodium hydroxide solution followed by 1.05 g (1.1 equivalents) of p-toluenesulphonyl chloride. The mixture was stirred vigorously for 90 minutes. 50 ml of dichloromethane were added, the organic layer was separated, washed with 50 ml of brine, dried over magnesium sulphate and evaporated to an oil which crystallised upon the addition of petroleum ether. The solid was filtered off, washed with petroleum ether and dried to yield 1.94 g (93%) of N-(p-toluenesulphonyl)-Lalanyl-L-proline anilide of melting point 145 --147 C; [a] D20= - 126.20 (c=1.0% in glacial acetic add).
Analysis for C21H2sO4N3S (415.51) Calculated: C: 60.70; H: 6.06; N: 10.11; S: 7.72.
Found: C: 59.83; H: 6.10; N: 9.88; S: 7.80; H2O: 1.85.
Water-free: C: 60.96; H: 6.00; N: 10.07; S: 7.95.
(xiii) N - Benzenesulphonyl - L L-proline anilide.
In a manner analogous to that described in part (xii) of this Example, from L-alanyl Gproline anilide hydrobromide and benzenesulphonyl chloride there was obtained in 60% yield (recrystallised from ethyl acetate/ether) N - benzenesulphonyl - L - alanyl - L - proline anilide of melting point 1260--1270C; [α]D20= -113.0 (c=0.96% in glacial acetic acid).
Analysis for C20H2,ON,S (401.48) Calculated: C: 59.83; H: 5.78; N: 10.47.
Found: C: 58.93; H: 5.87; N: 10.09; H2O: 1.06.
Water-free: C: 59.55; H: 5.81; N: 10.20.
(xiv) N - (4 - Nitrobenzenesulpnonyl)- Lonyl-L-proline anise.
In a manner analogous to that described in part (xii) of this Example, from L-alanyl-L proline anilide hydrobromide and 4-nitrobenzenesulphonyl chloride there was obtained in 83% yield (recrystallised from ethyl acetate/petroleum ether) N - (4 - nitro benzenesulphonyl) - L - alanyl - L - proline anilide of melting point 1130-1150C; [α]D20=--60.6 (c=0.98% in dimethyl formamide).
Analysis for C20H22ON4S (446.48) Calculated: C: 53.80; H: 4.97; N: 12.55.
Found: C: 53.10; H: 5,05; N: 12.18; H2O: 0.96.
Water-free: C: 53.60; H: 4.99; N: 12.30.
(xv) N - (1 - Naphthalenesulphonyl)- L-alanyl-L-proline anilide.
In a similar manner to that des
(xix) N - (4 - Acetytaminobenzenesut- phottyl) - L - afenyl - L - proline anijide.
In a manner analogous to that described in part (xii) of this Example, from L-alanyl L-proline anilide hydrobromide and pacetylaminobenzenesulphonyl chloride there was obtained in 37% yield (recrystallised - from ethyl acetate/petroleum ether) N-(4-acetylaminobenzenesulphonyl) - L - alanyl - U proline anilide of melting point 1400--1420C; [a]u20=-145.30 (c=0.99% in methanol).
Analysis for C22H2605N4S (458.54) Calculated: C: 57.63; H: 5.72; N: 12.22.
Found: C: 56.70; H: 5.69; N: 11.86; H2O: 1.94.
Water-free: C: 57.81; H: 5.80; N: 12.09.
(xx) N - (4 - - Methoxybenzenesid phony!) - L alony! - L - praline anilide.
In a manner analogous to that described in part (xii) of this Example, from L-alanyl L-proline anilide hydrobromide and 4methoxybenzenesulphonyl chloride there was obtained in 76% yield (recrystallised from ethyl acetate/ether) N - (4 - methoxybenzenesulphonyl) - L - alanyl - L - proline anilide of melting point 153 0--1540 C; [a]n20=131.30 (c=1.00% in glacial acetic acid).
Analysis for C21H2505N8S (431.51) Calculated: C: 58A5; H: 5.84; N: 9.74.
Found: C: 58.28; H: 5.77; N: 9.86.
(xxi) N - (Mesitylenesulphonyl) alanyll-prolirse anilide.
In a manner analogous to that described in part (xii) of this Example, from L-alanyl-Lproline anilide hydrobromide and mesitylenesulphonyl chloride there was obtained in 53% yield (recrystallised from ethyl acetate/ether) N - (mesitylenesulphonyl) - L - alanyl - U proline anilide of melting point 162"--163.5"C; [a]u20= - 130.70 (c=0.98% in glacial acetic acid).
Analysis for C,3H,0O4N2S (443.56) Calculated: C: 62.28; H: 6.59; N: 9.47.
Found: C: 62.12; H: 6.55; N: 9.45.
Example 5.
(A) The preparation of the starting material: N-Benzyloxycarbonyl - L - alanyl - U proline.
This compound was prepared as described in Example 3(A).
(B) The process: (i) N - Benzylaxyvarbonyl - L - alanyl- L-proline 4-nitroanilide.
3.2 g (0.01 mol) of N-benzyloxycarbonyl L - alanyl - L - proline were dissolved in 50 ml of dry tetrahydrofuran and the solution was cooled to -- 10"C. 1.27 ml (0.01 mol) of N-ethylmorpholine were added followed by 1.31 ml (0.1 mol) of isobutyl chloroformate and the mixture was stirred at - 100C for 20 minutes. 1.38 g (0.01 mol) of 4-nitroaniline were then added, the mixture was stirred at 0 C for 1 hour and then left to stand at room temperature for 72 hours. The mixture was then evaporated and the residue dissolved in 100 ml of ethyl acetate. The solution was washed with 80 ml of 1N hydrochloric acid, 80 ml of water and 80 ml of 5% sodium bi bicarbonate solution, dried over magnesium sulphate and evaporated. The resulting oil was chromatographed on 100 g of silica gel using chloroform for the elution. The residue obtained after evaporating the chloroform eluate was taken up in ether and left to stand for 16 hours, the pure crystalline N-benzyloxycarbonyl - L - alanyl - L - proline 4 - nitro anilide separating out. The yield was 1.5 g (34%) and the melting point 1600--163"C; [eg]D20=178.1 (c=0.975% in methanol).
Analysis for C22H2406N4 (440.46) Calculated: C: 59.99; H: 5.49; N: 12.72.
Found: C: 59.74; H: 5.67; N: 12.51.
(ii) N - Propionyl - L - alanyl praline 4-nitroan:tide.
1.1 g (0.0025 mol) of N-benzyloxycarbonyl - L - alanyl - L - proline 4 - nitroaniline were dissolved in 10 ml of 4N hydrogen bromide in acetic acid and the mixture was stirred at room temperature for 1 hour. 80 ml of dry ether were added. An oil precipitated and was allowed to settle out. The solution was decanted off and the oil was washed with two 80 ml portions of ether and then dissolved in 20 ml of dry pyridine. 0.64 ml (0.005 mol) of propionic anhydride was added and the solution stirred at room temperature for 1 hour. The solution was then evaporated.
Final traces of pyridine were removed by addition of 50 ml of toluene and re-evaporation.
The residue was dissolved in 100 ml of chloro form and the solution was washed twice with 80 ml of water each time, dried over mag nesium sulphate and evaporated to give an oil. The desired N - propionyl - L - alanyl L-proline 4-nitroanilide crystallised from ethyl acetate/petroleum ether in a yield of 0.62 g (68%) and with a melting point of 1830-1860C; [a]D20=--211.6" (c=1.014% in methanol).
Analysis for C17H22O5N4 (362.39) Calculated: C: 56.35; H: 6.12; N: 15.46.
Found: C: 56.33; H: 6.21; N: 15.46.
Example 6.
(A) The preparation of the starting material: N - Benzyloxycarbonyl - L- alanyl - L- proline.
This compound was prepared as described in Example 3(A).
(B) The process: (i) N - Benzyloxycarbonyl - L - alanyl- L-proline 4-methoxyanilide.
In a manner analogous to that described in Example 3 (B) (i), from N-benzyloxy carbonyl - L - alanyl - L - proline 4 methoxyaniline there was obtained N benzyloxvcarbonyl - L - alanyl - L- proline 4-methoxyanilide in a yield of 69% (recrystal lised from ethyl acetate/ether); melting point 1630-1640C; [a]n20=150.90 (c=1% in methanol).
Analysis for C23H2T05Ns (425.49) Calculated: C: 64.93; H: 6.40; N: 9.87.
Found: C: 64.79; H: 6.57; N: 9.76.
(ii) N - Propionyl - L - alony! L- proline 4-methoxyanilide.
In a manner analogous to that described in Example 3 (B) (ii), from N-benzyloxycarbonyl - L - alanyl - L - proline 4 - methoxyanilide there was obtained N-propionyl-Lalanyl - L - proline 4 - methoxyanilide in a yield of 52% (recrystallised from ethyl acetate); melting point 1690-1710C; [a] n2= - 191.60 (c= 1.02% in methanol).
Analysis for Ct8H2504Ns (347.42) Calculated: C: 62.63; H: 7.25; N: 12.09.
Found: C: 62.16; H: 7.16; N: 11.99.
Example 7.
* (A) The preparation of the starting material: N - Benzyloxycarbonyl - L - alanyl - L- proline.
This compound was prepared as described in Example 3 (A).
(B) The process: (i) N - Benayloxycarbonyl - L - alanyl- L-rolirae cyclopentylamide.
6.4 g (0.02 mol) of N-benzyloxycarbonyl L-alanyl-L-proline were dissolved in 100 ml of dry tetrahydrofuran and the solution was cooled to - 100 C. 2.54 ml of N-ethylmorpholine and 2.62 ml of isobutyl chloroformate were added and the mixture was stirred at - 100C for 20 minutes. 1.98 ml of cyclopentylamine were then added and the mixture was stirred at 0 C for 1 hour and then at room temperature overnight. The mixture was then evaporated and the product which crystallised on the addition of water was extracted into ethyl acetate. The organic layer was washed neutral, dried over sodium sulphate and evaporated, the product crystallising on the addition of ether. There were obtained 4.8 g (71%) of N-benzyloxycarbonyl-L-alanyl-L- proline cyclopentylamide of melting point 1180--1190C; [ajn20=-93.50 (c=1.0228% in methanol).
Analysis for C21H29O4N3 (387.48).
Calculated: C: 65.10; H: 7.54; N: 10.84.
Found: C: 65.05; H: 7.47; N: 10.79.
(ii) L - Alanyl - L - proline cyclopentyl amide hydrobromide.
3.9 g of N - benzyloxycarbonyl - L- alanyl-L-proline cyciopentylamide were treated with 4N hydrogen bromide in acetic acid in a manner analogous to that described in Example 8 (B) (ii) hereinafter. There were thus obtained 3.3 g (99%) of L-alanyl-L-proline cyclopentylamide hydrobromide of melting point 2090--2120C.
(iii) N - Propionyl - L - alanyl praline cyclopentylamide.
The L-alanyl-L-proline cyclopentylanaide hydrobromide obtained according to part (B) (ii) of this Example was dissolved in 40 ml of pyridine and the solution was treated with 2.6 ml of propionic anhydride. The mixture was stirred at room temperature for 2 hours. The mixture was then evaporated, final traces of pyridine being removed by addition of toluene and re-evaporation. The residue was recrystallised from ethyl acetate to give 2.1 g of N-propionyl-L-alanyl-Lproline cyclopentylamide of melting point 1720--1730C; [α]D20=-122.8 (c= 1.0314% in methanol).
Analysis for C10H27O2N2 (309.41).
Calculated: C: 62.11; H: 8.80; N: 13.58.
Found: C: 62.27; H: 8.85; N: 13.59.
Example 8.
(A) The preparation of the starting material: N - Benzyloxycarbonyl - L- alanyl - L- proline.
This compound was prepared as described in Example 3 (A).
(B) The process: (i) N - Benzyloxycarbonyl - L - alanyl L-proline cyclohexylamide.
3.2 g (0.01 mol) of N-benzyloxycarbonyl L-alanyl-L-proline were dissolved in 50 ml of dry tetrahydrofuran and the solution was cooled to --10"C. 1.27 ml (0.01 mol) of Nethylmorpholine were added followed by 1.31 ml (0.01 mol) of isobutyl chloroformate and the solution was stirred at - 100C for 20 minutes. 1.21 ml (0.01 mol) of cyctohexyl- amine were then added and the mixture was stirred at 0 C for 1 hour and then left to stand at room temperature for 16 hours. The mixture was evaporated and the residue was treated with 100 ml of ethyl acetate, washed with 80 ml of 1N hydrochloric acid, 80 ml of water and 80 ml of 5% sodium bicarbonate solution, dried over sodium sulphate and evaporated to an oil. The product crystallised from ethyl acetate/ether to yield 2.36 g of N - benzyloxycarbonyl - L - alanyl - U proline cyclohexylamide of melting point 130.50-131.50C. A second crop (0.95 g; melting point 130.50-131.50C) was obtained on leaving the mother liquor to stand overnight. The total yield was 83%; [a]20=--96.30 (c=1.175% in methanol).
Analysis for C22H21O4N2 (401.51).
Calculated: C: 65.81; H: 7.78; N: 10.47.
Found: C: 65.71; H: 7.66; N: 10.54.
(ii) L - Alanyl - L - proline cyclo hexylamide hydrob romide.
2 g (0.005 mol) of N-benzyloxycarbonyl L - alanyl - L - proline cyclohexylamide were dissolved in 10 ml of 4N hydrogen bromide in acetic acid and the mixture was stirred at room temperature for 1 hour. 100 ml of dry ether were then added. An oil precipitated and was allowed to settle. The solution was decanted off, the oil washed with 100 ml of ether, dissolved in the minimum volume of methanol and an excess of ethyl acetate added. Crystallisation soon took place and there were obtained 1.75 g (100%) of L - alanyl - L - proline cyclohexylamide hydrobromide of melting point 233"--2360C.
(iii) N - Propionyl - L - alanyl proline cyclohexylamide.
1.75 g (0.00502 mol) of L-alanyl-L-proline cyclohexylamide hydrobromide were dissolved in 30 ml of dry pyridine and 1.3 ml (0.01 mol) of propionic anhydride were added. The solution was stirred at room temperature for 2 hours and then evaporated. Final traces of pyridine were removed by addition of 15 ml of toluene and re-evaporation. The residue was dissolved in 80 ml of chloroform and the solution washed with two 50 ml portions of water, dried over magnesium sulphate and evaporated to a white solid which was recrystallised from ethyl acetate to give 1.05 (65%) of N - propionyl - L - alanyl - L - proline cyclohexylamide of melting point 1720--1740C; [a] 20 = - 125.10 (c=0.991% in methanol).
Analysis for Cl7H29o5Ns (323.44).
Calculated: C: 63.13; H: 9.04; N: 12.99.
Found: C: 63.10; H: 8.75; N: 12.78.
(iv) N (p - Toluenesuiphonyl) alanyl - L - proline cyclohexyl amide hemihydrate.
In a manner analogous to that described in Example 4 (B) (xii), from Galanyl-Gproline cyclohexylamide hydrobromide and p-toluenesulphonyl chloride there was obtained in 79% yield (crystallised from ethyl acetate after 7 days at 4"C) N - (p - toluenesulphonyl) L - alanyl - L - proline cyclohexylamide of melting point 850-880C; [a]n20=8320 (c=1.02% in glacial acetic acid).
Analysis for C21H31O4N3S .0.5 H2O (430.56).
Calculated: C: 58.58; H: 7.49; N: 9.68.
Found: C: 58.29; H: 7.30; N: 9.76.
Example 9.
(A) The preparation of the starting material: N - Benzyloxycarbonyl - L - alanyl - L- proline.
This compound was prepared as described in Example 3 (A).
(B) The process: (i) N - Benzyloxycarbonyl - L - alayryl- L-proline cycloheptylamide.
6.4 g (0.02 mol) of N-benzyloxycarbonyl L-alanyl-L-proline were dissolved in 75 ml of dry tetrahydrofuran and the solution was cooled to - 100 C. 2.54 ml (0.02 mol) of Nethylmorpholine and 2.62 ml (0.02 mol) of isobutyl chloroformate were added and the solution was stirred at - 100C for 20 minutes.
A solution of 2.25 g (0.02 mol) of cycle heptylamine in 25 ml of dry tetrahydrofuran was then added. The mixture was stirred at 0 C for 1 hour and then left to stand at room temperature for 16 hours. The mixture was then evaporated and the residue extracted twice with 50 ml of ethyl acetate each time. The combined ethyl acetate extracts were washed successively with 1N hydrochloric acid, water, 5% sodium bicarbonate solution and water and then dried over magnesium sulphate. Evaporation yielded an oil which solidified upon trituration with petroleum ether. The solid was recrystallised from ethyl acetate/petroleum ether to yield 5.6 g (67.5%) of N-benzyloxycarbonyl-L alanyl-l-proline cycloheptylamide of melting point 110"--113"C; [a].D20= --92AO (c=1.05% in methanol).
Analysis for C2,H,,O4N0 (415.54).
Calculated: C: 66.48; H: 8.00; N: 10.11.
Found: C: 66.32; H: 7.98; N: 10.22.
(ii) N - Propionyl - L - dany' pr6tine cycloheptylamide.
2.6 g (0.0063 mol) of N-benzyloxycarbonyl L-alanyl-L-proline cycloheptylamide were dissolved in 15 ml of 4N hydrogen bromide in acetic acid and the mixture was stirred at room temperature for 1 hour. 100 ml of anhydrous ether were added and an oil precipitated from the solution. The ether phase was decanted off and the oil washed with 100 ml of anhydrous ether. The ether layer was again decanted off and the oil dissolved in 30 ml of dry pyridine. 1.6 g (0.0126 mol) of propionic anhydride were added and the solution was stirred at room temperature for 2 hours. The pyridine was removed by evaporation, 50 ml of toluene were added to the residue and the mixture was again evaporated.
The solid residue was taken up in 100 ml of chloroform and the solution was washed with sodium chloride solution and dried over magnesium sulphate. The chloroform was removed by evaporation to yield an oil. This oil was dissolved in the minimum volume of ether and petroleum ether was added, whereby a white solid crystallised out of the solution.
There were obtained 1.85 g (88.1%) of N propionyl - L - alanyl - L - proline cycle heprylamide of melting point 1550-1560C; [α]D20=--119.4 (c=0.91% in methanol).
Analysis for c10H,1O,N, (337.47).
Calculated: C: 64.07; H: 9.26; N: 12.45.
Found: C: 63.91; H: 9.14; N: 12.50.
Example 10.
(A) The preparation of the starting material: N - Benzyloxycarbonyl - L - alanyl - U proline.
This compound was prepared as described in Example 3 (A).
(B) The process: (i) N - Benzylaxycarbonyl - L - alzyl- L-proline cyclooctylamide.
6.4 g (0.02 mol) of N-benzyloxycarbonyl L-alanyl-L-proline were dissolved in 75 ml of dry tetrahydrofuran and the solution was cooled to -100C. 2.54 ml (0.02 mol) of Nethylmorpholine and 2.62 ml (0.02 mol) of isobutyl chloroformate were added and the resulting solution was stirred at - 100C for 20 minutes. A solution of 2.5 g (0.02 mol) of cyclooctylamine in 25 ml of dry tetrahydrofuran was then added. The resulting mixture was stirred at 0 C for 1 hour and then left to stand at room temperature for 16 hours.
The tetrahydrofuran was removed by evaporation and the residue extracted with two 50 ml portions of ethyl acetate. The combined ethyl acetate extracts were washed successively with 1N hydrochloric acid, water, 5% sodium bicarbonate solution and water and then dried over magnesium sulphate. Evaporation yielded an oil which solidified upon trituration with ether/petroleum ether. After recrystallisation from ethyl acetate/petroleum ether, there were obtained 5.1 g (59.3%) of N-benzyloxycarbonyl - L - alanyl - L - proline cycle octylamide of melting point 940--960C; [a]D20=95.0 (c=1.02% in methanol).
Analysis for C24H35O4N, (429.56).
Calculated: C: 67.11; H: 8.21; N: 9.78.
Found: C: 67.11; H: 8.07; N: 9.72.
(ii) N - Propicnyl - L - 'danyt proEine cyclooctylamide.
2 g (0.0047 mol) of N-benzyloxycarbonyl L-alanyl-L-proline cyclooctylamide were dissolved in 10 ml of 4N hydrogen bromide in acetic acid and the solution was stirred at room temperature for 1 hour. 100 ml of anhydrous ether were added and an oil precipitated out of the solution. The ether layer was decanted off and the oil washed with 100 ml of anhydrous ether. The ether layer was again decanted off and the oil dissolved in 30 ml of dry pyridine. 1.2 g (0.0094 mol) of propionic anhydride were added and the solution was stirred at room temperature for 2 hours. The pyridine was removed by evaporation, 50 ml of toluene were added to the residue and the mixture was again evaporated in order to azeotropically remove any residual pyridine. The solid obtained was taken up in 100 ml of chloroform, the solution was washed with sodium chloride solution and dried over magnesium sulphate. The solution was then evaporated to yield an oil. This oil was dissolved in the minimum volume of ether and petroleum ether was added, whereby a white solid crvstallised out of the solution. There was obtained 0.900 g (56.3%) of N-propionyl L-alanyl-L-proline cyclooctylamide of melting point 1420-1430C; [a]D29=120 3 (c=0.82% in methanol).
Analysis for C19H3,N,O3 (351.49).
Calculated: C: 64.93; H: 9.46; N: 11.95.
Found: C: 64.76; H: 9.39; N: 11.84.
Example 11.
(A) The preparation of the starting material: N - Benzyloxycarbonyl - L - alanyl - U proline.
This compound was prepared as described in Example 3 (A).
(B) The process: N - Benzyloxycarbonyl - L - alanyl - U proline n-pentylamide.
2 g (0.06 mol) of N-benzyloxycarbonyl L-alanyl-L-proline were dissolved in 20 ml of dry tetrahydrofuran and the solution was cooled to - 100 C. 0.76 ml (0.06 mol) of Nethylmorpholine and 0.79 ml (0.006 mol) of isobutyl chloroformate were added and the resulting mixture was stirred at - 100C for 20 minutes. 0.69 ml (0.006 mol) of n-pentyl- amine was then added and the resulting solution was stirred at -200C for 1 hour and then left to stand at room temperature overnight. The solution was then evaporated to an oil which was dissolved in ethyl acetate. The ethyl acetate solution was washed twice with water, twice with 3% citric acid solution, once with water, twice with 5% sodium bicarbonate solution and twice with water, dried and evaporated to an oil. The desired N-benzyloxycarbonyl - L - alanyl - L - proline n - pentyl- amide was crystallised from ethyl acetate/ petroleum ether in a yield of 1 g (42.8%) and with a melting point of 102"--1040C.
Example 12.
(A) The preparation of the starting material (i) N - BenayThxycarbony! - L - proline n-pentylanaide.
12.46 g (0.05 mol) of N-benzyloxycarbonyl L-proline were dissolved in 100 ml of dry tetrahydrofuran and the solution was cooled to - 100 C. The solution was stirred and there were added thereto 6.56 ml (0.or mol) af isobutyl chloroformate and 6.35 ml (0.05 mol) of N-ethylmorpholine. The mixture was then stirred at -100C for 15 minutes. 5.75 ml (0.05 mol) of n-pentylamine were then added and the resulting mixture was stirred at 0 C for 1 hour and then at room temperature for 16 hours. The mixture was evaporated to an oil and 400 ml of water were added. The resulting mixture was extracted with two 150 ml portions of ethyl acetate, the organic layers were combined and washed successively with two 100 ml portions of 5% citric acid solution, once with 100 ml of water, twice with 100 ml portions of 5% sodium bicarbonate solution and once with 100 ml of water. The organic layer was dried over sodium sulphate, evaporated to an oil and triturated with 350 mi of petroleum ether. On scratching, the product crystallised out, was filtered off and washed with 100 ml of petroleum ether. There were thus obtained 10.16 g (64%) of Nbenzyloxycarbonyl - L - proline n - pentyl- amide of melting point 740--760C. A second crop (0.800 g) of melting point 760-790C was obtained from the mother liquor.
(ii) L-Proline n-pentylamide hydro bromide.
5 g of N - benzyloxycarbonyl - L- proline n-pentylamide were dissolved in 20 ml of 4N hydrogen bromide in acetic acid and the mixture was stirred for 1 hour. 150 ml of dry ether were then added. A clear oil precipitated out and was allowed to settle.
The ether was decanted off and the oil washed with a further 100 ml of dry ether. Evaporation yielded 3.4 g (82%) of L-proline npentylamide in the form of an oil.
(B) The process: (i) N - Bennyloxycarbonyl - L - Alanyl- L-proline n-pentylamide.
2.86 g (0.0128 mol) of N-benzyloxy carbonyl-L-alanine were dissolved in 20 ml of dry tetrahydrofuran and the mixture was cooled to - 100C. 1.63 ml (0.0128 mol) of N-ethylmorpholine and 1.68 ml (0.0128 mol) of isobutyl chloroformate were added and the mixture was stirred at - 100C for 13-20 minutes.
3.4 g (0.0128 mol) of Gproline npentyl- amide hydrobromide were dissolved in 20 ml of dry dimethylformamide and the solution was cooled to 0 C. 2 ml of N-ethylmorpholine were then added to this solution. The result ing mixture was combined with the mixed anhydride solution prepared as described in the preceding paragraph, stirred at 0 C for 1 hour and then at room temperature over night. Evaporation of the solvents yielded an oil which was dissolved in 150 ml of ethyl acetate and washed successively with two 60 ml portions of 5% citric acid solution, 60 ml of water, two 60 ml portions of 5% sodium bicarbonate solution and 60 ml of water. The organic phase was dried over magnesium sul phate and evaporated to give an oil which soon crystallised. Recrystallisation from ethyl acetate/petroleum ether yielded 2.7 g (54%) of N - benzyloxycarbonyl - L - alanyl - L- proline opentylamide of melting point 1030--105"C; [a]020=--94.6" (c=1.114% in methanol).
Analysis for C21 H3104N3 (389.30).
Calculated: C: 64.76; H: 8.02; N: 10.79.
Found: C: 64.79; H: 8.14; N: 10.87.
(ii) L-AIanyt-L-proline n-pentylamide.
2.5 g of N-benzyloxycarbonyl-L-alanyl-L proline n-pentylamide were dissolved in 15 ml of 4N hydrogen bromide in acetic acid and the solution was stirred for 1 hour at room temperature. 150 ml of dry ether were added.
An oil precipitated out and was allowed to settle. The ether was decanted off and the procedure repeated using 1SO ml of fresh ether.
On evaporation there were obtained 2.5 g of L-alanyl-Gproline npentylamide in the form of a white solid.
(iii) N - Propionyl - L - ala7ryl ptpEine n-pentylamide.
2.15 g (0.0064 mol) of L-alanyl-Gproline n-pentylamide was dissolved in 40 ml of dry pyridine and 3.6 ml of propionic anhydride were added to the solution. The mixture was stirred at room temperature for 1.5 hours.
The solution was then evaporated to an oil which was dissolved in 150 ml of chloroform and washed with 50 ml of 5% citric acid solution, 50 ml of water and 50 ml of 5% sodium bicarbonate solution. The organic phase was dried over magnesium sulphate and evaporated to an oil. This oil was crystallised from ethyl acetate/petroleum ether to give 1.16 g of N - propionyl - L - alanyl - L- proline npentylamide of melting point 1050--1080C; [a]2a=131.70 (c=1.114% in water).
Analysis for C,0H2,O0N, (311.43).
Calculated: C: 61.71; H: 9.39; N: 13.49.
Found: C: 61.49; H: 9.45; N: 13.60.
The following Example illustrates parma ceutical preparations containing the dipep

Claims (107)

**WARNING** start of CLMS field may overlap end of DESC **. procedure repeated using 1SO ml of fresh ether. On evaporation there were obtained 2.5 g of L-alanyl-Gproline npentylamide in the form of a white solid. (iii) N - Propionyl - L - ala7ryl ptpEine n-pentylamide. 2.15 g (0.0064 mol) of L-alanyl-Gproline n-pentylamide was dissolved in 40 ml of dry pyridine and 3.6 ml of propionic anhydride were added to the solution. The mixture was stirred at room temperature for 1.5 hours. The solution was then evaporated to an oil which was dissolved in 150 ml of chloroform and washed with 50 ml of 5% citric acid solution, 50 ml of water and 50 ml of 5% sodium bicarbonate solution. The organic phase was dried over magnesium sulphate and evaporated to an oil. This oil was crystallised from ethyl acetate/petroleum ether to give 1.16 g of N - propionyl - L - alanyl - L- proline npentylamide of melting point 1050--1080C; [a]2a=131.70 (c=1.114% in water). Analysis for C,0H2,O0N, (311.43). Calculated: C: 61.71; H: 9.39; N: 13.49. Found: C: 61.49; H: 9.45; N: 13.60. The following Example illustrates parma ceutical preparations containing the dipeptide derivatives provided by the present invention: Example A. An aerosol composition can contain the following ingredients: Ingrediamt Per cent by weight Dipeptide derivative 1-3 Ethanol 15-35 Propellant+ ad 100 +The propellant can be dichlorodifluoro methane or a 5:1 by weight mixture of 1,2 dichloro - 1,1,2,2 - tetrafluoroethane and dichlorodifluoromethane. WHAT WE CLAIM IS:
1. Dipeptide derivatives of the general formula
wherein R represents a phenyl, substituted phenyl, lower cycloalkyl or n-(C4-C0)- alkyl group; R1 and R2 each represent a hydrogen atom or a methyl group, with the proviso that R1 and R2 do not simul taneously represent a hydrogen atom, or R1 and R2 together represent a trimethylene group; R3 represents an acyl group derived from a carboxylic acid, a sulphonic acid or a sulphinic acid; and the asterisk denotes that the configuration at the carbon atom so-marked is L when Rl represents other than a hydrogen atom.
2. Dipeptide derivatives according to claim 1, wherein R3 represents an alkanoyl, haloalkanoyl, nitro-alkanoyl, cyano-alkanoyl, cydo alkylcarbonyl, cycloalkyl-alkanoyl, aroyl, arylalkanoyl, alkoxycarbonyl, aryloxycarbonyl, aryl-alkoxycarbonyl, arylsulphonyl, alkylsulphonyl, cycloalkylsulphonyl, cycloalkylsulphinyl, cycZoalkyl-alkylsulphonyl or cycloalkylalkylsulphinyl group.
3. Dipeptide derivatives according to claim 1, wherein R3 represents the trifluoroacetyl group or a lower alkanoyl, lower cycloalkyl- carbonyl, benzoyl, phenyl-(lower alkanoyl), lower alkoxycarbonyl, phenoxycarbonyl, phenyl- (lower alkoxycarbonyl), benzenesulphonyl, naphthalenesulphonyl or lower alkylsulphonyl group, the benzoyl, phenoxycarbonyl and benzenesulphonyl groups and the phenyl portion of the phenyl-(lower alkanoyl) and phenyl-(lower alkoxycarbonyl) groups optionally carrying one or more substituents selected from halogen, lower alkyl, lower alkoxy and nitro.
4. Dipeptide derivatives according to claim 1, wherein R3 represents a lower alkanoyl, lower cycloalkylcarbonyl, benzoyl, phenyl (lower alkanoyl), lower alkoxycarbonyl, phenoxycarbonyl or phenyl- (lower alkoxycarbonyl) group, the benzoyl and phenoxycarbonyl groups and the phenyl portion of the phenyl- (lower alkanoyl) and phenyl- (lower alkoxycarbonyl) groups optionally carrying one or more substituents selected from halogen, lower alkyl, lower alkoxy and nitro.
5. Dipeptide derivatives according to claim 2, wherein R3 represents an alkanoyl, aroyl, aryl - alkoxycarbonyl, aryl - sulphonyl, cycloalkylsulphonyl, cycloalkylsulphinyl, cydo alkyl-alkylsulphonyl or cycloalkyl-alkylsulphinyl group.
6. Dipeptide derivatives according to claim 3, wherein R3 represents a lower alkanoyl, benzoyl, phenyl- (lower alkoxycarbonyl), benzenesulphonyl or naphthalenesulphonyl group, the benzoyl and benzenesulphonyl groups and the phenyl portion of the phenyl (lower alkoxycarbonyl) group optionally carrying one or more substituents selected from halogen, lower alkyl, lower alkoxy and nitro.
7. Dipeptide derivatives according to claim 4, wherein R3 represents a lower alkanoyl, benzoyl or phenyl-(lower alkoxycarbonyl)
group, the benzoyl group or the phenyl portion of the phenyl-(lower alkoxycarbonyl) group optionally carrying one or more substituents selected from halogen, lower alkyl, lower alkoxy and nitro.
8. Dipeptide derivatives according to any one of claims 1 to 7 inclusive, wherein R1 represents a hydrogen atom and R2 represents a methyl group or R1 and R2 together represent a trimethylene group.
9. Dipeptide derivatives according to any one of claims 1 to 7 inclusive, wherein R represents the phenyl group.
10. N - Benzyloxycarbonyl - L - alanyl - L- proline anilide.
11. N - Benzyloxycarbonyl - L - alanyl - L- proline 2,4-dichloroanilide.
12. N - Benzyloxycarbonyl - L - alanyl - L- proline 4-nitroanilide.
13. N - Benzyloxycarbonyl - L - alanyl - L- proline 4-methoxyanilide.
14. N-Acetyl-L-alanyl-L-proline anilide.
15. N - Propionyl - L - alanyl - L - proline anilide.
16. N-Benzoyl-L-alanyl-L-proline anilide.
17. N-Pivaloyl-L-alanyl-L-proline anilide.
18. N-Hexanoyl-L-alanyl-Lproline anilide.
19. N - Trifluoroacetyl - L - alanyl - L- proline anilide.
20. N - Cyanoacetyl - L - alanyl - L- proline anilide.
21. N - (1 - Adamantylcarbonyl) - U alanyl-l-proline anilide.
22. N - (1 - Adamantylacetyl) - L - alanyl L-proline anilide.
23. N - (p - Toluenesulphonyl) - L - alanyl L-proline anilide.
24. N - Benzenesulphonyl - L - alanyl L-proline anilide.
25. N - (4 - Nitrobenzenesulphonyl) - L- alanyl-l-proline anilide.
26. N - (1 - Naphthalenesulphonyl) L- alanyl-l-proline anilide.
27. N - (1 - Adamantylsulphinyl) - L- alanyl-l-proline anilide.
28. N - (1 - Adamantylsulphonyl) - U alanyl-l-proline anilide.
29. N - (D - 10 - Camphorsulphonyl) L-alanyl-L-proline anilide.
30. N - (4 - Acetylaminobenzenesulphonyl) L-alanyl-L-proline anilide.
31. N - (4 - Methoxybenzenesulphonyl) L-alanyl-L-proline anilide.
32. N - Mesitylenesulphonyl - L - alanyl L-proline anilide.
33. N - Propionyl - L - alanyl - L - proline 2,4-dichloroanilide.
34. N - Propionyl - L - alanyl - L - proline 4-nitroanilide.
35. N - Propionyl - L - alanyl - L - proline 4-methoxyanilide.
36. N - Benzyloxycarbonyl - L - alanyl - L- proline cyclopentylamide.
37. N Benzyloxycarbonyl - L - alanyl - L- proline cyclohexylamide.
38. N - Benzyloxycarbonyl - L - alanyl - L- proline cycloheptylamide.
39. N - Benzyloxycarbonyl - L - alanyl Gproline cyclooctylamide.
40. N - Propionyl - L - alanyl - L - proline cyclopentylamide.
41. N - Propionyl - L - alanyl - L - proline cyclohexylamide.
42. N - (p - Toluenesulphonyl) - L - alanyl Gproline cyclohexylamide.
43. N - Propionyl - L - alanyl - L - proline cycloheptylamide.
44. N - Propionyl - L - alanyl - L - proline cyctooctylamide.
45. N - Benzyloxycarbonyl - L - alanyl L-alanine anilide.
46. N - Propionyl - L - alanyl - L - alanine anilide.
47. N-Benzoyl-L-alanyl-L-alanine anilide.
48. N - Benzyloxycarbonyl - L - alanyl L-alanine cyclohexylamide.
49. N - Propionyl - L - alanyl - L - alanine cyclohexylamide.
50. N - Benzyloxycarbonyl - L - alanyl L-proline n-pentylamide.
51. N - Propionyl - L - alanyl - L - proline n-pentylamide.
52. A process for the manufacture of the dipeptide derivatives of formula I given in claim 1, which process comprises (a) condensing an amide of the general formula
wherein R, R1, R2 and the asterisk are as defined in claim 1, with an N-pro tected-Galanine of the general formula
wherein R4 represents a protecting group or (b) amidating a carboxylic acid of the general formula
wherein Rl, R2, R4 and the asterisk are as defined in claim 1, and, in either case and where required, cleaving off the protecting group denoted by R" and introducing a group denoted by R3, as defined in claim 1, and, if desired, oxidising a resulting dipeptide derivative of formula I in which R3 represents an acyl group derived from a sulphinic acid to give a corresponding dipeptide derivative of formula I in which R3 represents an acyl group derived from a sulphonic acid.
53. A process according to claim 52, wherein there is manufactured a dipeptide derivative in which R3 represents an alkanoyl, halo-alkanoyl, nitro-alkanoyl, cyano-alkanoyl, cycloalkylcarbonyl, cydealkyl-alkanoyl, aroyl, arylalkanoyl, alkoxycarbonyl, aryloxycarbonyl, aryl - alkoxycarbonyl, arylsulphonyl, alkylsulphonyl, cycloalkylsulphonyl, cyclo9lkyl- sulphinyl, cycloalkyl-alkylsulphonyl or cycle alkyl-alkylsulphinyl group.
54. A process according to claim 52, wherein a dipeptide derivative in which Ra represents the trifluoroacetyl group or a lower alkanoyl, lower cycloalkylcarbonyl, benzoyl, phenyl (lower alkanoyl), lower alkoxycarbonyl, phenoxycarbonyl, phenyl-(lower alkoxycarbonyl), benzenesulphonyl, naphthalenesulphonyl or lower alkylsulphonyl group, the benzoyl, phenoxycarbonyl and benzenesulphonyl groups and the phenyl portion of the phenyl- (lower alkanoyl) and phenyl- (lower alkoxycarbonyl) groups optionally carrying one or more substituents selected from halogen, lower alkyl, lower alkoxy and nitro, is manufactured by condensing an amide of formula II with an N-protected-L-alanine of formula III or by amidating a carboxylic acid of formula IV and, in either case and where required, cleaving off the protecting group denoted by R4 and introducing a group denoted by R3 given earlier in this claim.
55. A process according to claim 52, wherein a dipeptide derivative in which Ra represents a lower alkanoyl, lower cycloalkylcarbonyl, benzoyl, phenyl-(lower alkanoyl), lower alkoxycarbonyl, phenpxycarbonyl or phenyl (lower alkoxycarbonyl) group, the benzoyl and phenoxycarbonyl groups and the phenyl portion of the phenyl-(lower alkanoyl) and phenyl (lower alkoxycarbonyl) groups optionally carrying one or more substituents selected from halogen, lower alkyl, lower alkoxy and nitro, is manufactured by condensing an amide of formula II with an N-protected-L-alanine of formula III or amidating a carboxylic acid of formula IV and, in either case and where required, cleaving off the protecting group denoted by R4 and introducing a group denoted by R3 given in this claim.
56. A process according to claim 53, wherein there is manufactured a dipeptide derivative in which R3 represents an alkanoyl, aroyl, arylalkoxycarbonyl, arylsulphonyl, cycloalkylsulphonyl, cycloalkylsulphinyl, cycloalkyl-alkylsulphonyl or cycloalkyl-alkylsulphinyl group.
57. A process according to claim 54, wherein there is manufactured a dipeptide derivative in which R3 represents a lower alkanoyl, benzoyl, phenyl- (lower alkoxycarbonyl), benzenesulphonyl or naphthalenesulphonyl group, the benzoyl and benzenesulphonyl groups and the phenyl portion of the phenyl (lower alkoxycarbonyl) group optionally carrying one or more substituents selected from halogen, lower alkyl, lower alkoxy and nitro.
58. A process according to claim 55, wherein there is manufactured a dipeptide derivative in which R3 represents a lower alkanoyl, benzoyl or phenyl-(lower alkoxycarbonyl) group, the benzoyl group or the phenyl portion of the phenyl - (lower alkoxycarbonyl) group optionally carrying one or more substituents selected from halogen, lower alkyl, lower alkoxy and nitro.
59. A process according to any one of claims 52 to 58 inclusive, wherein there is manufactured a dipeptide derivative in which R1 represents a hydrogen atom and R2 represents a methyl group or R1 and R2 together represent a trimethylene group.
60. A process according to any one of claims 52 to 59 inclusive, wherein there is manufactured a dipeptide derivative in which R represents the phenyl group.
61. A process according to claim 55, wherein N - benzyloxycarbonyl - L - alanyl - L- proline anilide is manufactured.
62. A process according to claim 55, wherein N - benzyloxycarbonyl - L - alanyl - L- proline 2,4-dichloroanilide is manufactured.
63. A process according to claim 55, wherein N - benzyloxycarbonyl - L - alanyl - L- proline 4-nitroanilide is manufactured.
64. A process according to claim 55, wherein N - benzyloxycarbonyl - L - alanyl - U proline 4-methoxyanilide is manufactured.
65. A process according to claim 55, wherein N - acetyl - L - alanyl - L - proline anilide is manufactured.
66. A process according to claim 55, wherein N - propionyl - L - alanyl - L - proline anilide is manufactured.
67. A process according to claim 55, wherein N - benzoyl - L - alanyl - L - proline anilide is manufactured.
68. A process according to claim 55, wherein N - pivaloyl - L - alanyl - L - proline anilide is manufactured.
69. A process according to claim 55, wherein N - hexanoyl - L - alanyl - L - proline anilide is manufactured.
70. A process according to claim 54, wherein N - trifluoroacetyl - L - alanyl - L - proline anilide is manufactured.
71. A process according to claim 53, wherein N - cyanoacetyl - L - alanyl - L - proline anilide is manufactured.
72. A process according to claim 53, wherein N - (1 - adamantylcarbonyl) - L - alanyl L-proline anilide is manufactured.
73. A process according to claim 53, wherein N - (1 - adamantylacetyl) - L - alanyl - L- proline anilide is manufactured.
74. A process according to claim 54, wherein N - (p - toluenesulphonyl) - L - alanyl - L- proline anilide is manufactured.
75. A process according to claim 54, wherein N - benzenesulphonyl - L - alanyl - L - proline anilide is manufactured.
76. A process according to claim 54, wherein N - (4 - nitrobenzenesulphonyl) - L - alanyl L-proline anilide is manufactured.
77. A process according to claim 54, wherein N - (1 - naphthalenesulphonyl) - L - alanyl L-proline anilide is manufactured.
78. A process according to claim 53, wherein N - (1 - adamantylsulphinyl) - L - alanyl L-proline anilide is manufactured.
79. A process according to claim 53, wherein N - (1 - adamantylsulphonyl) - L - alanyl L-proline anilide is manufactured.
80. A process according to claim 53, wherein N - (D - 10 - camphorsulphonyl) - U alanyl-l-proline anilide is manufactured.
81. A process according to claim 53, wherein N - (4 - acetylaminobenzenesulphonyl) - L- alanyl-Uproline anilide is manufactured.
82. A process according to claim 53, wherein N - (4 - methoxybenzenesulphonyl) - L- alanyl-Uproline anilide is manufactured.
83. A process according to claim 53, wherein N - mesitylenesulphonyl - L - alanyl - U proline anilide is manufactured.
84. A process according to claim 55, wherein N - propionyl - L - alanyl - L - proline 2,4-dichloroanilide is manufactured.
85. A process according to claim 55, wherein N - propionyl - L - alanyl - L - proline 4nitroanilide is manufactured.
86. A process according to claim 55, wherein N - propionyl - L - alanyl - L - proline 4methoxyanilide is manufactured.
87. A process according to claim 55, wherein N - benzyloxycarbonyl - L - alanyl - L- proline eyelopentylamide is manufactured.
88. A process according to claim 55, wherein N - benzyloxycarbonyl - L - alanyl - U proline cyclohexylamide is manufactured.
89. A process according to claim 55, wherein N - benzyloxycarbonyl - L - alanyl - U proline cycloheptylamide is manufactured.
90. A process according to claim 55, wherein N - benzyloxycarbonyl - L - alanyl - L- proline cyclooctylamide is manufactured.
91. A process according to claim 55, wherein N - propionyl - L - alanyl - L - proline cyclopentylamide is manufactured.
92. A process according to claim 55, wherein N - propionyl - L - alanyl - L - proline cyclo hexylamide is manufactured.
93. A process according to claim 53, wherein N - (p - toluenesulphonyl) - L - alanyl - L- proline cyclohexylamide is manufactured.
94. A process according to claim 55, wherein N - propionyl - L - alanyl - L - proline cycle; heptylamide is manufactured.
95. A process according to claim 55, wherein N - propionyl - L - alanyl - L - proline cyclooctylamide is manufactured.
96. A process according to claim 55, wherein N - benzyloxycarbonyl - L - alanyl - L- alanine anilide is manufactured.
97. A process according to claim 55, wherein N - propionyl - L - alanyl - L - alanine anilide is manufactured.
98. A process according to claim 55, wherein N - betizoyl -- L - alanyl - L - alanine anilide is manufactured.
99. A process according to claim 55, wherein N - benzyloxycarbonyl - L - alanyl - L- alanine cyclohexylamide is manufactured.
100. A process according to claim 55, wherein N - propionyl - L - alanyl - U alanine cyclohexylamide is manufactured.
101. A process according to claim 55, wherein N - benzyloxycarbonyl - L - alanyl L-proline n-pentylamide is manufactured.
102. A process according to claim 55, wherein N - propionyl - L - alanyl - L- proline npentylamide is manufactured.
103. A process for the manufacture of the dipeptide derivatives of formula I given in claim 1, substantially as hereinbefore described with reference to Part (B) of any one of Examples 1 to 12.
104. A dipeptide derivative of formula I given in claim 1, when manufactured by the process claimed in any one of claims 52 to 103 inclusive or by an obvious chemical equivalent thereof.
105. A pharmaceutical preparation which contains a dipeptide derivative as set forth in any one of claims 1 to 51 inclusive in association with a compatible pharmaceutical carrier material.
106. A compound of the general formula
wherein R, R1, R2 and the asterisk are as defined in claim 1 and R4 represents a protecting group, with the proviso that R4 does not represent the trifluoroacetyl or ptoluenesulphonyl group or a lower alkoxycarbonyl, aryloxycarbonyl or aryl- (lower alkoxycarbonyl) group.
107. A compound of the general formula
wherein R, R1, R2 and the asterisk are as defined in claim 1, or a hydrohalide salt thereof.
GB26662/76A 1976-06-25 1976-06-25 Dipeptide derivatives Expired GB1564317A (en)

Priority Applications (26)

Application Number Priority Date Filing Date Title
GB26662/76A GB1564317A (en) 1976-06-25 1976-06-25 Dipeptide derivatives
CH704377A CH627735A5 (en) 1976-06-25 1977-06-08 METHOD FOR PRODUCING DIPEPTIDE DERIVATIVES.
US05/804,680 US4187216A (en) 1976-06-25 1977-06-08 Dipeptide derivatives
PH19860A PH14141A (en) 1976-06-25 1977-06-08 Pharmaceutical composition containing dipeptide derivatives
ZA00773634A ZA773634B (en) 1976-06-25 1977-06-17 Dipeptide derivatives
IL52337A IL52337A (en) 1976-06-25 1977-06-17 Dipeptide derivatives,their manufacture and pharmaceutical compositions containing them
CA280,942A CA1092097A (en) 1976-06-25 1977-06-20 Dipeptide derivatives
NZ184428A NZ184428A (en) 1976-06-25 1977-06-20 N-acyl-l-alanyl-aminoacyl-amides untermediates and pharmaceutical compositions
AU26243/77A AU510722B2 (en) 1976-06-25 1977-06-20 Dipeptide derivatives
IE1254/77A IE45517B1 (en) 1976-06-25 1977-06-20 Dipepide derivatives
IT24908/77A IT1080679B (en) 1976-06-25 1977-06-21 DIPEPTIDES DERIVATIVES
FR7719277A FR2360561A1 (en) 1976-06-25 1977-06-23 NEW USEFUL DIPEPTIDES AS ELASTASE INHIBITORS
NL7706967A NL7706967A (en) 1976-06-25 1977-06-23 METHOD FOR PREPARING DIPEPTIDE DERIVATIVES.
SE7707339A SE7707339L (en) 1976-06-25 1977-06-23 DIPEPTID DERIVATIVES AND PROCEDURES
JP7394677A JPS532417A (en) 1976-06-25 1977-06-23 Derivatives of dipeptide
AT448177A AT355742B (en) 1976-06-25 1977-06-24 METHOD FOR PRODUCING NEW DIPEPTIDE DERIVATIVES
BE178738A BE856064A (en) 1976-06-25 1977-06-24 DIPEPTIDES
LU77603A LU77603A1 (en) 1976-06-25 1977-06-24
DK283177A DK283177A (en) 1976-06-25 1977-06-24 PROCEDURE FOR PREPARING DIPEPTIDE DERIVATIVES
DE19772728593 DE2728593A1 (en) 1976-06-25 1977-06-24 DIPEPTIDES
AT0300379A AT363205B (en) 1976-06-25 1979-04-20 METHOD FOR PRODUCING NEW DIPEPTIDE DERIVATIVES
AT0300479A AT363626B (en) 1976-06-25 1979-04-20 METHOD FOR PRODUCING NEW DIPEPTIDE DERIVATIVES
AT0300579A AT363206B (en) 1976-06-25 1979-04-20 METHOD FOR PRODUCING NEW DIPEPTIDE DERIVATIVES
CH388481A CH628873A5 (en) 1976-06-25 1981-06-12 (N)-Acyl-(L)-alanyl-(L)-proline anilides and (cyclo)alkyamides
CH388581A CH628874A5 (en) 1976-06-25 1981-06-12 (N)-Acyl-(L)-alanyl-(L)-proline anilides and (cyclo)alkyamides
CH388381A CH628616A5 (en) 1976-06-25 1981-06-12 (N)-Acyl-(L)-alanyl-(L)-proline anilides and (cyclo)alkyamides

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000015207A2 (en) * 1998-09-15 2000-03-23 Naeja Pharmaceutical Inc. Combination for the treatment of inflammation using elastine inhibitor(s) and antibacterial agent(s)
WO2017217855A1 (en) 2016-06-17 2017-12-21 Erasmus University Medical Center Rotterdam Geminoid lipopeptide compounds and their uses

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000015207A2 (en) * 1998-09-15 2000-03-23 Naeja Pharmaceutical Inc. Combination for the treatment of inflammation using elastine inhibitor(s) and antibacterial agent(s)
WO2000015207A3 (en) * 1998-09-15 2000-05-25 Naeja Pharmaceutical Inc Combination for the treatment of inflammation using elastine inhibitor(s) and antibacterial agent(s)
WO2017217855A1 (en) 2016-06-17 2017-12-21 Erasmus University Medical Center Rotterdam Geminoid lipopeptide compounds and their uses

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BE856064A (en) 1977-12-27

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