NZ225188A

NZ225188A - Somatostatin derivatives and pharmaceutical compositions

Info

Publication number: NZ225188A
Application number: NZ225188A
Authority: NZ
Inventors: Rainer Albert; Wilfried Bauer
Original assignee: Sandoz Ltd
Priority date: 1987-06-29
Filing date: 1988-06-27
Publication date: 1991-04-26
Also published as: JPS6426599A; GB2206352B; AU1840988A; SE8802413D0; BE1002663A4; ES2010283A6; DK353788A; NL8801640A; FR2617171A1; SE8802413L; CH679045A5; IL86876A0; FR2617171B1; IT1221065B; DK353788D0; KR890000520A; LU87262A1; GB2206352A; IT8848133A0; GB8815257D0

Description

<div id="description" class="application article clearfix"> New Zealand Paient Spedficaiion for Paient Number £25188 Patents Form No. 5 No.: Date. NO DRAWINGS Priority Date/s): 23-..k:57.- Complete Specification Filedr^O.'.^Vri^ )S27/.^ Class: <&} ColKI • » »T| I a a , Publication Date: P.O. Journal, No: NEW ZEALAND PATENTS ACT, 1953 22 5 1 8 8 -fV i/*V r27JUN!988' V ,*V' COMPLETE SPECIFICATION POLYPEPTIDES We SANDOZ LTD., 35 Lichtstrasse, CH-4002 Basle, Switzerland; a Swiss Body Corporate 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 -1- (followed by page -la-) m- 225188 —[a-— POLYPEPTIDES The present invention relates to somatostatin derivatives, processes for their production, pharmaceutical compositions containing them and their use as pharmaceuticals. More particularly the present inven-tion provides compounds of formula I ?1 ?VS'Y1 Y2"S"^H2 X "A-NH-CH-CO-N-CH-CO-B-C-D-E-NH-CH-F 1 2 3 4 5 6 7 wherein c? A is a radical of formula (ax) or (0X) Z-R-CO- or R3HN-^H-CO- '' (ax) NHR2 <&) wherein R is Ci-n alkylene or C2_n alkenylene, © Z is -0H,-NR4R5,-NR4R5R6,-NHOH, or guanidino or ureido, Ri is Ci_5 alkylene, R2 is hydrogen, -C0-NHz, -C = NH or a sugar residue^? Ah2 225188 - 2 - R3 is hydrogen or a sugar residue, R4 is hydrogen, Ci_3 alkyl or a sugar residue^ R5 is hydrogen or Cj.3 alkyl, and R6 is Cx_3 alkyl, >N-CH(Z!)-C0-is i) a (L)-or (D)-phenylalanine residue optionally ring-substituted by halogen, N02> NH2, OH, Ci_3 alkyl and/or Ci_3 alkoxy, or ii) the residue of a natural a-amino acid other than defined under i) above or of a corresponding (D)-amino acid, zi in >n-ch-(zi)-C0-being the remainder of said residue i) or ii), A' is hydrogen or Ci_3 alkyl, Yx and Y2 represent together a direct bond or each of Yj. and Y2 is independently hydrogen or a radical of formulae (1) to (5) r -co-c- .ch2 co-c-(ch2)m-h -CO-CH -CO-NHRc Rb (1) <ch2)„ (2) (3) -co-nh-jjh-coor. Rd (4) (5) <caZ> "a - 3 - 225188 O wherein Ra is methyl or ethyl, Rb is hydrogen, methyl or ethyl, m is a whole number from 1 to 4, n is a whole number from 1 to 5, Rc is (Ci_6)alkyl, Rd represents the substituent attached to the o-carbon atom of a natural a-amino-acid (including hydrogen), R, is (Ci_5)alkyl, Ra' and Rb' are independently hydrogen, methyl or ethyl, Ra and Rg are independently hydrogen, halogen, (Ci_3)alkyl or (Ci-3)alkoxy, p is 0 or 1, q is 0 or 1, and r is 0, 1 or 2, B is -Phe- optionally ring-substituted by halogen, N02, NH2, OH, Ci_3alkyl and /or C^-salkoxy, or naphthylAla, C is (L)-Trp- or (D)-Trp- optionally a-N-methylated and optionally benzene-ring-substituted by halogen, N02, NH2, OH, Ci_3 alkyl and/or Ci_3 alkoxy, © D is -Lys-, ThiaLys, yF-Lys, 5F-Lys or Orn, optionally a-N-methylated, or a 4-arainocyclohexylAla or 4-arainocyclohexylGly residue, E is Thr, Ser, Val, Phe, lie or an aminoisobutyric acid residue, ^.^li F is a group of formula -COOR7, -CH2OR10» -CON^ or .Ri] ^12 -C0-N 1— X-, 22 5 1 8 8 - 4 - 100-7168 Rio is hydrogen or the residue of a physiologically acceptable. physiologically hydrolysable ester, Rn is hydrogen, Ci_3alkyl, phenyl or C7_10phenyl-alkyl, R12 is hydrogen, Ci_3alkyl or a group of formula-CH(Ri 3 )-Xi , R13 is CH20H, -(CH2)2-OH, -(CH2)3-0H, or -CH(CH3)0H or repre sents the substituent attached to the a-carbon atom of a natural a-amino acid (including hydrogen) and Xi is a group of formula -C00R7, -CH2ORi0 or R7 and Rio have the meanings given above, R14 is hydrogen or Cx_3alkyl and R15 is hydrogen, Ci_3alkyl, phenyl or C7_i0phenylalkyl, and Ris is hydrogen or hydroxy, with the proviso that when R12 is -CH(R13)-Xi then Rn is hydrogen or methyl, wherein the residues B, D and E have the L-configuration, and the residues in the 2-and 7-position and any residues Yi 4) and Y2 4) each independently have the (L)- or (D)- configuration, in free form, salt form or complex form. Throughout the present specification and claims by "halogen" is meant fluorine, chlorine and bromine. In accordance with conventional practice, amino acid residues referred to by abbreviation, e.g. -Phe-, -Cys- etc., are to be understood as having the (L)-configuration unless otherwise indicated. The term natural amino acid refers to amino acids derived from natural sources or produced otherwise e.g. by synthesis or cell culture. R4 and/or R5 is preferably hydrogen or methyl. R6 is preferably methyl. wherein 22 5 1 8 8 - 5 - 100-7168 A' is preferably hydrogen or methyl, especially hydrogen. When A is a radical offormula (ai) it is preferably u»-aminohexanoyl, optionally containing a sugar residue. When A is a radical of formula (Pi), it is preferably a residue such as derived from lysine, ornithine, arginine or citrulline. A particularly preferred significance for A is u»-aminohexanoyl. When >N-CH(Zi)-C0- has the meaning i), it is preferably an (L)-or (D)-phenylalanine, pentafluorophenylalanine or (L)-or (D)-tyrosine residue (wherein is benzyl or p-OH-benzyl), most preferably a (D)-phenylalanine residue. When >N-CH(Zi)-C0- has the meaning ii), the defined residue is preferably lipophilic. Preferred residues ii) are residues in which Zi is alkyl having 3, preferably 4 or more carbon atoms, or is a radical -CH2-A2 wherein A2 is naphthyl or pyridyl. Most preferably >-N-CH(Zi)-C0- has the meaning i). Preferably Yi and Y2 together represent a direct bond or each of Yx and Y2 is independently hydrogen or a radical of formula (1) or (3). More preferably Yx and Y2 together represent a direct bond. In the compounds of formula I, the following significances or combinations thereof are furthermore preferred: - 6 - 225188 © B is Phe or Tyr C is -(D) Trp or 5-halo-(D)Trp, particularly D-Trp D is Lys or 4-aminocyclohexylAla E is Thr, Ser or Val, particularly Thr or Val F is -CO-N , especially -CO-N Ria ^^.CHCRiaJXi wherein Rn is hydrogen, R12 is as defined above, Rx3 is CH2OH, CH(CH3)OH, i-butyl, i-propyi; CH2CH20H, (CH2)3OH or a residue derived from Trp, 5-fluoro-Trp, (3-Nal, Ala, MeAla or Gly, preferably CH2OH or CH(CH3)0H, especially CH(CH3)0H, ^■1 4 Xx is -CO-N or CH2ORi0, especially CH2OR10 Ri 5 Rio is hydrogen Rio as an ester residue is preferably formyl, C2-i2alkylcar- bonyl, Cs-i2phenylalkylcarbonyl or benzoyl, and/or the group -CH(Ri3)-Xi has preferably the L-configuration. Preferably the residues in the 2- and 7-positions have the L-configuration. Suitable sugar residues (referred to as X) as R2 and/or R3 and/ or R4 include the following residues: - 7 - 225188 the residue being linked via the CH2 group to the NH group of the compound of formula I b) X is the deoxy residue of an aldose of formula (b) /• «o o~ OH (b) the radical being linked via the free bond to the NH group of the compound of formula I c) X is a residue of formula (c) G3 - CO - NRy - (c) wherein G3CO is the residue of an uronic acid, or of a polyhydroxy- mono- or di-carboxylic acid, and Ry is hydrogen, alkyl with 1 to 5 C-atoms or alkanoyl with 1 to 4 C-atoms, d) X is a residue of formulae (d), (e), (f) or (g) S> NH—Q—N — ( d) ."O :''4> ly -N - (e) .--O OH R g"4 V lY ^CH2-nh-Q' '-N- (f) '—9 C •14 ^OH "i NH-Q'"-N- (9) 22 5 1 8 8 - 8 - 100-7168 wherein Ry is hydrogen, alkyl with 1 to 4 C-atoms, and Q, Q', Q" and Q"' are groups with the sugar residue, 1 to 5 C-atoms or alkanoyl with coupling the peptide residue or e) X is a residue of formulae (h), (i) or (j) HOH2C-(CHOH)c-CY-CH2-NH- (h) HOH2C-(CHOH)c-CH-CH2OH (i) NH- H0H2C-(CHOH)c-CH-COOH (j) Ah- wherein Y is H2 or H, OH c is 2 or 3 or 4 and any one of the free hydroxy groups in the polyol moiety of formula (h), (i) or (j) is optionally bound in glycosylic manner to a reducing mono-, di- or oligosaccharide or amino sugar. In all the formulae (a) to (g) mentioned above only one sugar moiety per residue has been shown. However, the invention also covers sugar residues containing 1 to 3 monosaccharide residues, which may be joined together as a disaccharide or tri-saccharide. In all the above-mentioned residues, the line*wmeans that the bond may be in the a- or 3-position. - 9 - 225188 In formula (a) . - -O preferably is i) a residue of formula (ax) G C (at) G Gd wherein one of radicals Ga and Gb is hydrogen and the other is one of radicals Gc and Gd is hydrogen and the other is OH or O-glycosyl, wherein the glycosyl radical is derivable from a reducing mono-, di- or oligosaccharide, one of radicals G, and Gf is hydrogen and the other is one of radicals Gg and Gh is hydrogen and the other is hydrogen or CH20H, e.g. wherein radicals Ga to Gh are selected such that the residue of formula (ax) corresponds to a radical which is obtainable by means of an Amadori rearrangement from a natural or a .synthetically accessible mono-, di- or oligosar~u-*--J~ OH, OH, - 10 - The following residues may be mentioned as examples of sugar residues of formula (ax): Deoxyfructosyl, deoxytagatosyl, deoxysorbosyl, cc-gluco syl-(1-4)-deoxyfructosyl, cc-glucosyl(l-4)-a-glucoxyl-(1-4)-deoxyfructosyl. ii) a residue of formula (a2) .0 (a2 ) wherein one of radicals Ga and Gb is hydrogen and the other is OH one of radicals Gc and Gj is hydrogen and the other is OH or 0-glycosyl, wherein the glycosyl radical is derivable from a reducing mono-, di- or oligosaccharide one of radicals G, and Gf is hydrogen and the other is hydrogen, COOH, CH20H, CH2-0-P(0)-(OH)2 or CH20- glycosyl, wherein the glycosyl radical is derivable from a reducing mono-, di- or oligosaccharide, e.g. wherein radicals Ga to G* are selected such that the radical of formula (a2) corresponds to a radical which is obtainable by means of an Amadori rearrangement from a natural or a synthetically accessible mo£iQ=»._di- or oligosaccharide. - 11 - 225188 Residues of formula (a2) may be obtained for example by means of an Amadori rearrangement from saccharides such as gentiobiose, meli-biose, ribose, xylose or from uronic acids such as glucuronic acid or galacturonic acid. In formula (b), O preferably is i) a residue of formula (bi) (bi) 'd ^ wherein one of radicals Ga or Gb is hydrogen and the other is a free bond, one of radicals Gc or Gd is hydrogen and the other is OH, one of radicals G, or Gf is hydrogen and the other is OH or 0-glycosyl, wherein the glycosyl radical is derivable from a reducing mono-, di- or oligosaccharide, one of radicals Gg and Gh is hydrogen and the other is CH2OH, or CH2-O-glycosyl, wherein the glycosyl radical is derivable from a reducing mono-, di- or oligosaccharide, e.g. wherein radicals Ga to Gh are selected such that the radical of formula (bj.) corresponds to a radical which is obtainable by means of a Heyns rearrangement from a natural or a synthetically accessible mono-, di- or oligoketose. 22 5 1 8 8 - 12 - 100-7168 ii) a residue of formula (b2) G_ .n S (b2) wherein one of radicals G„ and Gb is hydrogen and the other is a free bond, one of radicals Gc and Gd is hydrogen and the other is OH, one of radicals G, and Gf is hydrogen and the other is CH20H or CH2-0-glycosyl, wherein the glycosyl radical is derivable from a reducing mono-, di- or oligosaccharide e.g. wherein radicals Ga to Gf are selected such that the radical (b2) corresponds to a radical which is obtainable by means of a Heyns rearrangement from a natural or a synthetically accessible mono-, di- or oligoketose. Residues of formula (bi) or (b2) may be obtained for example by means of Heyns rearrangement from sugar such as D-fructose, lactulose, L-sorbose, D-tagatose or D-ribulose. In formula c, the polyhydroxymono- or -dicarboxylic acid, e.g. contains at least 3 hydroxy groups and may also contain further subs-tituents, e.g. amino or acetylamino groups. 22 5 1 8 8 - 13 - 100-7168 Examples of such polyhydroxycarboxylic acids are: the "onic acids" derived from sugar, such as gluconic acid, or "aric acids" such as glucaric acid, furthermore quinic acid, acetyl-muranic acid, acetylneutaminic acid or D-glucosarainic acid. Examples of uronic acids are glucuronic and galacturonic acids. In the residues of formula (d) to (g), G4, G4', G4" and G4'1' have the definitions given above for Gi or G2. The radical Q or Q' joins the -NH- group of the compound of formula I with a NH2 or HO group of the sugar residue, and is e.g. the radical of a dicarboxylic acid or preferably a -CbH2b-C0-radical wherein b is 0 to 6. The radical may be branched. Q' denotes for example - NH-CO-CH2-CH2-CO-, or in particular a -CbH2b-C0- radical (e.g. b is 1 to 6). Q is e.g. a -CH2-C0-moiety. Especially Q is -CO- or -CS-. -NH-Q"- and -NH-Q"' denote radicals which join the -NH- group of the compound of formula I with the sugar residue, especially radicals of co-aminocarboxylic a-cids. They may signify for example a -NH-CbH2b-C0- radical. In the case of a residue of formula (h), (i) or (j) preferred are those of formula (h), especially wherein c is 3. The compounds of formula I may exist e.g. in free form, in salt form or in the form of complexes thereof. Acid addition salts may be formed with e.g. organic acids, polymeric acids and inorganic acids. Such acid addition salt forms include e.g. the hydrochlorides and acetates. Complexes are formed from compounds of formula I on 22 5 1 8 - 14 - 100-7168 addition of inorganic substances, e.g. inorganic salts or hydroxides such as Ca- and Zn-salts, and/or on addition of polymeric organic substances. The present invention in another aspect provides a process for the production of compounds of formula I. These compounds may be produced by methods known in the art of peptide chemistry or by obvious chemical equivalents thereof, for example by a process comprising i) removing the protecting group or groups from a protected polypeptide having the sequence .indicated in formula I, ii) coupling together by an amide bond two peptide fragments, each of which contains at least one amino acid or amino alcohol residue in protected or unprotected form and one peptide fragment containing a residue A, the peptide fragments being such that a protected or unprotected polypeptide having the sequence indicated in formula I is obtained and, if necessary, carrying out process step i); iii) converting the group F of a protected or unprotected polypeptide having the sequence indicated in formula I, into another group F, and, if necessary, carrying out process step i); iv) introducing at least one optionally protected residue into a protected or unprotected peptide and, if necessary, carrying out process step i); or v) oxidising a compound of formula I, wherein the mercapto groups of the Cys-residues are in free form to provide a polypeptide, wherein Yi and Y2 together are a direct bond, and recovering the compound of formula I thus obtained in free or salt form or in the form of a complex. 22 5 1 8 8 - 15 - 100-7168 The above process may for example be carried out analogously to the processes described in the accompanying examples. Amino-acids or peptide fragments used as starting materials and containing on the a-N-atom a radical of formula (ax) of (ft) may be prepared by reacting the corresponding amino acids or peptides free of a radical of formula (a*) or (Px) in conventional manner, e.g. using a corresponding acid or reactive acid derivative, for example an acid of formula Z-R-COOH or a reactive acid derivative thereof such as an active ester, or an amino-acid of formula Ri7HN-CH-CORxe i' NHR2 in which R17 is a protecting group and R16 is hydroxy or a carboxy activating group. Examples of active ester groups or carboxy activating groups are e.g. 4-nitrophenyl, pentachlorophenyl, penta-fluorophenyl, succinimidyl or 1-hydroxy-benzotriazolyl. The introduction of groups Yx and Y2 into the SH-groups of the Cys-residues in the positions 2 and 7 can be effected in conventional manner for acylation reactions, e.g. by reacting a polypeptide containing a free SH-group with a reactive acid derivative, especially an acid halide, to introduce the residues 1), 2) and 5) (wherein p=o) as defined above for Yx and Y2) or with an isocyanate to introduce the residues 3), 4) and 5) (wherein p=l) as defined above for and Y2. Compounds, wherein Yx and Y2 have the meaning 4) can be prepared by employing isocyanates of amino acids, which can be obtained in known manner, e.g. by reacting an amino acid with phosgene and removal of HCl. The peptide fragments used as starting material or compounds of formula I bearing a sugar residue of formula (a) may be produced by reacting a protected peptide having a free amino group in a slightly acidic medium with a reducing mono-, di- or oligosaccharide or a cor- 225188 - 16 - 100-7168 responding uronic acid or ester thereof (Amadori rearrangement), and subsequently optionally removing the protecting group. This reaction may take place in a conventional manner for the Amadori rearrangement. The acid added may be e.g. glacial acetic acid. When reacting with uronic acid, an additional acid may be dispensed with. It is preferable to use an excess of carbohydrate, e.g. ten equivalents for one equivalent of peptide compound. The reaction may be carried out in a polar solvent such as methanol, preferably at temperatures of ca. 50 to 70°C. A peptide fragment or compound of formula I bearing a sugar residue of formula (b) may be produced by reacting a protected peptide having a free amino group in a slightly acidic medium with a ketose (Heyns rearrangement). The reaction can be carried out under the same conditions as for the Amadori rearrangement (see above). A peptide fragment or compound of formula I bearing a sugar residue of formula (c) can be produced by reacting a protected peptide having a free amino group with an acid of formula G3-COOH or a reactive derivative of such an acid, and then optionally removing the protecting group(s). This may be a conventional amidation reaction, which can be effected in known manner. The amides can e.g. preferably be produced with the free acids in the presence of hydroxybenzotri-azole and dicyclohexylcarbodiimide. A peptide fragment or compound of formula I bearing a sugar residue of formula (d), (e), (f) or (g) may be produced by a) reacting the peptide first of all with the bridge member and the reacting the product with the sugar, or b) reacting the sugar first of all with the bridge member and then reacting the glycated bridge member with the peptide. 22 5 1 8 8 - 17 100-7168 These reactions may be effected in conventional manner. A peptide fragment or peptide of formula I bearing a sugar residue of formula (d) wherein Q is -CO- or -CS- may be produced for example by coupling the corresponding glycosylisocyanate or glycosyl-isothiocyanate of formula wherein L is 0 or S, and G4 is as defined above and wherein the free hydroxyl groups present in G4 are protected, e.g. by acylation, to a protected peptide with a free amino group, and thereafter splitting off the protecting groups. This reaction may be effected in conventional manner for the production of urea derivatives. A peptide fragment or compound of formula I bearing a sugar residue of formula (f) or (g) may be obtained by means e.g. of an Amadori or Heyns rearrangement, e.g. as described above for the production of compounds bearing a sugar residue of formula (a) or (b). A peptide fragment or compound of formula I bearing a sugar residue of formula (h), (i) or (j) may be produced e.g. by a') reductive amination of an aldose, deoxyaldose or ketose with the peptide bearing a free amino group, b') reducing the hemi-acetal group in a compound bearing a sugar residue of formula (a) or (b), 22 5 1 - 18 - 100-7168 c') reacting a linear sugar amino-carboxylic acid with the peptide wherein if desired any reactant may be temporarily protected. The reductive amination and reduction may be effected in conventional manner. The reductive amination may be effected for example with NaBH3CN. The preferred pH is 7. The reduction of the hemi-acetal group may be effected with borohydrides, for example with NaBH4. The preferred pH is about 6. Insofar as the production of any starting material is not particularly described herein, it is known or may be produced and purified in conventional manner, e.g. by using methods known in the literature or described herein for analogous compounds, e.g. as in the examples hereinafter. In the following examples, all temperatures are given in degrees celsius and the a D values are uncorrected. The following abbreviations are used: Boc = tert. butyloxycarbonyl DMF = dimethylformamide Fmoc = 9-fluorenylmethoxycarbonyl AcOH = acetic acid MeOH = methanol Thr-ol = threoninol radical = CH3-CH0H-CH (CH20H)-NH- TFA = trifluoroacetic acid All peptides are obtained as polyacetates-polyhydrates with a peptide content of 70 to 90 %. HPLC analysis shows that the polypeptides contain less than 5 X of other peptides. 22 5 1 8 8 - 19 - 100-7168 The factor "F" given in the following examples indicates the peptide content in the products obtained (F = 1 conforms with 100 % peptide content). The difference up to 100 % [(1—F)xlOO] consists of acetic acid and water. 1 1 Example 1: H2N-(CH2)5-CO-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol I 1 a. 0.56 g of H-DPhe-Cys-Phe-DTrp-Lys(BOC)-Thr-Cys-Thr-ol, 0.5 mmole of Fmoc-e-aminocaproic acid and 115 mg of hydroxybenzo-triazole are dissolved in 10 ml of DMF and cooled to -30° C. To this solution is added a solution of 115 mg of dicyclohexylcarbodiimide in 5 ml of DMF (cooled to -10° C). After a reaction time of 24 hours, during which the mixture warms to the room temperature, the resulting dicyclohexylurea is filtered off and the filtrate is diluted with water to ten times its volume. The precipitated reaction product is filtered off, washed and dried over phosphorus pentoxide. The crude product is used without further purification for the next step. b. Fmoc-cleavage 0.5 g of crude product from coupling reaction (a) are treated for 10 minutes at room temperature with 5 ml of DMF/piperidine 4/1 v/v (clear solution) and subsequently mixed with 100 ml of diisopropyl-ether. The reaction product which is thus precipitated is filtered off, washed and dried. This crude product is used without further purification in the next step. c. B0C cleavage 300 mg of crude product obtained in (l.b) are treated for 5 minutes at room temperature with 5 ml of 100 % TFA (completely dissolved) and subsequently mixed with 50 ml of diisopropylether. After addition of 2 ml of HCl/diethylether, the resulting deposit is filtered off, washed and dried in a high vacuum. - 20 - 22 5 1 8 8 100-7168 The end product is purified by chromatography on silica gel (CHC13/-Me0H/H2O/Ac0H 7/3/0.5/0.5), with subsequent de-salting over Duolite (gradient: H2O/Ac0H 95/5)—>H20/dioxane/Ac0H 45/50/5). The title compound is obtained as an acetate (white lyophilisate). [<x]^ = -32° (c = 0.5 95 % AcOH) F = 0.79 Example 2: H2N-(CH2)3-CO-DPhe-fcys-Phe-DTrp-Lys-Thr-c£s-Thr-ol The title compound is obtained as a white lyophilisate in analogous manner to Example 1 (a. and c.) by reacting with B0C-NH-(CH2)3C00H instead of Fmoc-NH-(CH2)s-C00H. [«]Zd = -34.4° (c = 0.5 in 95 X AcOH) F = 0.93 Example 3: H2N-(CH2)io-CO-DPhe-Cys-Phe-(D)Trp-Lys-Thr-cys-Thr-ol The title compound is obtained by following the procedure of Example 2 but using B0C-NH-(CH2)10-C00H. [a]" = -37.2° (c = 0.5 in 95 X AcOH) F = 0.89. Example 4: H-Lys-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol a. 0.56 g of H-DPhe-Cys-Phe-DTrp-Lys(BOC)-Thr-Cys-Thr-ol and 0.5 mmole of Fmoc-Lys(B0C)-0H and 115 mg of hydroxybenzotriazole are dissolved in 10 ml of DMF and cooled to -30° C. To this solution is added a solution of 115 mg of dicyclohexylcarbodiimide in 5 ml of DMF (cooled to -10° C). After a reaction time of 24 hours, during which the mixture warms to the room temperature, the resulting dicyclohexylurea is filtered c 22 5 1 8 8 - 21 - 100-7168 off and the filtrate is diluted with water to ten times its volume. The precipitated reaction product is filtered off, washed, and dried over phosphorus pentoxide. The crude product is used without further purification in the next step. b. Fmoc-cleavage 0.5 g of crude product from coupling reaction (a) are treated for 10 minutes at room temperature with 5 ml of DMF/piperidine 4/1 v/v (clear solution) and subsequently mixed with 100 ml of diisopro-pylether. The reaction product which is thus precipitated is filtered off, washed and dried. This crude product is used without further purification in the next step. c. B0C cleavage 300 mg of crude product obtained in (l.b) are treated for 5 minutes at room temperature with 5 ml of 100 X TFA (completely dissolved) and subsequently mixed with 50 ml of diisopropylether. After addition of 2 ml of HCl/diethylether, the resulting precipitate is filtered off, washed and dried in a high vacuum. The end product is purified by chromatography on silica gel using as eluant CHCl3/Me0H/H20/Ac0H 7/3/0.5/0.5, with subsequent de-salting over Duolite (gradient: H2O/ACOH 95/5)—>H20/dioxane/Ac0H 45/50/5). The title compound is obtained as a white lyophilisate. [a]" = -23.8° (c = 0.63 in 95 X AcOH) F = 0.86 Example 5: H-DLys-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol The title compound is obtained as a white lyophilisate by following the procedure of Example 4 but using Fmoc-DLys(B0C)-0H. [a]^ = -26.4° (c = 0.54 in 95 X AcOH) F = 0.81 - 22 - 22 5 1 8 8 100-7168 —i Example 6: H-Arg-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol The title compound is obtained by following the procedure of Example 2 but using Boc-Arg-OH^HCl [a]*® = -18.0° (c = 1, in 95 % AcOH) F = 0.84 Example 7; H2N-C-NH-(CH2)s-C-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol The title compound is obtained by following the procedure of Exam- NH pie 2 but using H2N-i'-NH-(CH2)5-C00H;HC1 [a]4® = -25.2° (c = 1, in 95 % AcOH) F = 0.87 0 0 II II I 1 Example 8: H2N-C-NH-(CH2)5-C-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol The title compound is obtained by following the procedure of Exam- 0 II pie 2 but using H2N-C-NH-(CH2)5-C00H. [ajif = -40.3° (c = 1, in 95 % AcOH) F = 0.85 Example 9: Na-Desoxy-D-fructosyl-Lys-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol 250 mg H-Lys(Boc)-DPhe-Cys-Phe-DTrp-Lys(Boc)-Thr-Cys-Thr-ol obtained in Example 4b, are dissolved in 25 ml of methanol/acetic acid 9/1 (v/v) and 250 mg of D(+)-glucose are added. The reaction mixture is heated at 65° C for 6 hours and then the solvent is removed by evaporation under reduced pressure. After flash chromatography over silica gel, the resulting N-Boc protected product is used for the next step without further characterisation. Cleavage of the Boc-group 22 5 1 8 8 - 23 - 100-7168 is carried out in the usual manner (Example lc or Example 4c) and leads to the title compound. [<x]d° = -21.8° (c = 0.95 in 95 % AcOH) F = 0.92 0 Example 10: Na-Desoxy-D-fructosyl-NH-(CH2)5-$-DPhe-c]rs-Phe-DTrp-Lys-Tir-Cys Thr-ol The title compound is obtained by following the procedure of example 9, but using H2N-(CH2)s-Cj-DPhe-Cys-Phe-DTrp-Lys(Boc)-Thr-C^s- Thr-ol as starting material. [a]^ = -44.4° (c = 0.8 in 95 % AcOH) F = 0.87 22 5 1 8 8 - 24 - 100-7168 The compounds of formula I in free form or in the form of pharmaceu-tically acceptable salts and complexes (hereinafter the compounds of the invention) exhibit valuable pharmacological properties as indicated in animal tests and are therefore indicated for therapy. In particular they exhibit GH-secretion inhibiting activity as indicated e.g. by depression of serum GH-levels in the rat. This test is carried out employing male rats. The test-substance is administered at varying, logarithmically staggered doses employing at least 5 rats per dose. 1 hour after s.c. administration of the test substance blood is taken. The determination of the blood serum GH-level is effected by radio-immuno-assay. The compounds of formula I are active in this test when administered at a dosage in the range of from 0.01 to 100, e.g. to 1, wg/kg s.c.. Furthermore, the GH-reducing activity of the compounds of the invention was examined also after oral application to male rats with oestradiol implants. This test is carried out as follows: A loop (length 50 mm ^ 3 mm) of silastic with 50 rag of oestradiol is implanted with ether anaesthesis under the dorsal skin of male OFA rats which have a weight of ca. 300 g. At various times (1 to 6 months later), these animals, in a fasted state, are used repeatedly for tests. The test substance is administered orally at a dose from 30 to 5000 ug/kg. The GH level in the blood serum is determined by radio-immuno-assay 1 and 2 hours after oral administration. The compounds of the invention are accordingly indicated for use in the treatment of disorders with an aetiology comprising or associated with excess GH-secretiori, e.g. in the treatment of acromegaly as well o 5 18 6 - 25 - 100-7168 as in the treatment of diabetes mellitus, especially vascular compli-cations thereof, e.g.angiophathy, proliferative retinopathy, dawn ~~ phenomenon and nephropathy. The compounds of the invention, also inhibit gastric- and pancreatic secretion, e.g. exocrine and endocrine pancreatic, as indicated in standard tests using rats with gastric and pancreatic fistula, wherein the compounds are active orally at a dose from 0.1 to 10 mg/kg. The compounds of the invention additionally are thus indicated for use in the treatment of gastro-intestinal disorders, for example in the treatment of peptic ulcer, pancreatic fistula, irritable bowel syndrom, dumping syndrom, acute pancreatitis and gastro-intestinal hormone secreting tumors (e.g. vipomas, glucagonamas, insulinomas, carcinoids and the like) as well as gastro-intestinal bleeding. The compounds of the invention are also effective in inhibiting the proliferation and/or keratinisation of epidermal cells and are thus indicated for use in the treatment of dermatological diseases involving morbid proliferation and/or keratinisation of epidermal cells, in particular in the treatment of psoriasis. Furthermore the compounds of the invention are indicated for use in the treatment of degenerative senile dementia, also known as senile dementia of the Alzheimer type (SDAT), as well as of cluster head- The compounds of the invention are also effective in the treatment of varous kinds of tumors, particularly the somatostatin receptor positive tumors, e.g. meningiomas. For all the above uses an indicated daily dosage is in the range from about 2 jig to about 20 m'g^e.g. about 10 to about 5000 Mg s.c. and 22 5 1 8 - 26 - 100-7168 from about 300 to 5000 yg p.o. of the compound conveniently administered in divided doses up to 4 times a day in unit dosage form containing for example from about 0.5 yg to about 10 mg of the compound or in sustained release form. The Example 1 compound is the preferred compound. The GH-secretion inhibiting utility is the preferred utility. The compounds of formula I may be administered in free form or in pharmaceutically acceptable salt form or complexes. Such salts and complexes may be prepared in conventional manner and exhibit the same order of activity as the free compounds. The present invention also provides a pharmaceutical composition comprising a compound of formula I in free base form or in pharmaceutically acceptable salt form or complex form in association with a pharmaceutically acceptable diluent or carrier. Such compositions may be formulated in conventional manner. The compounds may be administered by any conventional route in particular preferably parenterally e.g. in form of injectable solutions or suspensions or in a nasal or a suppository form. In accordance with the foregoing the present invention further provides: 1) a method of treating disorders with an aetiology comprising or associated with excess GH-secretion (such as acromegaly, diabetes mellitus and angiopathy), of treating gastro-intestinal disorders (such as peptic ulcer, acute pancreatitis, pancreatic fistula, irritable bowel syndrom, dumping syndrom, gastro-intestinal hormone secreting tumours and gastro-intestinal bleeding) of inhibiting the proliferation and/or keratinisation of epidermal cells (such as psoriasis), of treating degenerative senile dementia or cluster headache as well as of treating various kinds of tumors (such as meningiomas) in a subject in need of 22 5 1 8 - 27 100-7168 O o G O such treatment, which method comprises administering to said subject an effective amount of a compound of formula I or of a pharmaceutically acceptable salt or complex thereof and 2) pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt or complex thereof, together with a pharmaceutically acceptable diluent of carrier therefor. In one group of compounds of formula I, A is the radical of a w-aminocarboxylic acid containing from 3 to 12 carbon atoms, >N-CH(Zi)-C0-is i) a (L)- or (D)-phenylalanine radical which is optionally substituted by halogen, N02, NH2, OH, Ci_3 alkyl and/or Ci_3 alkoxy, or ii) the residue of a natural a-amino-acid other than defined under i) above or of a corresponding (D)-amino-acid, A' is hydrogen or Ci_3 alkyl Yj. and Y2 represent together a direct bond or each of Yx and Y2 is independently hydrogen or a radical of formulae (1) to (5) as indicated above B is Phe optionally ring-substituted by halogen, N02, NH2, OH, C]._3alkyl and/or Ci_3alkoxy, C is as defined above D is Lys optionally a-N-methylated wherein R7, Ri0> Rii> Rj.2 and Xx are as defined above, wherein the residues B, D and E have the L-configuration, and the residues in the 2- and 7- position and any residue Y: 4) and Y2 4), each independently, have the (L)- or (D)- configuration, in free form, salt form or complex form. </div>

Claims

<div id="claims" class="application article clearfix printTableText"> 22 5 1 8 - 28 - 100-7168 In another group of compounds of formula I A is H-Lys-or H- (D)Lys- >N-CH(Z!)-CO-is i) a (L) or (D)-phenylalanine radical which is optionally substituted by halogen, N02 , NH2, OH, Ci_3 alkyl and/or Ci_3 alkoxy, or ii) the residue of a natural a-amino-acid other than defined under i) above or of a corresponding (D)-amino-acid, A' is hydrogen or C]._3 alkyl Y; and Y2 represent together a direct bond or each of Yj. and Y2 is independently hydrogen or a radical of formulae (1) to (5) as indicated above B is -Phe- optionally ring-substituted by halogen, N02, NH2, OH, Ci_3alkyl and/or Ci_3alkoxy, C is as defined above D is Lys, optionally a-N-methylated E is Thr, Ser, Val wherein R-j, R10j Rm R12 and xi are as defined above, wherein the residues B, D and E have the L-configuration, and the residues in the 2- and 7- position and any residue Yx 4) and Y2 4), each independently, have the (L)- or (D)- configuration, in free form, salt form or complex form. / [ \ F is -COOR7, -CH2OR10, -CON or -CON Rl2 - 29 - 2251 what we claim is: 1. A compound of formula I Z-, A' CH„-S-Y, Y„-S-CH„ I II 2 | 2 x A - NH - CH - CO-N-CH-CO-B-C-D-E-NH-CH-F 1 2 3 4 5 6 7 wherein A is a radical of formula (<*i) or Oi) Z-R-CO- or R3HN-|H-C0-(«i) JlHR2 (Pi)- wherein R is Cj-n alkylene or C2-n alkenylene, Z is -0H,-NR4R5,-NR4R5R6,-NHOH, or guanidino or ureido, G Ri is Ci_5 alkylene, R2 is hydrogen, -C0-NH2, -C = NH or a sugar residue, Ah2 R3 is hydrogen or a sugar residue, R4 is hydrogen, Ci_3 alkyl or a sugar residue, R5 is hydrogen or Ci_3 alkyl, and Rs is C^_3 alkyl, >N-CH(zj. )-C0-is i) a (L)-or (D)-phenylalanine residue optionally ring-substituted by halogen, NOj, NH2, OH, Cj__3 alkyl and/or Ci_3 alkoxy, or ii) the residue of a natural a-amino acid other than defined under i) above or of a corresponding (D)-amin'o acid, - 30 - 225188 O Zi in >N-CH-(Z^)-CO-being the remainder of said residue i) or ii), A' is hydrogen or Cx_3 alkyl, Yi and Y2 represent together a direct bond or each of Yj. and Y2 is independently hydrogen or a radical of formulae (1) to (5) Ra -C0-C-(CH2)„-H Rb (1) -C0-CH CH, (CH2)„. (2) -CO-NHR, (3) G -CO-NH-CH-COOR. L (4) (5) (CH2}r O wherein Ra is methyl or ethyl, Rb is hydrogen, methyl or ethyl, m is a whole number from 1 to 4, n is a whole number from 1 to 5, Rc is (Ci_6)alkyl, Rd represents the substituent attached to the a-carbon atom of a natural a-amino acid (including hydrogen), R, is (C1_5)alkyl, Rs' and Rb' are independently hydrogen, methyl or ethyl, R8 and R9 are independently hydrogen, halogen, (Ci_3)alkyl or (Ci_3)alkoxy, p is 0 or 1, q is 0 or 1, and r is 0, 1 or 2, B is-:<wsjsfgi|?he- optionally ring-substituted by halogen, N02, NH2, OH, Ci_3alkyl and /or Ci_3alkoxy, or naphthylalanine, 225188 - 31 - C is (L)-Trp- or (D)-Trp- optionally a-N-methylated and optionally benzene-ring-substituted by halogen, N02, NH2, OH, C!_3 alkyl and/or Ci_3 alkoxy, D is -Lys-, ThiaLys, yF-Lys, 5F-Lys or Orn, optionally a-N-methylated, or a 4-aminocyclohexylAla or 4-aminocyclohexylGly residue, E is Thr, Ser, Val, Phe, lie or an aminoisobutyric acid residue, -Rn F is a group of formula -C00R7, -CH2ORi0> -CON or -CO-N 1 Xt wherein R7 is hydrogen or Cx_3alkyl, Rio is hydrogen or the residue ofa physiologically acceptable, physiologically hydrolysable ester, Rn is hydrogen, Ci_3alkyl, phenyl or C7_i0phenyl-alkyl, R12 is hydrogen, Ci_3alkyl or a group of formula-CH(Ri3)-Xi, Ri3 is CH2OH, -£H2)2-0Ht -(CH2)3-0H, or -CH(CH3)0H or repre sents the substituent attached to the a-carbon atom of a natural a-amino acid (including hydrogen) and Xi is a group of formula -COOR7, -CH2ORi0 or 4 -CO-N^ wherein Ri 5 R7 and R10 have the meanings given above, Ri4 is hydrogen or Ci_3alkyl and Ris is hydrogen, Ci-3alkyl, phenyl or C7_iophenylalkyl, and Rig is hydrogen or hydroxy, - 32 - 225188 with the proviso that when Ri2 is -CH(R13)-X1 then Rn is hydrogen.or methyl, wherein the residues B, D and E have the L-configuration, and the residues in the 2-and 7-position and any residues Y], 4) and Y2 4) each independently have the (L)- or (D)- configuration, in free form, salt form or complex form. 2. A compound according to Claim 1, in which A is the radical of a «-aminocarboxylic acid containing from 3 to 12 carbon atoms, >N-CH(ZX)-CO-is i) a (L)- or (D)-phenylalanine radical which is optionally substituted by halogen, N02, NH2, OH, Ci_3 alkyl and/or Ci_3 alkoxy, or ii) the residue of a natural a-amino-acid other than defined under i) above or of a corresponding (D)-amino-acid, A' is hydrogen or Ci_3 alkyl, Yx and Y2 represent together a direct bond or each of Yi and Y2 is independently hydrogen or a radical of formulae (1) to (5) as defined in Claim 1, B is Phe optionally ring-substituted by halogen, N02, NH2, OH, Ci_3 alkyl and/or Cj._3 alkoxy, C is as defined in Claim 1, D is Lys optionally a-N-methylated, E is Thr, Ser, Val, 225188 - 33 - wherein the residues B, D and E have the L-configuration, and the residues in the 2- and 7- position and any residue Yx 4) and Y2 4), each independently, have the (L)- or (D)- configuration, in free form, salt form or complex form. 3. A compound according to Claim 1, in which A is H-Lys-or H- (D)Lys >N-CH(Zi)-CO-is i) a (L)- or (D)-phenylalanine radical which is optionally substituted by halogen, N02, NH2, OH, Ci_3 alkyl and/or Cx_3 arlkoxy, or ii) the residue of a natural a-amino-acid other than defined under i) above or of a corresponding (D)-amino-acid, A' is hydrogen or Cx_3 alkyl, Yi and Y2 represent together a direct bond or each of Yi and Y2 is independently hydrogen or a radical of formulae (1) to (5) as defined in Claim 1, B is Phe optionally ring-substituted by halogen, N02, NH2, OH, Cx-3 alkyl and/or Ci_3 alkoxy, C is as defined in Claim 1, D is Lys optionally a-N-methylated, E is Thr, Ser, Val, wherein R7, Rio» ^12 and are as in Claim 1, wherein the residues B, D and E have the L-configuration, and the residues in the 2- and 7- position and any residue Yx 4) and Y2 4), each independently, have the (L)- or (D)- configuration, in free form, salt form or complex form. or - 34 - 225188 4. A compound according to Claim 1, wherein A is w-aminohexanoyl which may optionally bear a sugar residue. o G 5. A compound according to Claim 1, wherein A is a residue of formula p R -NH-CH-CO- \ I I R1 '■ I i nhr2 derived from Lys, Orn, Arg or citrulline, or being hydrogen or a sugar residue. 6. A compound according to any one of Claims 1 to 5, wherein >n-CH(zi)-C0- is DPhe. \ 7. A compound according to any one of Claims 1 to 6 wherein Yx and \ Y2 represent together a direct bond. 8. A compound according to any one of Claims 1 to 7, wherein o B is Phe or Tyr C is -(D) Trp D is Lys E is Thr, Ser or Val ^11 F is -CO-N^ VnVv-ch(R13)X1 wherein RX1 is hydrogen, R13 is CH2OH, CH(CH3)0H, i-butyl, i-propyl, CH2CH2OH, (CH2)3OH or a residue derived from Trp, 5-fluoro-Trp, (N 14FEB!99f& R / Xx is -CO-N \ 14 or CH20RX0, Ri! Rio is hydrogen Rio as an ester residue is formyl, C2-l2alkylcarbonyl, C8-i2- phenylalkylcarbonyl or benzoyl, and the group -CH(Ri3)-Xi has the L-configuration. - 35 - 225188 9. A compound according to any one of Claims 1 and 4 to 8, wherein the sugar residue is selected from a) a deoxy residue of a ketose of formula (a) . - 0 _ OH G, * X % •/ ^2 (a) the residue being linked via the CH2 group to the NH group of the compound of formula I b) a deoxy residue of an aldose of formula (b) .0 G* vwOH (b) the radical being linked via the free bond to the NH group of the compound of formula I c) a residue of formula (c) G3 - CO - NRy - (c) wherein G3CO is the residue of an uronic acid, or of a polyhydroxy- mono- or di-carboxylic acid, and Ry is hydrogen, alkyl with 1 to 5 C-atoms or alkanoyl vith 1 to 4 C-atoms, d) a residue of formulae (d), (e). (f) or (g) 225 - 36 - G ; °\ !V ly f , '4 NH-Q-n- Cd; g'4 V^O-Q'-n- (e) 0 ♦ * * 0 OH ft '' '4 X iy , s":« /- - O^-NH-Q' '-N- (f; "i \Y NH-q'•«-n- (9) wherein Ry is hydrogen, alkyl with 1 to 5 C-atoms or alkanoyl with 1 to 4 C-atoms, and Q, Q', Q" and Q"' are groups coupling the peptide residue with the sugar residue, or e) a residue of formulae (h), (i) or (j) HOH2C-(CHOH)c-CY-CH2-NH- (h) HOH2C-(CHOH)c-CH-CH2OH (i) NH- HOH2C-(CHOH)c-CH-COOH (j) NH- wherein Y is H2 or H, OH c is 2 or 3 or 4 and any one of the free hydroxy groups in the polyol moiety of formula (h), (i) or (j) is optionally bound in glycosylic manner to a reducing mono-, di- or oligosaccharide or amino sugar. r'*"— - 37 - 225 A compound according to Claim 9, wherein in formula (a) the residue is i) a residue of formula (ai) (at) wherein one of radicals Ga and Gb is hydrogen and the other is OH, one of radicals Gc and Gd is hydrogen and the other is OH or 0-glycosyl, wherein the glycosyl radical is derivable from a reducing mono-, di- or oligosaccharide, one of radicals Ge and Gf is hydrogen and the other is OH, one of radicals Gg and Gh is hydrogen and the other is hydrogen or CH20H, ii) a residue of formula (a2) - 38 - 225 (^2 ) Gd s wherein one of radicals Ga and Gb is hydrogen and the other is OH one of radicals Gc and Gd is hydrogen and the other is OH or 0-glycosyl, wherein the glycosyl radical is derivable from a reducing mono-, di- or oligosaccharide one of radicals Ge and Gf is hydrogen and the other is hydrogen, COOH, CH20H, CH2-0-P(0)-(OH)2 or CH20- glycosyl, wherein the glycosyl radical is derivable from a reducing mono-, di- or oligosaccharide, in formula (b), is i) a residue of formula (bi) 2251 39 wherein one of radicals Ga or Gb is hydrogen and the other is a free bond, one of radicals Gc or G<j is hydrogen and the other is OH, one of radicals Ge or Gf is hydrogen and the other is OH or 0-glycosyl, wherein the glycosyl radical is derivable from a reducing mono-, di- or oligosaccharide, one of radicals G, and Gh is hydrogen and the other is CH20H, or CH2-0-glycosyl, wherein the glycosyl radical is derivable from a reducing mono-, di- or oligosaccharide, ii) a residue of formula (b2) wherein one of radicals Ga and Gb is hydrogen and the other is a free bond, one of radicals Gc and Gd is hydrogen and the other is OH, one of radicals G, and Gf is hydrogen and the other is CHzOH or CH2-0-glycosyl, wherein the glycosyl radical is derivable from a reducing mono-, di- or oligosaccharide, 11. A compound according to Claim 1 which is H2N-(CH2)s-CO-DPhe-Cys-Phe-DTrp-Lys-Tht-Cys-Thr-ol in free_form, salt r d -^25 1 88 o o o form or complex form. !?. A compound according to Claim 1 which is H-Lys-DPhe-£ys-Phe-DTrp-Lys-Thr-Cyk-Thr-ol in free form, salt form or complex form. 13. a compound according to Claim 1 which is H-DLys-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol in free form, salt form or complex form. 14. A compound according to Claim 1 which is Na-Desoxy-D-fructosyl-Lys-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol in free form, salt form or complex form. 15. A compound according to Claim 1 which is 0 N= -Desoxy-D-frue tosyl-NH-(CH2) 5 -(!!-DPhe-Cys-Phe-DTrp-Lys~Thr-Cys-Thr-o 1 in free form, salt form or complex form. 16. A compound according to any one of Claims 1 to 15 in free form or in pharmaceutically acceptable salt form or complex form for use as a pharmaceutical. 17. A compound according to any one of Claims 1 to 15 in free form or in pharmaceutically acceptable salt form or complex form for use in the treatment of disorders with an aetiology comprising or associated vith excess growth hormone secretion. 18. A compound according to any one of Claims 1 to 15 in free form or in pharmaceutically acceptable salt form or complex form for use in the treatment of gastro-intestinal disorders. 19. A compound according to any one of Claims 1 to 15 in free form or ^^pharmaceutically acceptable salt form or complex form for use the treatment of dermatological diseases involving morbid proli- '25188 - 41 - feration and/or keratinisation of epidermal cells. 20. A compound according to any one of Claims 1 to 15 in free form or in pharmaceutically acceptable salt form or complex form for use in the treatment of degenerative senile dementia and of cluster headache. 21. A compound according to any one of Claims 1 to 15 in free form or in pharmaceutically acceptable salt form or complex form for use in the treatment of tumours. 22. A pharmaceutical composition comprising a compound of any one of Claims 1 to 15 in free form, or in pharmaceutically acceptable salt form or complex form in association with a pharmaceutically carrier or diluent. 23. A compound substantially as herein before described with reference to any of Examples 1 to 10. DATED THIS ^ A. J. PARK& SON per agents for the applicants </div>