GB2227488A - Modified somatostatin - Google Patents
Modified somatostatin Download PDFInfo
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- GB2227488A GB2227488A GB8924612A GB8924612A GB2227488A GB 2227488 A GB2227488 A GB 2227488A GB 8924612 A GB8924612 A GB 8924612A GB 8924612 A GB8924612 A GB 8924612A GB 2227488 A GB2227488 A GB 2227488A
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- residue
- hydrogen
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- peptide
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/655—Somatostatins
- C07K14/6555—Somatostatins at least 1 amino acid in D-form
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
Somatostatin peptides containing at least one residue of formula (a), (b) or (c> <IMAGE> wherein one of Y1 and Y2 is hydrogen and the other is hydroxy or both are hydrogen, each of f and g independently is 0 or 1, one of X1 and X2 is hydrogen and the other is hydrogen or an amino protecting group, and X3 is C2-4 alkylene, the free bond in each residue (a), (b) or (c) being located at the N-terminal group of the peptide, and the physiologically-acceptable ethers and physiologically-hydrolysable and -acceptable esters thereof when the peptide contains at least one residue of formula (a) or (b). In free form, salt form or complex form have pharmacological activity, in particular GH-, gastric and pancreatic secretion inhibiting activity.
Description
PEPTIDE DERIVATIVES
The present invention relates to somatostatin peptides, processes for their production, pharmaceutical preparations containing them and their use as medicaments.
More particularly the present invention provides a somatostatin peptide comprising at least one residue of formula (a), (b) or (c)
wherein one of Y1 and Y2 is hydrogen and the other is hydroxy or both are hydrogen, each of f and g independently is O or 1, one of X1 and X2 is hydrogen and the other is hydrogen or an amino protecting group, and
X3 iS C2alkylene, the free bond in each residue (a), (b) or (c) being located at the N-terminal group of the peptide, and the physiologically-acceptable ethers and physiologicallyhydrolysable and -acceptable esters thereof when the peptide contains at least one residue of formula (a) or (b), in free form or acid addition salt form or complex form.
The term "somatostatin peptides" includes its analogues or derivatives thereof. By derivatives and analogues is understood straight-chain, bridged or cyclic polypeptides wherein one or more amino acid units have been omitted and/or replaced by one or more other amino radical(s) and/or wherein one or more functional groups have been replaced by one or more other functional groups and/or one or more groups have been replaced by one or several other isosteric groups. In general, the term covers all modified derivatives of a biologically active peptide which exhibit a qualitatively similar effect to that of the unmodified somatostatin peptide. Preferred somatostatin peptides are those containing e.g. of from 4 to 9 amino-acids.Such compounds are disclosed e.g. in EP Specifications EP-A3-1295, EP-A2-203 031, 214 872, 215 171, 277 419 and 298 732, the contents of which including the examples thereof are incorporated herein by reference.
Hereinafter these compounds are referred to as compounds of the invention.
The compounds of the invention include also such compounds in which the N-terminal amino group is disubstituted by residues of formulae (a) and/or (b) and/or (c), preferably of formula (a) and/or (b).
In the residue of formula (a), either g is preferably 0 or g and f are each 0.
In the residue of formula (b), f is preferably 0.
Any alkylene as X3 in the residue of formula (c) may be linear or branched. X3 is preferably C24alkylene, more particularly linear C2 - 4alkylene.
Examples of amino protecting groups as X1 or X2 may be any such groups as used e.g. in peptide chemistry, and include for example benzyl, acyl groups such as formyl, acetyl, benzoyl, p-toluenesulphonyl or benzenesulphonyl, benzyloxycarbonyl, substituted benzyloxycarbonyl groups, e.g. substituted in the aromatic radical by halogen, nitro and/or lower alkyl or alkoxy, cycloaliphatic oxycarbonyl groups and aliphatic oxycarbonyl groups such as tert.-butoxycarbonyl or 9-fluorenylmethoxycarbonyl.
Preferably X1 and X2 are each hydrogen.
Residue of formula (a) is most preferred.
By the term "physiologically-acceptable ethers" as applied to compounds of the invention containing at least one residue of formula (a) or (b), is meant ethers in which the hydroxy group(s) in residue (a) or (b) is(are) etherified and which are not toxic at desired dosage levels. Such ethers include linear, branched or cyclic ethers, e.g. C1 4alkyl ethers, for example ethers in which one or all hydroxy present are substituted by methyl, and cyclic ethers in which 2 vicinal hydroxy groups are substituted by
By the term "physiologically-hydrolysable and -acceptable esters" as applied to compounds of the invention containing at least one residue of formula (a) or (b), is meant esters in which one, two or all hydroxy groups in residue (a) or (b) are esterified and which are hydrolysable under physiological conditions to yield an acid which is itself physiologically acceptable, e.g. non-toxic, at desired dosage levels. Such esters include e.g. esters with aliphatic carboxylic acids having 2 to 8 carbon atoms.
In the compounds of the invention any one of the free hydroxy groups in the residue of formula (a) or (b) may also be bound in glycosydic manner to a reducing mono-, di- or oligosaccaride or amino sugar.
Depending on the substitution pattern, the residue of formula (a) or of formula (b) may contain one or two asymetric carbon atoms and thus the compounds of the invention may exist in racemic or isomeric form or as diastereoisomers (without taking into account the stereochemistry of the peptide chain). Racemic and diastereoisomeric mixtures may be separated into individual isomers in conventional manner. Alternatively optically active starting materials may be employed. The invention covers all forms.
The compounds of the invention may exist in free form or in salt form or in the form of complexes thereof. Acid addition salts may be formed with e.g. organic acids, including polymeric acids and inorganic acids. Such acid addition salt forms include e.g. the hydrochlorides and acetates. By complexes are to be understood compounds of known type, formed from compounds of the invention on addition of inorganic substances, e.g. inorganic salts or hydroxides such as Ca- and Zn-salts, and/or on addition of polymeric organic substances.
One group of compounds in accordance with the invention is that containing at least one residue of formula (a) or (b).
Preferred compounds of the invention are compounds of formula I
wherein
R1 is a residue of formula (a), (b) or (c) as defined
above,
R2 is hydrogen, alkyl with 1 to 12 C-atoms, alkanoyl
with 1 to 4 C-atoms, C7,lophenalkyl or a residue of
formula (a), (b) or (c) as defined above > N-CH(Z1)-CO is a) a (L)- or (D)-phenylalanine residue which is optionally
substituted by halogen, NO2, NH2, OH, alkyl with 1 to
3 C-atoms and/or alkoxy with 1 to 3 C-atoms, or b) the residue of a natural a-amino acid or of a corresponding
(D)-amino acid, other than that given under a), or of a
synthetic a-amino acid, wherein Z1 in > N-CH(Z1)-CO- represents the residue of an amino
acid residue as defined under a) and b),
A' is hydrogen or alkyl with 1 to 3 C-atoms, Y1' and Y2' represent together a direct bond or each of
Y1' and Y2' is independently hydrogen or a radical of formulae
(1) to (5)
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 (C1~6)alkyl
Rd represents the substituent attached to the a-carbon
atom of a natural a-amino acid (including hydrogen)
Re is (C1~5)alkyl R' and Rb' are independently hydrogen, methyl or ethyl,
R8 and R9 are independently hydrogen, halogen, (C1~3)alkyl or (C13 )alkoxy, p is O or 1, q is O or 1, and r is 0, 1 or 2,
B is -Phe- optionally ring-substituted by halogen,
NO2, NH2, OH, Alkyl and /or C13alkoxy, or
naphthylalanine,
C is (L)-Trp- or -(D)Trp- optionally a-N-methylated
and optionally benzene-ring-substituted by halogen,
NO2, NH2, OH, C13alkyl and/or C13 alkoxy,
D is -Lys-, Lys in which the side chain contains 0 or
S in 6 position, rF-Lys, SF-Lys or Orn, optionally
a-N-methylated, or a 4-aminocyclohexylAla or
4-aminocyclohexylGly residue
E is Thr, Ser, Val, Phe, Tyr, Ile, an aminoisobutyric
or aminobutyric acid residue
F is a group of formula
wherein R7 is hydrogen or C1~3alkyl, R10 is hydrogen or the residue of a physiologically
acceptable, physiologically hydrolysable ester,
R11 is hydrogen, C1~3alkyl, phenyl or C7-10phenyl-alkyl,
R12 is hydrogen, C13alkyl or a group of formula -CH(R13 )-X4, R13 is CH20H, -(CH2)2-OH, -(CH2)3-OH, or -CH(CH3)0H or
represents the substituent attached to the a-carbon
atom of a natural or synthetic a-amino acid (in
cluding hydrogen) and
X4 is a group of formula -COOR7, -CH20R1o or
wherein
R7 and Rlo have the meanings given above,
R14 is hydrogen or Cl~3alkyl and
R15 is hydrogen, C1,3alkyl, phenyl or C7,Lophenylalkyl, and
R16 is hydrogen or hydroxy, with the proviso that when R12 is -CH(R13)-X4 then R11 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 Y1 4) and Y2 4) each independently have the (L)- or (D)- configuration, and the physiologically-acceptable ethers and physiologicallyhydrolysable and -acceptable esters thereof when the compounds of formula I contain at least one residue of formula (a) or (b).
Throughout the present specification and claims by "halogen" is meant preferably 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.
A' is preferably hydrogen or methyl, especially hydrogen.
When > N-CH(Z1)-CO- has the meaning a), it is preferably an (L)
or (D)-phenylalanine, pentafluorophenyl
alanine or (L)- or (D)-tyrosine residue
(wherein Z1 is benzyl or p-OH-benzyl),
most preferably a (D)-phenylalanine
residue.
When > N-CH(Z1)-CO- has the meaning b), the defined residue is
preferably lipophilic. Preferred residues
b) are residues in which Z1 is alkyl
having 3, preferably 4 or more carbon
atoms, or is a radical -CH2-A2 wherein A2
is naphthyl, pyridyl or 3-indolyl.
Most preferably > -N-CH(Z1)-CO- has the meaning a).
Preferably Y'1 and Y'2 together represent a direct bond or each of Y'1 and Y'2 is independently hydrogen or a radical of formula (1) or (3). More preferably Y'1 and Y'2 together represent a direct bond.
Examples of B as -Phe- ring-substituted by halogen may also include pentafluoroalanine.
In the compounds of formula I, the following significances are furthermore preferred either individually or in any combination or sub-combination:
B is Phe or Tyr;
C is -(D) Trp or 5-halo-(D)Trp, particularly D-Trp;
D is Lys or 4-aminocyclohexylalanine;
E is Thr, Ser or Val, particularly Thr or Val;
F is
especially
wherein R11 is hydrogen; R12 is as defined above, R13 is
CH20H, CH(CH3)OH, CH2CH20H, (CH2)30H or as the substituent attached to the a-carbon atom of an a-amino-acid is i-propyl, i-butyl, a residue derived from Trp, 5-fluoro-Trp, B-Nal, Ala, MeAla or Gly, preferably CH2OH or CH(CH3)OH, especially CH(CH3)OH;; X4 is
or CH20Rlow especially CH2OR10 Rlo is hydrogen
R10 as an ester residue is preferably formyl, C2-l2alkylcar- bonyl, C8-12phenylalkylcarbonyl or benzoyl; the group -CH(R13)-X4 has preferably the L-configuration.
Preferably the residues in the 2- and 7-positions have the
L-configuration.
Individual compounds of formula I are for example:
More preferred compounds of the invention are the compounds of formula I in which R1 and/or R2 are a residue of formula (a).
Especially preferred compounds of the invention are those which have two residues of formula (a) and/or (b) on the N-terminal amino group, e.g. compounds of formula II
wherein
Z1, A', Y1', B, C, D, E, F and Y2, are as defined above, and each of R17 and R18 iS a residue of formula (a) or (b), preferably a residue of formula (a), more preferably identical, and their physiologically ethers and physiologically-hydrolysable and -acceptable esters.
The present invention in another aspect provides a process for the production of the compounds of the invention, comprising a. removing at least one protecting group from a protected
peptide containing at least one residue of formula (a), (b)
or (c) as defined above; or b. reductively aminating either a compound of formula III
wherein either f is as defined above,
g is O or 1, Y1 and Y2 have one of the significances given above
and
Z2 is -CHO, or g is 1, Z2 is CH2OH and -CY1Y2-form together carbonyl, and the free hydroxy groups thereof may be etherified or es terified or a compound of formula IV
X'1-NH-X'3-CHO (IV) wherein
X'1 is an amino protecting group, and
X'3 is C15alkylene, with a compound of formula V
P-NH2 (V) wherein P is a somatostatin peptide residue in protected form, e.g. a compound of formula V'
wherein Z1, Y'1, Y'2, A', B, C, D, E and F are as defined above, the free amino groups present in
being in protected form,
and, if necessary, carrying out process step a); c. coupling together by an amide bond two peptide fragments,
each of which contains at least one amino-acid or a deri
vative thereof in protected or unprotected form, and at least
one peptide fragment contains at least one residue of
formula (a), (b) or (c) as defined above, the peptide frag
ments being such that a protected or unprotected polypeptide
sequence is obtained and, if necessary, carrying out process
step a); or d. removing or converting a functional group of an unprotected
or a protected polypeptide into another functional group so
that an unprotected or a protected polypeptide is obtained,
and in the latter case stage a) of the process is effected; e. introducing at least one optionally protected residue into a
protected or unprotected pep tide and if necessary carrying
out process step a); f. separating optically active isomers from any mixture of such
isomers obtained in accordance with steps (a) to (e); and recovering a compound thus obtained in free or salt form or in the form of a complex.
The above process may for example be carried out analogously to the processes described in the accompanying examples.
Process steps a), c), d) and e) may be carried out by methods known in the art of peptide chemistry.
Where desired, in these reactions, protecting groups which are suitable for use in peptides may be used for functional groups which do not participate in the reaction. The term protecting group may also include a polymer resin having functional groups.
Process step b) may be effected in a conventional manner for the reductive amination of an aldose or ketose. It may be performed for example in the presence of NaBH3CN, preferably at an acidic pH, e.g. from pH 5 to 7. The temperature of the reaction may be e.g. from room temperature to 100 C. It may be advantageous to carry out the reaction in an inert solvent, e.g. water, an alcohol, dioxane or DMF or a mixture thereof.
The final compounds may be purified in accordance with known methods.
The non-modified polypeptides used as starting products for processes b) or c) may be produced in known manner in solution or by the solid phase process, e.g. as disclosed in US Patent 4,395,403 including the oxidising of straight-chain polypeptide to provide a mono-cyclic polypeptide. The peptide fragment containing at least one residue of formula (a), (b) or (c), used as starting material in step c) may be produced by analogy to process step b).
Insofar as the production of the starting materials is not particularly described, the compounds are known or may be produced and purified in accordance with methods known in the art.
In the following examples all temperatures are in C and []20- D values are uncorrected. The following abbreviations are employed.
BOC = tert.-butyloxycarbonyl
DMF = dimethylformamide
MeOH = methanol
AcOH = acetic acid
All peptides are obtained as a polyacetate polyhydrate except where otherwise stated with a peptide content of from 70 to 90 %.
The polypeptides contain less than 5 X of other peptides by HPLCanalysis.
"F" as used herein after refers to the proportion of polypeptides (= peptide content) in the preparations obtained (F = 1 corresponds to 100 per cent), the difference to 100 % corresponds to acetic acid and water.
EXAMPLE 1
3 ml of trifluoroacetic acid (100 %) are added to 300 mg of
Thr-ol and kept at room temperature until all the starting material has dissolved (5 minutes). After adding 20 ml of diisopropylether, the title compound is precipitated and subsequently filtered off and washed with diisopropylether. The title compound is purified by chromatography on silica gel (eluant:
CHCl3/MeOH/AcOH/H20 7/3/0.5/0.5) and is isolated as a white lyophilisate.
[al20 = - 24.5 0 (c = 1 in AcOH 95 t), F = 0.83.
D
The starting material may be produced as follows:
2.25 g of di-tert.butyl-pyrocarbonate, dissolved in 30 ml of
DMF, are slowly added in drops at room temperature to a solution of 10 g of
acetate in 100 ml of DMF. After two hours at room temperature, the solvent is drawn off under vacuum, and 200 ml of diisopropylether are added to the residue. The deposit which is being formed is filtered off, washed with diisopropylether and dried. The crude product is purified by chromatography over silica gel (eluant: CH2Cl2/MeOH 9/1) and is then isolated as a white amorphous powder.
[a]20 = 29.8 0 (e = 1.28 in DMF).
D
Procedure A
0.5 g of the end product of stage a) in 30 ml dioxane/H20
3 : 7 are treated with 50 mg Na BH3CN and 130 mg glyceral
dehyde are added. The pH of the mixture is adjusted to 7 with
0.1 ml HC1 and the mixture heated to 100 C for 6 hours. The
mixture is cooled, freezed and lyophilized. The residue is
taken up in ethyl acetate (50 ml) and shaken with water. The
organic phase is dried and evaporated in a vacuum to give the
title compound in amorphous form.
[aJ2o = 23.2 (c = 1.2 in DMF)
D
Procedure B
Instead of a mixture of water/dioxane, a mixture of
methanol/water (2/1, v/v) can be used and the reaction
mixture will be adjusted to pH 5 with a phosphate buffer.
After a reaction time of 4 to 6 hours at 50 C the title
compound can be isolated as an amorphous powder after
addition of water, filtration and drying over P4010.
EXAMPLE 2
The procedure of Example 1 is repeated but using 130 mg (D)-glyceraldehyde.
[ ]20 = - 25.1 (c = 1 in 95 x AcOH), F = 0.86.
D
EXAMPLE 3
The procedure of Example 1 is repeated but using 130 mg (L)-glyceraldehyde.
[α]D20 = - 18.40 (c = 1 in 95 % AcOH), P = 0.90.
EXAMPLE 4
The procedure of Example 1 is repeated but replacing the glyceraldehyde by an equivalent amount of glycolaldehyde. The following compounds are obtained:
[a]20 = - 28.8 (c = 1 in 95 % AcOH), F = 0.90.
D
[a]ZO = - 21.9 0 (c = 1 in 95 % AcOH), F = 0.83.
D EXAMPLE 5
In repeating the procedure of Example 1 but using 2-methoxyacetaldehyde, the following compounds are obtained:
[a120 - 8.5 0 = 0.25 in 95 % AcOH), F = 0.76.
D and
[aJ20 = - 50 (c = 0.5 in 95 XAcOH) F s 0.79.
D
In the following compounds, SMS denotes the polypeptide radical
EXAMPLE 6 2,3-Di-propionyloxy-(2S)-propyl-SHS The procedure of Example 1 is repeated but using 2,3-di-0propionyl-D-glyceraldehyde: la]20 = - 21.7 (c = 0.9 in 95 % AcOH), F = 0.88.
D
EXAMPLE 7 2,3-Di-hexanoyloxy-(2S)-propyl-SHS The procedure of Example 1 is repeated but using 2,3-di-0hexanoyl-D-glyceraldehyde: [a]20 = - 18.8 (c = 0.25 in 95 % AcOH), F = 0.79.
D
EXAMPLE 8 2,3-Di-O-isopropyliden-2,3-dihydroxy-(2S)-propyl-SMS
The procedure of Example 1 is repeated but using 2,3-di-0-isopropyliden-D-glyceraldehyde: [a]20 = - 38 (c = 0.25 in 95 X AcOH), F = 0.76.
D
EXAMPLE 9 2,3,4-Tri-hydroxy-(2S,3R)-butyl-SMS
The procedure of Example 1 is repeated but using D(-)-erythrose: [a]20 = - 29.2 0 (c = 0.25 in 95 % AcOH), F = 0.81.
D EXAHPLE 10 2-Aminoethyl-SHS
The procedure of Example 1 is repeated but using N-Boc-2-aminoacetaldehyde: [a]20 = - 32 0 (c = 0.13 in 95 % AcOH), F = 0.84.
D
EXAMPLE 11 3-Aminopropyl-SHS The procedure of Example 1 is repeated but using N-Boc-3-aminopropionaldehyde: [a]20 = - 21 (c = 0.29 in 95 % AcOH), F = 0.76.
D
The compounds of the invention in free form or in the form of pharmaceutically acceptable salts and complexes exhibit valuable pharmacological properties as indicated in animal tests and are, therefore, indicated for therapy.
In particular, the compounds of the invention show GH-release 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 the invention are active in this test when administered at a dosage in the range of from 0.02 to 100, e.g.
to 30, ug/kg s.c..
Furthermore, the GH-reducing activity of the compounds of the invention was also examined after oral application to male rats with oestradiol implants. This test is carried out as follows:
A loop (length 50 mm B 3 mm) of silastic with 50 mg of oestradiol is implanted under the dorsal skin of anaesthetized 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 substances are active in this test at doses from 10 to 5000 ug/kg, when 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-secretion, e.g. in the treatment of acromegaly as well as in the treatment of diabetes mellitus, especially complications thereof, e.g.angiophathy, proliferative retinopathy, dawn phenomenon and nephropathy.
The compounds of the invention, also inhibit gastric- and exocrine and endocrine pancreatic secretion and the release of various peptides of the gastrointestinal tract, as indicated in standard tests using e.g. rats with gastric or pancreatic fistulae, wherein the compounds are active orally at a dose from 0.01 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 ulcers, enterocutaneous and pancreaticocutaneous fistula, irritable bowel syndrom, dumping syndrom, watery diarrhea syndrom, acute pancreatitis and gastrointestinal hormone secreting tumors (e.g. vipomas, glucagonomas, insulinomas, carcinoids and the like) as well as gastrointestinal 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).
The compounds of the invention are also effective in the treatment of varous kinds of tumors, particularly the somatostatin receptor positive tumors, as indicated in proliferation tests with various different cancer cell lines and in tumor growth experiments in nude mice with hormone dependent tumors (e.g.
gastric dependent colon cancer). Thus the compounds of the invention can be used in the treatment of, for example, cancers of the breast, the prostate, the colon, the pancreas and the brain.
For all the above uses an indicated daily dosage is in the range from about 2 ug to about 20 mg, preferably about 0.01 to about 20 mg, e.g. about 10 to about 5000 ug s.c. and from about 300 to 20000 ug 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 ug to about 10 mg, e.g. from about 2 ug to 10 mg, of the compound or in sustained release form.
The Examples 1, 4b and 10 are the preferred compounds.
The compounds of the invention 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 the invention 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, for example parenterally e.g. in form of injectable solutions or suspensions, enterally, preferably orally, e.g. in the form of tablets or capsules or in a nasal or a suppository form.
In accordance with the foregoing the present invention further provides: a) a somatostatin peptide containing at least one residue of
formula (a), (b) or (c), e.g. a compound of formula I or II,
or a pharmaceutically acceptable salt or complex thereof for
use as a pharmaceutical; b) a method of treating disorders with an aetiology comprising
or associated with excess of GH-secretion, e.g. diabetes
mellitus, prevention and treatment of nephropathy, angiopathy
and proliferative retinopathy, acromegaly, of treating
gastro-intestinal disorders, e.g. peptic ulcers, entero
cutaneous and pancreaticocutaneous fistulae, irritable bowel
syndrom, dumping syndrom, watery diarrhea syndrom, gastro
intestinal bleeding, acute pancreatitis and gastro-intestinal
hormone secreting tumours, of inhibiting proliferation and/or
keratinisation of epidermal cells, of treating degenerative
senile dementia as well as of treating tumors in a subject in
need of such treatment, which method comprises administering
to said subject an effective amount of a compound according
to the invention, e.g. a compound of formula I or II, or a
pharmaceutically acceptable salt or complex thereof.
Claims (1)
1. A somatostatin peptide comprising at least one residue of
formula (a), (b) or (c)
wherein one of Y1 and Y2 is hydrogen and the other is
hydroxy or both are hydrogen,
each of f and g independently is O or 1,
one of X1 and X2 is hydrogen and the other is hydrogen or an
amino protecting group, and
X3 iS C2-6 alkylene, the free bond in each residue (a), (b) or (c) being located
at the N-terminal group of the peptide,
and the physiologically-acceptable ethers and physiologi
cally-hydrolysable and -acceptable esters thereof when the
peptide contains at least one residue of formula (a) or (b),
in free form or acid addition salt form or complex form.
2. A somatostatin peptide comprising at least one residue of
formula (a) or (b)
wherein one of Y1 and Y2 is hydrogen and the other is
hydroxy or both are hydrogen, and
each of f and g independently is O or 1,
the free bond in each residue (a) or (b) being located at at
the N-terminal group of the peptide,
any one of the free hydroxy groups in the residue of
formulae (a) and (b) being optionally bound in glycosylic
manner to a reducing mono-, di- or oligosaccharide or amino
sugar,
in free form or acid addition salt form or complex form.
3. A somatostatin peptide according to claim 1 or 2, in which
the N-terminal amino group is disubstituted by said
residues.
4. A somatostatin peptide of formula I
wherein
R1 is a residue of formula (a), (b) or (c) as
defined in claim 1, R2 is hydrogen, alkyl with 1 to 12 C-atoms,
alkanoyl with 1 to 4 C-atoms, C7-iophenalkyl or a residue of formula (a), (b) or (c) as
defined in claim 1, > N-CH(Z1)-CO is a) a (L)- or (D)-phenylalanine residue which is optionally
substituted by halogen, NO2, NH2, OH, alkyl with 1 to
3 C-atoms and/or alkoxy with 1 to 3 C-atoms, or b) the residue of a natural a-amino acid or of a
corresponding (D)-amino acid, other than that given
under a), or of a synthetic a-amino acid, wherein Z1 in > N-CH(Z1)-CO- represents the residue of an
amino acid residue as defined under a) and b),
A' is hydrogen or alkyl with 1 to 3 C-atoms, Y1' and Y2' represent together a direct bond or each of Y1, and Y2' is independently hydrogen or a radical of
formulae (1) to (5)
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 (C1-6)alkyl Rd represents the substituent attached to the
a-carbon atom of a natural a-amino acid
(including hydrogen) R. is (C1~ 5 )alkyl R' and Rb' are independently hydrogen, methyl or ethyl, R8 and Rg are independently hydrogen, halogen, (C1~3 )alkyl or (C1-3)alkoxy, p is O or 1, q is O or 1, and r is 0, 1 or 2,
B is -Phe- optionally ring-substituted by
halogen, NO2, NH2, OH, C13alkyl and /or
C1(3alkoxy, or naphthylalanine,
C is (L)-Trp- or -(D)Trp- optionally a-N-methy
lated and optionally benzene-ring-substituted
by halogen, NO2, NH2, OH, Alkyl and/or
C1-3alkoxy,
D is -Lys-, Lys in which the side chain contains
O or S in ss position, yF-Lys, FF-Lys or Orn,
optionally α;-N-methylated, or a 4-aminocyclo
hexylAla or 4-aminocyclohexylGly residue
E is Thr, Ser, Val, Phe, Tyr, Ile, an aminoiso
butyric or aminobutyric acid residue
F is a group of formula
wherein
R7 is hydrogen or C~3alkyl, R10 is hydrogen or the residue of a physiologically
acceptable, physiologically hydrolysable ester,
R11 is hydrogen, C13alkyl, phenyl or C7~10phenyl- alkyl,
R12 is hydrogen, C1-3alkyl or a group of formula -CH(R13 )-X4, R13 is CH2OH, -(CH2)2-OH, -(CH2)3-OH, or -CH(CH3)0H
or represents the substituent attached to the
a-carbon atom of a natural or synthetic a-amino
acid (including hydrogen) and
X4 is a group of formula -COOR7, -CH20Rlo or
wherein
R7 and Rld have the meanings given above,
R14 is hydrogen or C1-3alkyl and
R15 is hydrogen, C1~3alkyl, phenyl or C7-10phenyl-
alkyl, and
R16 is hydrogen or hydroxy, with the proviso that when R12 is -CH(R13)-X4 then R11 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 Y1
4) and Y2 4) each independently have the (L)- or (D)- confi
guration,
and the physiologically-acceptable ethers and physiologi
cally-hydrolysable and -acceptable esters thereof when the
compounds of formula I contain at least one residue of
formula (a) or (b).
5. A somatostatin peptide according to any one of the preceding
claims wherein in the residue of formula (a), either g is O
or g and f is 0.
6. A somatostatin peptide according to any one of claims 1 to 4
wherein in the residue of formula (b) f is 0.
7. A somatostatin peptide according to claim 1, 3 and 4,
wherein in the residue of formula (c) X1 and X2 are each
hydrogen.
8. A somatostatin peptide according to claim 4 of formula II
wherein Zl, A', Y1', B, C, D, E, F and Y21 are as defined in
claim 4, and
R17 and R18 are each a residue of formula (a) as defined
in claim 1, and the physiologically ethers and physiologicallyhydrolysable and -acceptable esters thereof.
Thr-ol in free form, salt form or complex form.
free form, salt form or complex form.
Thr-ol in free form, salt form or complex form.
12. A somatostatin peptide selected from
e) 2,3-Di-propionyloxy-(2S)-propyl-SMS f) 2,3-Di-hexanoyloxy-(2S)-propyl-SMS
g) 2, 3-Di-O-isopropyliden-2, 3-dihydroxy-(25)-propyl-SMS h) 2,3,4-Tri-hydroxy-(2S,3R)-butyl-SMS i) 2-Aminoethyl-SMS
j) 3-Aminopropyl-SMS
in free form, salt form or complex form.
13. A process for the production of a somatostatine peptide
according to claim 1, in free form or in salt form or
complex form, which process comprises
a. removing at least one protecting group from a protected
peptide containing at least one residue of formula (a),
(b) or (c) as defined above; or
b. reductively aminating either a compound of formula III
wherein either g is O or 1,
Y1 and Y2 have one of the significances given
above and
Z2 is -CHO, or g is 1,
Z2 is CH2OH and -CY1Y2-form together
carbonyl,
and the free hydroxy groups thereof may be etherified or
esterified
or a compound of formula IV
X'1-NH-X'3-CHO (IV)
wherein
X'1 is an amino protecting group, and X'3 iS C1~salkylene, with a compound of formula V P-NH2 (V)
wherein P is a somatostatin peptide residue in protected
form,
and, if necessary, carrying out process step a); c. coupling together by an amide bond two peptide frag
ments, each of which contains at least one amino-acid or
a derivative thereof in protected or unprotected form,
and at least one pep tide fragment contains at least one
residue of formula (a), (b) or (c) as defined above, the
peptide fragments being such that a protected or un
protected polypeptide sequence is obtained and, if
necessary, carrying out process step a); or d. removing or converting a functional group of an un
protected or a protected polypeptide into another
functional group so that an unprotected or a protected
polypeptide is obtained, and in the latter case stage a)
of the process is effected;
e. introducing at least one optionally protected residue
into a protected or unprotected peptide and if necessary
carrying out process step a);
f. separating optically active isomers from any mixture of
such isomers obtained in accordance with steps (a) to (e); and recovering a compound thus obtained in free or salt form
or in the form of a complex.
14. A compound according to any one of Claims 1 to 12 in free
form or in pharmaceutically acceptable salt form or complex
form for use as a pharmaceutical.
15. A compound according to any one of Claims 1 to 12 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 with excess growth hormone
secretion.
16. A compound according to any one of Claims 1 to 12 in free
form or in pharmaceutically acceptable salt form or complex
form for use in the treatment of gastro-intestinal
disorders.
17. A compound according to any one of Claims 1 to 12 in free
form or in pharmaceutically acceptable salt form or complex
form for use in the treatment of dermatological diseases
involving morbid proliferation and/or keratinisation of
epidermal cells.
18. A compound according to any one of Claims 1 to 12 in free
form or in pharmaceutically acceptable salt form or complex
form for use in the treatment of degenerative senile
dementia.
19. A compound according to any one of Claims 1 to 12 in free
form or in pharmaceutically acceptable salt form or complex
form for use in the treatment of tumours.
20. A pharmaceutical composition comprising a compound of any
one of Claims 1 to 12 in free form, or in pharmaceutically
acceptable salt form or complex form in association with a
pharmaceutically carrier or diluent.
21. A compound substantially as herein before described with
reference to any of Examples 1 to 11.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB888826452A GB8826452D0 (en) | 1988-11-11 | 1988-11-11 | Peptide derivatives |
Publications (2)
Publication Number | Publication Date |
---|---|
GB8924612D0 GB8924612D0 (en) | 1989-12-20 |
GB2227488A true GB2227488A (en) | 1990-08-01 |
Family
ID=10646721
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB888826452A Pending GB8826452D0 (en) | 1988-04-11 | 1988-11-11 | Peptide derivatives |
GB8924612A Withdrawn GB2227488A (en) | 1988-11-11 | 1989-11-01 | Modified somatostatin |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB888826452A Pending GB8826452D0 (en) | 1988-04-11 | 1988-11-11 | Peptide derivatives |
Country Status (1)
Country | Link |
---|---|
GB (2) | GB8826452D0 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7189856B2 (en) | 2001-12-28 | 2007-03-13 | Gideon Shapiro | Non-peptide somatostatin receptor ligands |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2206352A (en) * | 1987-06-29 | 1989-01-05 | Sandoz Ltd | Peptides |
-
1988
- 1988-11-11 GB GB888826452A patent/GB8826452D0/en active Pending
-
1989
- 1989-11-01 GB GB8924612A patent/GB2227488A/en not_active Withdrawn
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2206352A (en) * | 1987-06-29 | 1989-01-05 | Sandoz Ltd | Peptides |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7189856B2 (en) | 2001-12-28 | 2007-03-13 | Gideon Shapiro | Non-peptide somatostatin receptor ligands |
Also Published As
Publication number | Publication date |
---|---|
GB8924612D0 (en) | 1989-12-20 |
GB8826452D0 (en) | 1988-12-14 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |