CA1092601A - Derivatives of somatostatin - Google Patents
Derivatives of somatostatinInfo
- Publication number
- CA1092601A CA1092601A CA247,515A CA247515A CA1092601A CA 1092601 A CA1092601 A CA 1092601A CA 247515 A CA247515 A CA 247515A CA 1092601 A CA1092601 A CA 1092601A
- Authority
- CA
- Canada
- Prior art keywords
- phe
- cys
- gly
- ala
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
-
- 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
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
Derivatives of Somatostatin Abstract of the Disclosure This invention provides new compounds of formula I, I
wherein R1, X, Y and Z are amino acid residues and each B is hydrogen or together are a bond, useful as growth hormone secretion inhibitors.
wherein R1, X, Y and Z are amino acid residues and each B is hydrogen or together are a bond, useful as growth hormone secretion inhibitors.
Description
.~09260~ c ase 100-4314 Derivatives of Somatostatin The present invention relates to new poly-peptides.
In accordance with the invention there are provided new compounds of formula I, :
SB SB
Rl-CH-CO-X-Y-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-NH-CH Z
wherein Rl ls (i) H, ~ .
(li~ NH2 ~ . :
(iii) H-Ala-NH-;
H-Tyr~NH-;
: H-Cys-NH-;
H-Val-NH-;
~ : . H-Lys-NH-;
¦: ~ H-(a-aminO~~iSObUtyryl~NH-;
H-Phe-NH-;
:15~ (iv~ NH2-NH-C0-NH-;
(vj C6H5.NH-CO-Gly-NH-;
H-Ala-Gly-NH-; . ~ :
H-Val-Gly-NH~
: H-a-phenyl-Gly-NH-;
!: . : : ~::
,: ~ '.:
1~9Z~ 100~4314 ~vi) R2-A-CO-NH-, wherein - R2 is lower alkyl, phenyl, or - phenyl substituted by halogen, hydroxy, amino, lower alkyl :
or lower alkoxy, : `
A is a direct bond, alkylene con-tainin~ up to 6 carbon atoms or -NH-, (vii) R2~Ala-NH-; .
R2-A1a-Gly-NH-; ..
wherein R2 is as defined above, ....
(viii) C6H5.A .C0-M-NH-, whereïn AI is an alkylene chain of up to 6 carbon atoms, and -M~ iB -(mono- or di-Hal)-Phe, .
Gly- or -Ala-, .. . .
~ (ix) ~-(mono- or di-Hal)-Phe-NH-, : 20 wherein .
T- is H-, H-Val- or benzoyl-, ., :
:, ' , , , , ',' ` ;':,' '
In accordance with the invention there are provided new compounds of formula I, :
SB SB
Rl-CH-CO-X-Y-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-NH-CH Z
wherein Rl ls (i) H, ~ .
(li~ NH2 ~ . :
(iii) H-Ala-NH-;
H-Tyr~NH-;
: H-Cys-NH-;
H-Val-NH-;
~ : . H-Lys-NH-;
¦: ~ H-(a-aminO~~iSObUtyryl~NH-;
H-Phe-NH-;
:15~ (iv~ NH2-NH-C0-NH-;
(vj C6H5.NH-CO-Gly-NH-;
H-Ala-Gly-NH-; . ~ :
H-Val-Gly-NH~
: H-a-phenyl-Gly-NH-;
!: . : : ~::
,: ~ '.:
1~9Z~ 100~4314 ~vi) R2-A-CO-NH-, wherein - R2 is lower alkyl, phenyl, or - phenyl substituted by halogen, hydroxy, amino, lower alkyl :
or lower alkoxy, : `
A is a direct bond, alkylene con-tainin~ up to 6 carbon atoms or -NH-, (vii) R2~Ala-NH-; .
R2-A1a-Gly-NH-; ..
wherein R2 is as defined above, ....
(viii) C6H5.A .C0-M-NH-, whereïn AI is an alkylene chain of up to 6 carbon atoms, and -M~ iB -(mono- or di-Hal)-Phe, .
Gly- or -Ala-, .. . .
~ (ix) ~-(mono- or di-Hal)-Phe-NH-, : 20 wherein .
T- is H-, H-Val- or benzoyl-, ., :
:, ' , , , , ',' ` ;':,' '
- 2 -: ' :' ..
',, : ` ' : ' , : . : . :
. .
~ ~ z~ ~ ~ 100-4314 (x) (CH2 ~ CH.A .CO-L-NH, wherein AI is as deined above, and -L- is -Val-, -Val-(mono- or di-~al)-Phe-, -a-phenyl-Gly-, and n is an integer between 4 and 10, each B is hydrogen or the two radicals8form a direct bond, X is -Lys-, -Nle- or -Cys-, and ~ . Y is -Asn-, -Gln- or -Thr-, and : 10 - Z signifies the radicals (i) H; (ii) COOH;
(iii) COOR3 (wherein R3 is lower alkyl~;
~iv) -CO-NR4R5 (wherein R4 and R5 independently are hydrogen or lower alkyl); (v) -CON îCH2)n (wherein n is as defined above); (vi) CH20H;
(vii) -CO-asparaginol; -CO-leucinol; -CO-iso-leucinol; -CO-valinol; -CO-norleucinol;
-CO-glutaminol; -CO-threoninol; (vili) -CO-Leu;
. -CO-Serj -CO-Iso-Leu; -CO-Val, and their .'` corresponding amides, wherein the amide : --~0 portion signifies the radical -CO NR4R5 or ~CO-N ~CH2)n (wherein n, R4 and R5 are as defined abov~), or (ix) -CO-ThrOR3 or : .:
-CO~SerOR3 (wherein R3 is as defined above);
_ 3 _ ~ ` :
: . . ,- ' , ~
. ' ' : ' ' "
.~
-~L~9Z6~JL
: ' ; (x) -CO-NH-(CH2)k-OH (wherein k is an integer be-tween 2 and 6), or -CO-NH-CH-[CH2]1 OH
L
[CH2]1 OH
wherein 11 and 12 independently signiy a whole number fxom 1 to 6);
(xi) -CO-N o;
(xii) -CO-NH-R6 (wherein R6 is a 5- or 6-membered saturated heterocyclic ring conta.~ning an oxygen atom as a ring member, or a 5- or 6-membered lactone ring), wherein in formula I
~ thè unit containing radicals Rl, X, Y and Z, as well as in the remaining units of the pep-tlde sequence, at least one unit may be pre-. ~ .
sent ln D orm, :`
: with~the provisos that when X ls ~ys and Y ls Asn, and all ' ` :~ lS the remainlng units of the peptide se~uence 3 to 14 are :~ present in the D or L f orm, and when (i) Rl is H-Ala-Gly-NH- ox Ala-Gly-NH-, ~
Z is other than COOH, COO~3, C~2OH or CONR~R5, or, when ii) Rl is H, NH2 or H-(D)-Ala Gly-NU~
Z iB other than H, COOH, CONR4R5 or (CN~_,CH2)4 or 5 - or, when ~ :
(lii) Rl is H-~-amlno-isobutyryl)-NH- or : 25 : H~(D)-Ala-NH-, : Z ls other than H or COOH, or, when ~ 4 _ : ~ -~92~
(iv) Rl is H-Ala-Gly-NH-, Z is other than H, or when (v) Rl is H-Ala-NH- or R2-CO-NH-(wherein R2 is lower alkyl or unsubstituted phenyl), Z is other than COOH, and with the further proviso tha~ when Rl is H-Cys-NH or H-(D)-Cys-NH and/or X ls -Cys- or -(D)-Cys, B-B is other than a direct bond.
10In the compounds of the formula I, when X is Lys and Y is Asn, Z is pref~ra~ly qelected from the radicals deined under (viij, (viii), (ix) and (x~ above.
~ Halogen signifies bromine, fluorlne, and preferably chlorine. The significance of lower alkyl or lower alkoxy comprises up to 6 carbon atoms, but prefer-ably signlfies 2 or 1 carbon atom.
When ~2 is substituted phenyl, this is pre-ferably mono- or disubstit~ted, especially, however monosubstituted. A substituent is preferably present in ~20 the para position.
: I :
A when alkylene or A preferably contains up to 3 carbon atoms. In regard to the significance ~
viii3, A preferably signifies trimethylene. In regard to the significance (x3, A preferably signifles methylene.
Examples of -(mono- or di-Hal)-Phe-moieties are -(2Cl)-Phe-; -(3C13-Phe-; -(4Cl)-Phe- or (3,4-di-Cl)-Phe-.
. :~: - : : .
~ - 5 -. . ~ .
~260~ 100-~314 n preferably signifies an integer 5 or 4.
Rl preferably signifies, e.g., H-(mono- or di-Hal)-Phe-NH-, phenyl-CO-NH-, H-Val (mono- or di-Hal)-Phe-NH-, phenylbutyryl-NH-or a radical containing -(D)-Ala, benzoyl-(mono- or di-Hal)-Phe-NH-, cyclohexylacetyl-a-phenyl-Gly-NH-, cyclohexylacetyl-Val-(mono- or di-Hal)-Phe-NH~, cyclohexylacetyl-Val-NH-, H-Val-NH, H, H-(a-amino-isobutyryl)-NH-, H-(mono- or di-Hal)-Phe-NH-.
X preferably signifies Lys and especially Nle.
Y preferably signifies Gln and especially Asn.
~ preferably signifies 2 ox 3 When Z is significance tx) or (xii), this preferably contains a moiety -CO-NH-CH-CH2-0-and signifies, for example, -CO.NH.CH(CH2.0H)CH2.CH2.CH2.0H;
-CO-NH-CH(CH20H).CH2.CH2.OH; -CO-NH-CH.CH2.CH2.CO.OjCH2;
-CO-NH.CH CH2.CO.O.CH2; -CO-NH.CH.CH2.CH2ØCH2;
-CO-NH.fH CH2.CH2.CH2 O.CH2.
Z preferably signifies other than H, ...
CH20H, COOH or COOR3.
~ ' In the preferred significance indicated above - ~ the aminoacids may be present~ in the D instead of the L form.
: : ' .' : :
:, ~
: : ' 1' . .. . " ., . . ;. . ,. , , . , .. . . , . . , . . ~., . ~ ... .. .
~Z6~ 100-~314 The present invention comprises processes for the production of compounds of the above formula. They may be produced in accordance with known methods for the . synthesis of compounds of this type or obvious chemical -~ 5 equivalents thereof.
The polypeptides or derivatives thereof of the above formula may be produced, for example, by a process comprising a) removing at least one protective group from a protected peptide having the sequence indicated in formula I, ox . b3 link~ng together by an amide bond two peptide units, ; each of which contains at least one amlnoacid and which is ln protected or unprotected form, the peptide , unlts being such that the aminoacid sequence given in formula I is obtained, and then if necessary carrying . out process step a), or . .
c~ converting one group Z ~f an unprotected or protectea peptide of formula I in to another group Z havlng the definitlon indicated above, and if necessar~ carr~ing out process step a), or ;
~ d) oxidizing a peptide of formula I whexeln B is hydrogen, to produce a peptide of formula I wherein B-B is a : `
direct bond. ~ :
.
~ _ 7 _ '` ` ` `
- .:
` .
:
. ~ .. .. ... .. . : . .. .. : , : . . . . . : : :.: . :.. .
- ~9260~ 100-431~
The above are methods known in peptide chemistry; they may be carried out in a manner analogous to the processes described in the following Examples. :
Insofar as the production of the starting materials is not particularly described, ~hese compounds are known or may be produced and purified in accordance with known methods. These compounds may also be produced in a manner analogous to the processes described in the Examples.
Thecompounds may exist in salt form or in the form of complexes thereof.
The salts of hydrochloric acid and acetic acld may particularly be mentioned as acid addition salts.
Complexes are understood to be the complex-like compounds of known type, but not of clear structure, which are formed from compounds of formula I upon adding certain inorganic or organic substances. Such inorganic substances are compounds which are derived from metals, such as calcium, magnesium, aluminium, cobalt and ~.
-~ 20 particularly zinc, especially difficultly soluble salts ~', such as phosphates, pyrophosphates and polyphosphates, as well as hydroxides of these metals, in addition alkali metal polyphosphates. Organic substances are, for example, '9` non-antigenic gelat~nes, e.g. oxypolygelatine, polyvinyl-pyrrolidone and carboxymethyl cellulose, in addition , ~ 7 :
~' ~ ' ' ' .
', , ' ' - ',' ,:
" ' .
~ ~ Z~ 0~ 100-~31~
sulphonic acid or phosphoric acld esters of alginic acid, dextrane, polyphenols and polyalcohols, especially polyphloretine phosphate and phytinic acid, as well as polymerization products of aminoacids, e.g. protamine, polyglutaminic acid or polyasparaginic acid.
In the following non-limitative Examples all temperatures are indicated in degrees centigrade and are uncorrected.
The following abbreviations are used:
Cbo = carbobenzyloxy MBzl = ~-methoxybenzyl Iabu = H-(~-amino-isobutyryl)-(4Cl)Phe - ~-chlorophenylalanyl AcOH = acetic acid OCP = trichlorophenyl ester OSu = O~succinimide ~' '' :'-All the final compounds are characterized in hydrochloride salt form. The aminoacids are present in the ~ form unless otherwise indicated.
i . ..
.
'','-',.~
,~ ' `, ' ' ~'~ :'' _ g ~
' ' ", ' . :
, . , ~
' ~ . ' ~9Z6~ 100-4314 .-;
In the following Table ~a] D0 refers to AcOH 1~ v/v (c = 1) unless otherwise indicated.
.
(1) refers to AcOH 20% v/v (c = 1) (2) refers to AcOH 1% v/v (c = 0.25)
',, : ` ' : ' , : . : . :
. .
~ ~ z~ ~ ~ 100-4314 (x) (CH2 ~ CH.A .CO-L-NH, wherein AI is as deined above, and -L- is -Val-, -Val-(mono- or di-~al)-Phe-, -a-phenyl-Gly-, and n is an integer between 4 and 10, each B is hydrogen or the two radicals8form a direct bond, X is -Lys-, -Nle- or -Cys-, and ~ . Y is -Asn-, -Gln- or -Thr-, and : 10 - Z signifies the radicals (i) H; (ii) COOH;
(iii) COOR3 (wherein R3 is lower alkyl~;
~iv) -CO-NR4R5 (wherein R4 and R5 independently are hydrogen or lower alkyl); (v) -CON îCH2)n (wherein n is as defined above); (vi) CH20H;
(vii) -CO-asparaginol; -CO-leucinol; -CO-iso-leucinol; -CO-valinol; -CO-norleucinol;
-CO-glutaminol; -CO-threoninol; (vili) -CO-Leu;
. -CO-Serj -CO-Iso-Leu; -CO-Val, and their .'` corresponding amides, wherein the amide : --~0 portion signifies the radical -CO NR4R5 or ~CO-N ~CH2)n (wherein n, R4 and R5 are as defined abov~), or (ix) -CO-ThrOR3 or : .:
-CO~SerOR3 (wherein R3 is as defined above);
_ 3 _ ~ ` :
: . . ,- ' , ~
. ' ' : ' ' "
.~
-~L~9Z6~JL
: ' ; (x) -CO-NH-(CH2)k-OH (wherein k is an integer be-tween 2 and 6), or -CO-NH-CH-[CH2]1 OH
L
[CH2]1 OH
wherein 11 and 12 independently signiy a whole number fxom 1 to 6);
(xi) -CO-N o;
(xii) -CO-NH-R6 (wherein R6 is a 5- or 6-membered saturated heterocyclic ring conta.~ning an oxygen atom as a ring member, or a 5- or 6-membered lactone ring), wherein in formula I
~ thè unit containing radicals Rl, X, Y and Z, as well as in the remaining units of the pep-tlde sequence, at least one unit may be pre-. ~ .
sent ln D orm, :`
: with~the provisos that when X ls ~ys and Y ls Asn, and all ' ` :~ lS the remainlng units of the peptide se~uence 3 to 14 are :~ present in the D or L f orm, and when (i) Rl is H-Ala-Gly-NH- ox Ala-Gly-NH-, ~
Z is other than COOH, COO~3, C~2OH or CONR~R5, or, when ii) Rl is H, NH2 or H-(D)-Ala Gly-NU~
Z iB other than H, COOH, CONR4R5 or (CN~_,CH2)4 or 5 - or, when ~ :
(lii) Rl is H-~-amlno-isobutyryl)-NH- or : 25 : H~(D)-Ala-NH-, : Z ls other than H or COOH, or, when ~ 4 _ : ~ -~92~
(iv) Rl is H-Ala-Gly-NH-, Z is other than H, or when (v) Rl is H-Ala-NH- or R2-CO-NH-(wherein R2 is lower alkyl or unsubstituted phenyl), Z is other than COOH, and with the further proviso tha~ when Rl is H-Cys-NH or H-(D)-Cys-NH and/or X ls -Cys- or -(D)-Cys, B-B is other than a direct bond.
10In the compounds of the formula I, when X is Lys and Y is Asn, Z is pref~ra~ly qelected from the radicals deined under (viij, (viii), (ix) and (x~ above.
~ Halogen signifies bromine, fluorlne, and preferably chlorine. The significance of lower alkyl or lower alkoxy comprises up to 6 carbon atoms, but prefer-ably signlfies 2 or 1 carbon atom.
When ~2 is substituted phenyl, this is pre-ferably mono- or disubstit~ted, especially, however monosubstituted. A substituent is preferably present in ~20 the para position.
: I :
A when alkylene or A preferably contains up to 3 carbon atoms. In regard to the significance ~
viii3, A preferably signifies trimethylene. In regard to the significance (x3, A preferably signifles methylene.
Examples of -(mono- or di-Hal)-Phe-moieties are -(2Cl)-Phe-; -(3C13-Phe-; -(4Cl)-Phe- or (3,4-di-Cl)-Phe-.
. :~: - : : .
~ - 5 -. . ~ .
~260~ 100-~314 n preferably signifies an integer 5 or 4.
Rl preferably signifies, e.g., H-(mono- or di-Hal)-Phe-NH-, phenyl-CO-NH-, H-Val (mono- or di-Hal)-Phe-NH-, phenylbutyryl-NH-or a radical containing -(D)-Ala, benzoyl-(mono- or di-Hal)-Phe-NH-, cyclohexylacetyl-a-phenyl-Gly-NH-, cyclohexylacetyl-Val-(mono- or di-Hal)-Phe-NH~, cyclohexylacetyl-Val-NH-, H-Val-NH, H, H-(a-amino-isobutyryl)-NH-, H-(mono- or di-Hal)-Phe-NH-.
X preferably signifies Lys and especially Nle.
Y preferably signifies Gln and especially Asn.
~ preferably signifies 2 ox 3 When Z is significance tx) or (xii), this preferably contains a moiety -CO-NH-CH-CH2-0-and signifies, for example, -CO.NH.CH(CH2.0H)CH2.CH2.CH2.0H;
-CO-NH-CH(CH20H).CH2.CH2.OH; -CO-NH-CH.CH2.CH2.CO.OjCH2;
-CO-NH.CH CH2.CO.O.CH2; -CO-NH.CH.CH2.CH2ØCH2;
-CO-NH.fH CH2.CH2.CH2 O.CH2.
Z preferably signifies other than H, ...
CH20H, COOH or COOR3.
~ ' In the preferred significance indicated above - ~ the aminoacids may be present~ in the D instead of the L form.
: : ' .' : :
:, ~
: : ' 1' . .. . " ., . . ;. . ,. , , . , .. . . , . . , . . ~., . ~ ... .. .
~Z6~ 100-~314 The present invention comprises processes for the production of compounds of the above formula. They may be produced in accordance with known methods for the . synthesis of compounds of this type or obvious chemical -~ 5 equivalents thereof.
The polypeptides or derivatives thereof of the above formula may be produced, for example, by a process comprising a) removing at least one protective group from a protected peptide having the sequence indicated in formula I, ox . b3 link~ng together by an amide bond two peptide units, ; each of which contains at least one amlnoacid and which is ln protected or unprotected form, the peptide , unlts being such that the aminoacid sequence given in formula I is obtained, and then if necessary carrying . out process step a), or . .
c~ converting one group Z ~f an unprotected or protectea peptide of formula I in to another group Z havlng the definitlon indicated above, and if necessar~ carr~ing out process step a), or ;
~ d) oxidizing a peptide of formula I whexeln B is hydrogen, to produce a peptide of formula I wherein B-B is a : `
direct bond. ~ :
.
~ _ 7 _ '` ` ` `
- .:
` .
:
. ~ .. .. ... .. . : . .. .. : , : . . . . . : : :.: . :.. .
- ~9260~ 100-431~
The above are methods known in peptide chemistry; they may be carried out in a manner analogous to the processes described in the following Examples. :
Insofar as the production of the starting materials is not particularly described, ~hese compounds are known or may be produced and purified in accordance with known methods. These compounds may also be produced in a manner analogous to the processes described in the Examples.
Thecompounds may exist in salt form or in the form of complexes thereof.
The salts of hydrochloric acid and acetic acld may particularly be mentioned as acid addition salts.
Complexes are understood to be the complex-like compounds of known type, but not of clear structure, which are formed from compounds of formula I upon adding certain inorganic or organic substances. Such inorganic substances are compounds which are derived from metals, such as calcium, magnesium, aluminium, cobalt and ~.
-~ 20 particularly zinc, especially difficultly soluble salts ~', such as phosphates, pyrophosphates and polyphosphates, as well as hydroxides of these metals, in addition alkali metal polyphosphates. Organic substances are, for example, '9` non-antigenic gelat~nes, e.g. oxypolygelatine, polyvinyl-pyrrolidone and carboxymethyl cellulose, in addition , ~ 7 :
~' ~ ' ' ' .
', , ' ' - ',' ,:
" ' .
~ ~ Z~ 0~ 100-~31~
sulphonic acid or phosphoric acld esters of alginic acid, dextrane, polyphenols and polyalcohols, especially polyphloretine phosphate and phytinic acid, as well as polymerization products of aminoacids, e.g. protamine, polyglutaminic acid or polyasparaginic acid.
In the following non-limitative Examples all temperatures are indicated in degrees centigrade and are uncorrected.
The following abbreviations are used:
Cbo = carbobenzyloxy MBzl = ~-methoxybenzyl Iabu = H-(~-amino-isobutyryl)-(4Cl)Phe - ~-chlorophenylalanyl AcOH = acetic acid OCP = trichlorophenyl ester OSu = O~succinimide ~' '' :'-All the final compounds are characterized in hydrochloride salt form. The aminoacids are present in the ~ form unless otherwise indicated.
i . ..
.
'','-',.~
,~ ' `, ' ' ~'~ :'' _ g ~
' ' ", ' . :
, . , ~
' ~ . ' ~9Z6~ 100-4314 .-;
In the following Table ~a] D0 refers to AcOH 1~ v/v (c = 1) unless otherwise indicated.
.
(1) refers to AcOH 20% v/v (c = 1) (2) refers to AcOH 1% v/v (c = 0.25)
(3) refers to AcOH 30% v/v (c = 1~
~4) refers to AcOH 40~ v/v (c = 1) (5) refers to AcOH 50% v/v (c = 1) - ~ ~
~, '.
.. '' .
.
': " ' '~', .
-: .
10 - .:
i,~ : ' ~ ' :
i : :
.. . .
26~ 00~43l4 EXaMPLE 1:
a~O~
480 mg of Cbo-(4Cl)Phe -Cy5 (MB zl )-Lys(BOC)-Asn-Phe-Phe-Trp-Lys(Cbo)-Thr-Phe-Thr Ser-Cys(MBzl)-OBzl, 410 mg of H-Try-OH, 320 mg of H-Cys-OH.HCl and 1,2 cc of thio-anisole are dissolved at 0 in 5 cc of trifluoroacetic acid, and 10 cc of 2 molar boron tris(trifluoroacetate) ~-in trifluoroacetic acid are added. The mixture is shaken for one hour at room temperature and cooled. 50 cc of tert~butyl alcohol are added, concentration is efEected by evaporation, in a vacuum and a solution of 0.01 molar 2~mercaptoethanol in ether is added to the residue.
Centrifuging is subsequently effected. The solid residue ls dlssolved ~n a small amount of 10~ acetic acid and is :, . .
purified by chromatography on "Sephadex G" 25 in a sys-tem of 0.01 molar 2-mercaptoethanol in 10~ acetic acid.
The residue may also be dissolved in 30% acetic acid or in~a mixture of n-butanoljacetic acid/water (e.g. 4 and purlfied by chromatography on "Sephadex G" 25 using 0.01 M 2-mercaptoethanol in 30% acetic acid or in the mixture o~ n-butanoljacetlc acid/water. The fractions con-; taining the desired product are combined, dissvlved in ::
0.1 normal hydrochloric acid and lyophilized, whereby tlletitle compound is obtained.
M.Pt, 195 (decom~.); [~12 = -20.5 in AcO~ (c = 1).
The starting material ls produced as follows:
Trademark for a dry, unsoluble, powdered material derlved from dextran; lt is used in chromatography.
, , - , . . . . ~: ,.. . .
26e~L
100~4314 , ' :
a) Cbo-Lys(BOC)-Asn-Phe-OMe ________________________ 74.8 g of Cbo-Lys(BOC)-ONP are reacted in a solution of 51 g of H-Asn-Phe-OMe . HCl and 21 cc of triethylamine in 300 cc of dimethyl formamide. After working up, the title compound is obtained.
M.P. 175; [1 D= ~4 4 in dimethyl formamide (c = 1.0).
b) H-Lys(EOC)-Asn-Phe-OMe _______________ ~ 2 g of Cbo-Lys(BOC)-Asn-Phe-OMe are sus-pended in a solution of 2 liters of dioxane and 400 cc of water. Palladium charcoal is added and hydrogenation is effected at normal pressure. After working up, the title compound is obtained.
' M.P. 122; [] D- -8.3 in dimethyl formamide (c = 1.0).
:, c) Cbo-(4Cl)Phe-C~s (MB21) -~H-NH
____________ 2 20 g of H-Cys(MBzl)-OMe.CH3S03H and 7 cc of triethylamine are disso:Lved in 120 c~ of dimethyl formamide, and 18.2 g of Cbo-(4Cl)Phe-ONP are added.
.
The mixture is allowed to stand for 16 hours and is concentrated at room temperature, whereby Cbo-(4Cl)Phe-Cys(MBzl)-OMe (M.P. 115) is obtained after worXing up.
, -The latter is dissolved in methanol and hydrazinehydrate is added. The mixture is allowed to stand at room temperature for one day. The title compound is . ~ ~
': : , , . : :
- ~ 12 -'~
~ .
~ ~. . ., ~ .
~IL0~2~1 100~431 obtained after working up.
M.P. 158; [a~ OD= -9.9 in dimethyl formamide (c = 1).
d) Cbo-(4Cl)Phe-Cys(MB~l)-Lys(BOC)-Asn-Phe-NH-NH
____________~______-_-_ 2 6 g of Cbo-(4Cl)Phe-Cys(MBzl)-~H-NH2 are dissolved in 80 cc of dimethyl formamide, the solution is cooled to -20, 6 cc of 5.3 normal hydrochloric acid in dioxane are added and then 1.3 cc of tert.butyl nitxite are added and stirring is effected at -20 for - 10 minutes. After the addition of 5.5 cc of triethyl-amine at -20, 8.4 g of H-Lys(BOC)-Asn-Phe-OMe are added, the mixture is allowed to stand over night at 0, ..
concentration is effected, and water is added at 0 up to pH 2. The precipitate is filtered off and washed with water. The resulting Cbo-(4Cl)Phe-Cys(MBzl)-1 15 Lys(Boc)-~sn-Phe-OMe is recrystallized from methanol, :` is then dissolved in dimethyl formamide,and 7 cc of hydrazine hydrate are adaea. The mixture is allowed to stand at room temperature for one day, is con-centrated, and the residue is recrystalliæed from ~ .
methanol, whereby the title compound is obtained.
M.P. 260; [a] D- -23~ in dimethyl formamide (c = 1.0).
e) BOC-Lys(Cbo)-Thr-Phe-Thr-Ser-Cys(MBzl)-oBzl _____ _______________--_-------- .. ::
2.3 g of BOC-Lys(Cbo)-Thr-Phe-Thr-Ser-NH-NH2 are reacted with 1.86 g of H-Cys(MBzl)-OBzl in a : -.
''.. " ':
:
; 13 - :
: .
I
' : ~: ' ' , .
~ . , , , . ,.,.... .. ; ., . . , . . . ,, .,. - ..
- 11 09Z6iD1 100-~314 manner analogous to that described in section d), where-by the title compound is obtained.
M.P. L69~j [~¦ D- -16 in dimethyl formamide (c = 1).
f) BOC-Trp-Lys(Cbo)-Thr-Phe-Thr-Ser-Cys~MBzl)-OBzl ___________________._________________ ________._ 2.3 g of BOC-Lys(Cbo)-Thr-Phe-Thr-Ser-Cys(MBzl)-OBzl are dissolved in a mixture of 10 cc of methylene chloride and 6 cc of trifluoroacetic acid and the solution is allowed to stand at room temperature for 25 minutes. H-Lys(Cbo)-Thr-Phe-Thr-Ser-Cys(MBzl)-OBzl ~ trifluoroacetate is subsequently precipitated with ether, filtered off and washed out well with ether. The residue is dissolved in 7 cc of dimethyl formamide, l.5 g of BOC-Trp-OCP and 0.3 cc of triethylamine are added and the mixture is allowed to stand at room temperature over night. The product is precipitated with ether/ethyl acetate (l : l) and is filtered. Drying is effected, whereby the title com-pound is obtained.
,~ M.P. 167; [~ D- -17.5 in dimethyl formamide (c = l).
, 20 g) BOC-Phe-Tr~-Lys(Cbo)-Thr-Phe-Thr-Ser-Cys(MBzl)-oB
~ __ __ _~__ __________._ _________~_ __ _ _ ____ _ _ 36 g of BOC-Trp-~s(Cbo)-Thr-Phe-Thr-Ser-Cys(MBzl)-OBzl are reacted with 20 g of BOC-Phe-ONP
~ in a manner analogous to that described in section f);
,.~
. . .
' :` : '' .
, 1 ~`
.
2~
100-~314 the title compound is obtained.
M.P. 210; [~] D- 15 in dimethyl formamide (c = 1.0).
h) Cbo-(4Cl)Phe-Cys(MBzl)-~ys(Boc)-Asn-phe-phe-Tr ~ys(Cbo)-Thr-Phe-Thr-Ser-Cys(MBzl)-OBzl ~: ----_ _ _ _ _ _ _ _ _ _ 1.5 g of BOC-Phe-Trp-Lys(Cbo)-Thr-Phe-Thr-Ser-Cys(MBzl)-OBzl are dissolved in 30 cc of methylene chloride and 30 cc of trifluoroacetic acid.
The mixture is allowed to stand at room temperature for 25 minu-tes, is concentrated by evaporation in a vacuum and precipitated with ether. After filtration, washing with ether and drying, H-Phe-Trp-Lys(Cbo)-Thr-Phe-Thr-Ser-Cys(MBzl)-OBzl . trifluoroacetate is ob-tained.
0~9 g of Cbo-(4Cl)Phe-Cys(MBzl)-Lys(BOC)-Asn-Phe-NH-NH2 are dissolved in 20 cc of dimethyl formamide, the solution is cooled to -20~, 0.6 cc of 5.3 normal hydrochloric acid in dioxane are added and then 0.1 cc of tert.~utyl nitrite is added and the mixture is stirred at -20 for 15 minutes. 0.7 cc of triethylamine and 1.5 g of H-Phe-Trp-~ys(Cbo)-Thr-Phe-Thr-Ser-Cys(MBzl)-OBzl trifluoroacetate are added.
The mixture is allowed to stand at 0 over night, is concenkrated by evaporation in a vacuum, is stirred -:
with 100 cc of water, filtration is effected, the resi-. .
~ .
. .
, ~ - 15 -, ._ . :
.
. .. . . . . ~ . .
~ Z61)~
, due is washed with water and then wi-th methanol, heating : in methanol and filtration are effected, whereby the title compound is obtained.
M.P. 270; [a~ D- -19.3 in dimethyl formamide (c = 1).
', The following compoundSo~
formula A are obtained in analogous manner after building up the corresponding protected compounds and splitting off the protective group, .~' .
P-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Q A
. ~ .
~ ~ .
, ~ .
: . . .
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:
:1 :
~:
~ 16 - ~ `
' ~ :` , ' -~ ~Z~9Z~ZO~
100-~l31~
No. _ _ _ l~}~O
Al ~ NH-CO-Cys-Lys Asn .Cys-OH -17 2/
A2 ~ -NH-CO-Cys Lys-Gln Cys-OH 150 ~
~3 II-Tyr-Cys-Lys-Asn Cys-OH 160 /
. . -20.0 A4 NH2 ~ CO~Cys-Lys-Asn Cys-OH -19.Z~O
A5 ~ (CH2)3-CO-Cys-Lys-Asn Cys-O~I -33 1 A6 ~ (CH2)3-CO-Gly-Cys-Lys-Asn Cys-OH -27 7 ' . A7 ~ NH-CO-Gly-Cys-Lys-Asn Cys-OH -34 3 A8 H-Cys-Cys-Lys-~sn Cys-N~2 -24 5 ~ A9 H-Cys-Cys~Asn -Cys-NH2 -23 3 : ~ A10 H-Lys-Cys-Lys-Asn C~s-NH2 ~27.8 All ~I-(4Cl)Phe-Cys-Nle-Asn ~ Cys-NH2 170 A12 N-(4Cl)Phe-Cys-Lys-Asn Cys-NH -23 2 Z A13 H-Iabu-Cys-Lys-Asn : Cys-NH2 -21.0 A14 H-Iabu-Cys-Lys-Thr Cys-NH 165 /
~, 20.~
:`, ' : ' .
- ~
:', ~ :
260~
100-431~l .
Ex __ l~J2(/
~; ~ A15 ~ -(CH2)3-co-~cl)phe-cys~Lys-Asn Cys-NH2 -1~ 7/
: A16 ~ -(cH2)3-co-Gly-cys-Nle-Gln Cys-NH -1~.7 :~
Al ~ (CH2)3-C0-Cys-Lys Asn Cys NK _19 r~o ~ Al ~ NH-C0-Cys-Lys~Asn Cys-NH2 -25 3/~1) : A19 ~ NH-C0-Cys-Lys-Gln Cys--NH -29.5 - :
A2 ~ NH-CO~Cys-Nle-Asn Cys-NH~ -10.7 A21 ~ NH-C0-Gly-Cys-Nle-Gln Cys-NH2 1134/ ~:
, A2 ¦~H2-N~-C0-Cys Lys-Asn Cys-NH 130 /
: A2 ~ (CH2)3-CO-(D)Ala-Cys-Lys~Asn Cys-NH -13.7 ~:~ A24 8enzoyl-Cys-Nle-Asn Cys-NH lGO /
. A25 8enzoyl-~y5-Lys-Asn Cys-NH2 -37~9 A26 ~ C~-(4Cl)Phe-Cys-Nle-Asn Cys-NH
¦A27~h-~D)-Al -Gly-C s-Lys-Asn ¦ Cys-Val-NH2 ¦24270~(/2) ¦
A2 H-Ala-Gl~-Cys-Lys-Asn Cys-N ~ 210 /
,~ . -45(2) , j ~ - 18 ~
.. . .
, .
.: , .
,,_ ,r~ ~ ' ' ~9Z6(~ 100-4 31~
_ ~
Ex . _ Q [c~]20 _ ___ __ _~___ ~
A29 1~-(4Cl)Phe~Cys-Nle^Asn Cys-Asparagi- 155 / --; llol -22.5 A30 ~ abu-Cvs-Nle~Asn Cys~Asparayi- 150 /
nol -44.3 A31 Il--Iabu-Cys-Lys--Asn Cys-Asparagi- 160 /
nol- -~7.4 A32 H-(D)-Ala-Gly-Cys-Lys-Asn Cys-Aspara~i- 150 /
. nol -52.7 ~:-A33 H^(D)-~la~Gly Cys-Nle~Asn Cys-Asparagi- 165 / ~:
; . nol _49.50(1) A34 ~I-(D)~Val-Cys~Lys-Asn Cys-NH 175 /
. 47.0~
A35 ~ Phenylc3~ycyl)-Cys-Lys-Asn Cys-NH2 ~33 3 A36 H-(D)~Val-(4Cl)Phe-Cys Lys-Asn Cys-NH 165 /
~37 ~I-(D~-Ala-Cys-Lys-Asn Cys-NH ~30.9 i A3~ H~Cys~Lys-Asn Cys-NH 180 /
;l A39 Cyclohexy].acetyl-(D~-Val-Cys-Lys-Asn Cys-NH2 ~19.80(3) A40 Cyc].ohexylacetyl~ -Phenylglycyl)-Cys- Cys-NH 1~5 /
Lys Asn -19.~(5 A41 Cyclohexylacetyl~(D)-Val-(4Cl)Phe-Cys- Cys-NH 165 /
Lys-Asn 2 -23.70~3) A42 8~nzoyl-(3,~-dichlo~^o~Phe-Cys-I.ys-P.sn Cys-NE~2 -22 5/(~) -:.
: A~ 3 Renzoyl- ( 3, 4 -dichloro) Phe-Cys-Nle-~sn Cys-NH -2~.So(4) ,~ . , .~ A44 H-(D)-Ala-Gly-Cys-Nle-Asn Cys~NH ~23.90(4) , ~ , `1 ~ ' '''.,.. ' ,''' ~ ' , .
~' ~ ' `' .
z~
: No, . ~ ~ I )2 ~ . _ _ ._ ~45 H-(D)-Phe-Cys-Nle-Asn Cys-NH -29 1(3 A46 H-Phe~Cys-Nle-Asn Cys-NH2 1730~/(3 . . ~47 H-(3Cl)Phe-Cys~Nle-Asn Cys Asparagi- 165 /
: . nol _35,0(3 A~ H-(2Cl)Phe-Cys-Nle~Asn Cys-~sparagi- 170 /
. nol -29.8(3 A49 H-(3,~diCl)Phe-Cys-Nle-Asn Cys-Asparagi- 162 /
. nol CH2-l=0 -25,5(3 :.
~ASO 1 - ~ 'O ~Cys- I l Cl~
. .
, ' , - ' . ~ , , .
.
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, ' ' 26~ loo-43l4 EXP~MPLE 2:
-.
r - - _ H-(D)-Ala-Gly-Cys-Nle-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys- - :
~ asparaginol ; 0.4 g of the compound of Example A33 are dissolved in a mixture of methanol and 0.5& acetic acid, and the pH is adlusted to 6 by the addition of an~onium hydroxide solution with stirring. A 0.1 molar potassium ferricyanide solution is sLowly added with stirring until the yellow colouration romains. After stir*ing for a fur- ;
ther 15 minutes, the pH is adjusted to 4-5 with acetic acid. Filtration is effected through a short column of "BLo Rad AG" 3/x4 (Cl~ form) [- slightly basic anion ex-change resin]. The filtrate ls then allowed to flow slowly at 0 through a column with "Bio Rex 70"
, ~ .
(-COOH form) [- sllghtly acid cation exchange resin].
The column is then eluted with an acetic acid gradient with increasing concentrations of acetic acid or with an , :
acetic acid/pyridine grad~ent. The fractions containing the desired product are combined and lyophilLzed.
The lyophiIization product is dissolved ln a smalL amount of n-butanol/glacial acetic acld/water (2 : 1 : l) or ` 30~ acetic acid and purified by chromatography on ~; "Sephadex"G 25 in the ., :
.`,~ `` : :: :
:
: - 21 ~
* Trademark ** Trademark ' .
' , ~2~ 100-~31~
same mixtu.re. The frac-tions containing the desired product are combined and lyophilIzed, whereby the title compound is obtained.
[a] D- ~36 (c = l in 95% acetic acid).
The corresponding compounds having an S-S- bridge are produced in analogous manner from the corresponding compounds having a free SH function (E~amples l, A 1-', A 10-32, A 34-50).
' , . , -' '.
. ` ' ' ' ''` ~ '`':
` - 22 - ' ',:
~: .
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:
0~
The compounds of formula I exhibit pharmacologi-cal activity. In particular they inhibit growth hormone secretion, as indicated in standard tests.
Male rats anaesthetized with "Nembutal" are administered with the peptide by injection in the jugular vein. The rats are decapitated 15 minu~es after admini-stration, collecting the blood. The growth hormone concen-tration in the blood serum is determined in conventional manner by radio immunoassay.
The compounds are therefore indicated for use as agents for the inhibition of growth hormone secretion and possibly as agents ~or the treatment of Diabetes ~lellitus, Acromegaly and Angiopathy.
For this use an indicated daily dose is from , 15 about 0.07 to about 70 mg, conveniently admlnistered in `~ divided doses 2 to 4 times a day in unlt dosage form con-talning from about 0.02 to about 35 mg, or in sustained release form.
~he compounds of A29, A47 and A48 exhibit èspecially interesting activity.
The compounds of formula I may be administered in pharmaceutically accept~ble acid addition salt or com-plex~ form. Such acid addition salt or complex form exhibit ~-the same order of activity as the free base forms and are readily prepared in conventional manner.
, :
23 ~
; ~ * Irademark for pento~arbital, either ln the calcium or -~ sodium salt form; it is a hypnotic. l ~
. ~ ,.
~: : .
0~
100-431~
The present invention al50 provides A pharmaceutical composition comprising a compound of formula I, in free base form, in complex form, or in pharmaceutically acceptable acid addltion salt form, in association with a pharmaceutical carrier or diluent. Such compositions may be in the form of, for example, a tablet or a solution for injection or infusion, buffered e.g. at from pH 5 to 8.
The present invention also comprises pharma-ceutical preparations containing compounds of formula I, wherein Rl is H~(a-amino)-isobutyryl-NH- or H-(D)-Ala-N~I, X is-Lys; Y is~Asn7 Z is -CONR4R5 or -CO-N (CH2~4 or 5 Each B preferably signifies hydrogen.
, :~ -' . ' '"
~.., - .
~: .
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. . .
.
.
~4) refers to AcOH 40~ v/v (c = 1) (5) refers to AcOH 50% v/v (c = 1) - ~ ~
~, '.
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26~ 00~43l4 EXaMPLE 1:
a~O~
480 mg of Cbo-(4Cl)Phe -Cy5 (MB zl )-Lys(BOC)-Asn-Phe-Phe-Trp-Lys(Cbo)-Thr-Phe-Thr Ser-Cys(MBzl)-OBzl, 410 mg of H-Try-OH, 320 mg of H-Cys-OH.HCl and 1,2 cc of thio-anisole are dissolved at 0 in 5 cc of trifluoroacetic acid, and 10 cc of 2 molar boron tris(trifluoroacetate) ~-in trifluoroacetic acid are added. The mixture is shaken for one hour at room temperature and cooled. 50 cc of tert~butyl alcohol are added, concentration is efEected by evaporation, in a vacuum and a solution of 0.01 molar 2~mercaptoethanol in ether is added to the residue.
Centrifuging is subsequently effected. The solid residue ls dlssolved ~n a small amount of 10~ acetic acid and is :, . .
purified by chromatography on "Sephadex G" 25 in a sys-tem of 0.01 molar 2-mercaptoethanol in 10~ acetic acid.
The residue may also be dissolved in 30% acetic acid or in~a mixture of n-butanoljacetic acid/water (e.g. 4 and purlfied by chromatography on "Sephadex G" 25 using 0.01 M 2-mercaptoethanol in 30% acetic acid or in the mixture o~ n-butanoljacetlc acid/water. The fractions con-; taining the desired product are combined, dissvlved in ::
0.1 normal hydrochloric acid and lyophilized, whereby tlletitle compound is obtained.
M.Pt, 195 (decom~.); [~12 = -20.5 in AcO~ (c = 1).
The starting material ls produced as follows:
Trademark for a dry, unsoluble, powdered material derlved from dextran; lt is used in chromatography.
, , - , . . . . ~: ,.. . .
26e~L
100~4314 , ' :
a) Cbo-Lys(BOC)-Asn-Phe-OMe ________________________ 74.8 g of Cbo-Lys(BOC)-ONP are reacted in a solution of 51 g of H-Asn-Phe-OMe . HCl and 21 cc of triethylamine in 300 cc of dimethyl formamide. After working up, the title compound is obtained.
M.P. 175; [1 D= ~4 4 in dimethyl formamide (c = 1.0).
b) H-Lys(EOC)-Asn-Phe-OMe _______________ ~ 2 g of Cbo-Lys(BOC)-Asn-Phe-OMe are sus-pended in a solution of 2 liters of dioxane and 400 cc of water. Palladium charcoal is added and hydrogenation is effected at normal pressure. After working up, the title compound is obtained.
' M.P. 122; [] D- -8.3 in dimethyl formamide (c = 1.0).
:, c) Cbo-(4Cl)Phe-C~s (MB21) -~H-NH
____________ 2 20 g of H-Cys(MBzl)-OMe.CH3S03H and 7 cc of triethylamine are disso:Lved in 120 c~ of dimethyl formamide, and 18.2 g of Cbo-(4Cl)Phe-ONP are added.
.
The mixture is allowed to stand for 16 hours and is concentrated at room temperature, whereby Cbo-(4Cl)Phe-Cys(MBzl)-OMe (M.P. 115) is obtained after worXing up.
, -The latter is dissolved in methanol and hydrazinehydrate is added. The mixture is allowed to stand at room temperature for one day. The title compound is . ~ ~
': : , , . : :
- ~ 12 -'~
~ .
~ ~. . ., ~ .
~IL0~2~1 100~431 obtained after working up.
M.P. 158; [a~ OD= -9.9 in dimethyl formamide (c = 1).
d) Cbo-(4Cl)Phe-Cys(MB~l)-Lys(BOC)-Asn-Phe-NH-NH
____________~______-_-_ 2 6 g of Cbo-(4Cl)Phe-Cys(MBzl)-~H-NH2 are dissolved in 80 cc of dimethyl formamide, the solution is cooled to -20, 6 cc of 5.3 normal hydrochloric acid in dioxane are added and then 1.3 cc of tert.butyl nitxite are added and stirring is effected at -20 for - 10 minutes. After the addition of 5.5 cc of triethyl-amine at -20, 8.4 g of H-Lys(BOC)-Asn-Phe-OMe are added, the mixture is allowed to stand over night at 0, ..
concentration is effected, and water is added at 0 up to pH 2. The precipitate is filtered off and washed with water. The resulting Cbo-(4Cl)Phe-Cys(MBzl)-1 15 Lys(Boc)-~sn-Phe-OMe is recrystallized from methanol, :` is then dissolved in dimethyl formamide,and 7 cc of hydrazine hydrate are adaea. The mixture is allowed to stand at room temperature for one day, is con-centrated, and the residue is recrystalliæed from ~ .
methanol, whereby the title compound is obtained.
M.P. 260; [a] D- -23~ in dimethyl formamide (c = 1.0).
e) BOC-Lys(Cbo)-Thr-Phe-Thr-Ser-Cys(MBzl)-oBzl _____ _______________--_-------- .. ::
2.3 g of BOC-Lys(Cbo)-Thr-Phe-Thr-Ser-NH-NH2 are reacted with 1.86 g of H-Cys(MBzl)-OBzl in a : -.
''.. " ':
:
; 13 - :
: .
I
' : ~: ' ' , .
~ . , , , . ,.,.... .. ; ., . . , . . . ,, .,. - ..
- 11 09Z6iD1 100-~314 manner analogous to that described in section d), where-by the title compound is obtained.
M.P. L69~j [~¦ D- -16 in dimethyl formamide (c = 1).
f) BOC-Trp-Lys(Cbo)-Thr-Phe-Thr-Ser-Cys~MBzl)-OBzl ___________________._________________ ________._ 2.3 g of BOC-Lys(Cbo)-Thr-Phe-Thr-Ser-Cys(MBzl)-OBzl are dissolved in a mixture of 10 cc of methylene chloride and 6 cc of trifluoroacetic acid and the solution is allowed to stand at room temperature for 25 minutes. H-Lys(Cbo)-Thr-Phe-Thr-Ser-Cys(MBzl)-OBzl ~ trifluoroacetate is subsequently precipitated with ether, filtered off and washed out well with ether. The residue is dissolved in 7 cc of dimethyl formamide, l.5 g of BOC-Trp-OCP and 0.3 cc of triethylamine are added and the mixture is allowed to stand at room temperature over night. The product is precipitated with ether/ethyl acetate (l : l) and is filtered. Drying is effected, whereby the title com-pound is obtained.
,~ M.P. 167; [~ D- -17.5 in dimethyl formamide (c = l).
, 20 g) BOC-Phe-Tr~-Lys(Cbo)-Thr-Phe-Thr-Ser-Cys(MBzl)-oB
~ __ __ _~__ __________._ _________~_ __ _ _ ____ _ _ 36 g of BOC-Trp-~s(Cbo)-Thr-Phe-Thr-Ser-Cys(MBzl)-OBzl are reacted with 20 g of BOC-Phe-ONP
~ in a manner analogous to that described in section f);
,.~
. . .
' :` : '' .
, 1 ~`
.
2~
100-~314 the title compound is obtained.
M.P. 210; [~] D- 15 in dimethyl formamide (c = 1.0).
h) Cbo-(4Cl)Phe-Cys(MBzl)-~ys(Boc)-Asn-phe-phe-Tr ~ys(Cbo)-Thr-Phe-Thr-Ser-Cys(MBzl)-OBzl ~: ----_ _ _ _ _ _ _ _ _ _ 1.5 g of BOC-Phe-Trp-Lys(Cbo)-Thr-Phe-Thr-Ser-Cys(MBzl)-OBzl are dissolved in 30 cc of methylene chloride and 30 cc of trifluoroacetic acid.
The mixture is allowed to stand at room temperature for 25 minu-tes, is concentrated by evaporation in a vacuum and precipitated with ether. After filtration, washing with ether and drying, H-Phe-Trp-Lys(Cbo)-Thr-Phe-Thr-Ser-Cys(MBzl)-OBzl . trifluoroacetate is ob-tained.
0~9 g of Cbo-(4Cl)Phe-Cys(MBzl)-Lys(BOC)-Asn-Phe-NH-NH2 are dissolved in 20 cc of dimethyl formamide, the solution is cooled to -20~, 0.6 cc of 5.3 normal hydrochloric acid in dioxane are added and then 0.1 cc of tert.~utyl nitrite is added and the mixture is stirred at -20 for 15 minutes. 0.7 cc of triethylamine and 1.5 g of H-Phe-Trp-~ys(Cbo)-Thr-Phe-Thr-Ser-Cys(MBzl)-OBzl trifluoroacetate are added.
The mixture is allowed to stand at 0 over night, is concenkrated by evaporation in a vacuum, is stirred -:
with 100 cc of water, filtration is effected, the resi-. .
~ .
. .
, ~ - 15 -, ._ . :
.
. .. . . . . ~ . .
~ Z61)~
, due is washed with water and then wi-th methanol, heating : in methanol and filtration are effected, whereby the title compound is obtained.
M.P. 270; [a~ D- -19.3 in dimethyl formamide (c = 1).
', The following compoundSo~
formula A are obtained in analogous manner after building up the corresponding protected compounds and splitting off the protective group, .~' .
P-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Q A
. ~ .
~ ~ .
, ~ .
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100-~l31~
No. _ _ _ l~}~O
Al ~ NH-CO-Cys-Lys Asn .Cys-OH -17 2/
A2 ~ -NH-CO-Cys Lys-Gln Cys-OH 150 ~
~3 II-Tyr-Cys-Lys-Asn Cys-OH 160 /
. . -20.0 A4 NH2 ~ CO~Cys-Lys-Asn Cys-OH -19.Z~O
A5 ~ (CH2)3-CO-Cys-Lys-Asn Cys-O~I -33 1 A6 ~ (CH2)3-CO-Gly-Cys-Lys-Asn Cys-OH -27 7 ' . A7 ~ NH-CO-Gly-Cys-Lys-Asn Cys-OH -34 3 A8 H-Cys-Cys-Lys-~sn Cys-N~2 -24 5 ~ A9 H-Cys-Cys~Asn -Cys-NH2 -23 3 : ~ A10 H-Lys-Cys-Lys-Asn C~s-NH2 ~27.8 All ~I-(4Cl)Phe-Cys-Nle-Asn ~ Cys-NH2 170 A12 N-(4Cl)Phe-Cys-Lys-Asn Cys-NH -23 2 Z A13 H-Iabu-Cys-Lys-Asn : Cys-NH2 -21.0 A14 H-Iabu-Cys-Lys-Thr Cys-NH 165 /
~, 20.~
:`, ' : ' .
- ~
:', ~ :
260~
100-431~l .
Ex __ l~J2(/
~; ~ A15 ~ -(CH2)3-co-~cl)phe-cys~Lys-Asn Cys-NH2 -1~ 7/
: A16 ~ -(cH2)3-co-Gly-cys-Nle-Gln Cys-NH -1~.7 :~
Al ~ (CH2)3-C0-Cys-Lys Asn Cys NK _19 r~o ~ Al ~ NH-C0-Cys-Lys~Asn Cys-NH2 -25 3/~1) : A19 ~ NH-C0-Cys-Lys-Gln Cys--NH -29.5 - :
A2 ~ NH-CO~Cys-Nle-Asn Cys-NH~ -10.7 A21 ~ NH-C0-Gly-Cys-Nle-Gln Cys-NH2 1134/ ~:
, A2 ¦~H2-N~-C0-Cys Lys-Asn Cys-NH 130 /
: A2 ~ (CH2)3-CO-(D)Ala-Cys-Lys~Asn Cys-NH -13.7 ~:~ A24 8enzoyl-Cys-Nle-Asn Cys-NH lGO /
. A25 8enzoyl-~y5-Lys-Asn Cys-NH2 -37~9 A26 ~ C~-(4Cl)Phe-Cys-Nle-Asn Cys-NH
¦A27~h-~D)-Al -Gly-C s-Lys-Asn ¦ Cys-Val-NH2 ¦24270~(/2) ¦
A2 H-Ala-Gl~-Cys-Lys-Asn Cys-N ~ 210 /
,~ . -45(2) , j ~ - 18 ~
.. . .
, .
.: , .
,,_ ,r~ ~ ' ' ~9Z6(~ 100-4 31~
_ ~
Ex . _ Q [c~]20 _ ___ __ _~___ ~
A29 1~-(4Cl)Phe~Cys-Nle^Asn Cys-Asparagi- 155 / --; llol -22.5 A30 ~ abu-Cvs-Nle~Asn Cys~Asparayi- 150 /
nol -44.3 A31 Il--Iabu-Cys-Lys--Asn Cys-Asparagi- 160 /
nol- -~7.4 A32 H-(D)-Ala-Gly-Cys-Lys-Asn Cys-Aspara~i- 150 /
. nol -52.7 ~:-A33 H^(D)-~la~Gly Cys-Nle~Asn Cys-Asparagi- 165 / ~:
; . nol _49.50(1) A34 ~I-(D)~Val-Cys~Lys-Asn Cys-NH 175 /
. 47.0~
A35 ~ Phenylc3~ycyl)-Cys-Lys-Asn Cys-NH2 ~33 3 A36 H-(D)~Val-(4Cl)Phe-Cys Lys-Asn Cys-NH 165 /
~37 ~I-(D~-Ala-Cys-Lys-Asn Cys-NH ~30.9 i A3~ H~Cys~Lys-Asn Cys-NH 180 /
;l A39 Cyclohexy].acetyl-(D~-Val-Cys-Lys-Asn Cys-NH2 ~19.80(3) A40 Cyc].ohexylacetyl~ -Phenylglycyl)-Cys- Cys-NH 1~5 /
Lys Asn -19.~(5 A41 Cyclohexylacetyl~(D)-Val-(4Cl)Phe-Cys- Cys-NH 165 /
Lys-Asn 2 -23.70~3) A42 8~nzoyl-(3,~-dichlo~^o~Phe-Cys-I.ys-P.sn Cys-NE~2 -22 5/(~) -:.
: A~ 3 Renzoyl- ( 3, 4 -dichloro) Phe-Cys-Nle-~sn Cys-NH -2~.So(4) ,~ . , .~ A44 H-(D)-Ala-Gly-Cys-Nle-Asn Cys~NH ~23.90(4) , ~ , `1 ~ ' '''.,.. ' ,''' ~ ' , .
~' ~ ' `' .
z~
: No, . ~ ~ I )2 ~ . _ _ ._ ~45 H-(D)-Phe-Cys-Nle-Asn Cys-NH -29 1(3 A46 H-Phe~Cys-Nle-Asn Cys-NH2 1730~/(3 . . ~47 H-(3Cl)Phe-Cys~Nle-Asn Cys Asparagi- 165 /
: . nol _35,0(3 A~ H-(2Cl)Phe-Cys-Nle~Asn Cys-~sparagi- 170 /
. nol -29.8(3 A49 H-(3,~diCl)Phe-Cys-Nle-Asn Cys-Asparagi- 162 /
. nol CH2-l=0 -25,5(3 :.
~ASO 1 - ~ 'O ~Cys- I l Cl~
. .
, ' , - ' . ~ , , .
.
~ ' ' . . . ' .
'`' . , "
, .
.
., ' :
-.'`~, . . .. .
- :, ,.
~ ~ .'''' '.
- - 20 - .
,, , .::
, ' ' 26~ loo-43l4 EXP~MPLE 2:
-.
r - - _ H-(D)-Ala-Gly-Cys-Nle-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys- - :
~ asparaginol ; 0.4 g of the compound of Example A33 are dissolved in a mixture of methanol and 0.5& acetic acid, and the pH is adlusted to 6 by the addition of an~onium hydroxide solution with stirring. A 0.1 molar potassium ferricyanide solution is sLowly added with stirring until the yellow colouration romains. After stir*ing for a fur- ;
ther 15 minutes, the pH is adjusted to 4-5 with acetic acid. Filtration is effected through a short column of "BLo Rad AG" 3/x4 (Cl~ form) [- slightly basic anion ex-change resin]. The filtrate ls then allowed to flow slowly at 0 through a column with "Bio Rex 70"
, ~ .
(-COOH form) [- sllghtly acid cation exchange resin].
The column is then eluted with an acetic acid gradient with increasing concentrations of acetic acid or with an , :
acetic acid/pyridine grad~ent. The fractions containing the desired product are combined and lyophilLzed.
The lyophiIization product is dissolved ln a smalL amount of n-butanol/glacial acetic acld/water (2 : 1 : l) or ` 30~ acetic acid and purified by chromatography on ~; "Sephadex"G 25 in the ., :
.`,~ `` : :: :
:
: - 21 ~
* Trademark ** Trademark ' .
' , ~2~ 100-~31~
same mixtu.re. The frac-tions containing the desired product are combined and lyophilIzed, whereby the title compound is obtained.
[a] D- ~36 (c = l in 95% acetic acid).
The corresponding compounds having an S-S- bridge are produced in analogous manner from the corresponding compounds having a free SH function (E~amples l, A 1-', A 10-32, A 34-50).
' , . , -' '.
. ` ' ' ' ''` ~ '`':
` - 22 - ' ',:
~: .
,; ' ` '. ~ .
, ~ :
:
0~
The compounds of formula I exhibit pharmacologi-cal activity. In particular they inhibit growth hormone secretion, as indicated in standard tests.
Male rats anaesthetized with "Nembutal" are administered with the peptide by injection in the jugular vein. The rats are decapitated 15 minu~es after admini-stration, collecting the blood. The growth hormone concen-tration in the blood serum is determined in conventional manner by radio immunoassay.
The compounds are therefore indicated for use as agents for the inhibition of growth hormone secretion and possibly as agents ~or the treatment of Diabetes ~lellitus, Acromegaly and Angiopathy.
For this use an indicated daily dose is from , 15 about 0.07 to about 70 mg, conveniently admlnistered in `~ divided doses 2 to 4 times a day in unlt dosage form con-talning from about 0.02 to about 35 mg, or in sustained release form.
~he compounds of A29, A47 and A48 exhibit èspecially interesting activity.
The compounds of formula I may be administered in pharmaceutically accept~ble acid addition salt or com-plex~ form. Such acid addition salt or complex form exhibit ~-the same order of activity as the free base forms and are readily prepared in conventional manner.
, :
23 ~
; ~ * Irademark for pento~arbital, either ln the calcium or -~ sodium salt form; it is a hypnotic. l ~
. ~ ,.
~: : .
0~
100-431~
The present invention al50 provides A pharmaceutical composition comprising a compound of formula I, in free base form, in complex form, or in pharmaceutically acceptable acid addltion salt form, in association with a pharmaceutical carrier or diluent. Such compositions may be in the form of, for example, a tablet or a solution for injection or infusion, buffered e.g. at from pH 5 to 8.
The present invention also comprises pharma-ceutical preparations containing compounds of formula I, wherein Rl is H~(a-amino)-isobutyryl-NH- or H-(D)-Ala-N~I, X is-Lys; Y is~Asn7 Z is -CONR4R5 or -CO-N (CH2~4 or 5 Each B preferably signifies hydrogen.
, :~ -' . ' '"
~.., - .
~: .
-;:
- 24 - ~
. . .
.
.
Claims (6)
1. A process for the production of a compound of formula I, wherein R1 is (i) H, (ii) NH2, (iii) H-Ala-NH-;
H-Tyr-NH-;
H-Cys-NH-;
H-Val-NH-;
H-Lys-NH-;
H-(.alpha.-amino-isobutyryl)-NH-;
H-Phe-NH-;
(iv) NH2-NH-CO-NH-;
(v) C6H5.NH-CO-Gly-NH-;
H-Ala-Gly-NH-;
H-Val-Gly-NH-;
H-.alpha.-phenyl-Gly-NH-;
(vi) R2-A-CO-NH, wherein R2 is lower alkyl, phenyl, or phenyl substituted by halogen, hydroxy, amino, lower alkyl or lower alkoxy, A is a direct bond, alkylene con-taining up to 6 carbon atoms or -NH-, (vii) R2-Ala-NH-;
R2-Ala-Gly-NH-;
wherein R2 is as defined above, (viii) C6H5.AI.CO-M-NH-, wherein AI is an alkylene chain of up to 6 carbon atoms, and -M- is -(mono- or di-Hal)-Phe, -Gly- or -Ala-, (ix) T-(mono- or di-Hal)-Phe-NH-, wherein T- is H-, H-Val- or benzoyl-, (X) , wherein AI is as defined above, and -L- is -Val-, -Val-(mono- or di-Hal)-Phe-, -.alpha.-phenyl-Gly-, and n is an integer between 4 and 10, each B is hydrogen or the two radicals B form a direct bond, X is -Lys-, -Nle- or -Cys-, and Y is -Asn-, -Gln- or -Thr-, and Z signifies the radicals (i) H; (ii) COOH;
(iii) COOR3 (wherein R3 is lower alkyl);
(iv) -CO-NR4R5 (wherein R4 and R5 independently are hydrogen or lower alkyl); (v) (wherein n is as defined above); (vi) CH2OH;
(vii) -CO-asparaginol; -CO-leucinol; -CO-iso-leucinol; -CO-valinol; -CO-norleucinol;
-CO-glutaminol; -CO-threoninol; (viii) -CO-Leu;
-CO-Ser; -CO-Iso-Leu; -CO-Val, and their corresponding amides, wherein the amide portion signifies the radical -CO-NR4R5 or (wherein n, R4 and R5 are as defined above), or (ix) -CO-ThrOR3 or -CO-SerOR3 (wherein R3 is as defined above);
(x) -CO-NH-(CH2)k-OH (wherein k is an integer between 2 and 6), or wherein l1 and l2 independently signify a whole number from 1 to 6; (xi) ;
(xii) -CO-NH-R6 (wherein R6 is a 5- or 6-membered saturated heterocyclic ring containing an oxygen atom as a ring member, or a 5- or 6-membered lactone ring), wherein in formula I
the unit containing radicals R1, X, Y and Z, as well as in the remaining units or the peptide sequence, at least one unit may be present in D form, with the provisos that when X is Lys and Y is Asn, and all the remaining units of the peptide sequence 3 to 14 are present in the D or L form, and when (i) R1 is H-Ala-Gly-NH- or H-(D)-Ala-Gly-NH-, Z is other than COOH, COOR3, CH2OH or CONR4R5, or, when (ii) R1 is H, NH2 or H-(D)-Ala-Gly-NH-, Z is other than H, COOH, CONR4R5 or or 5' or, when (iii) R1 is H-(.alpha.-amino-isobutyryl)-NH- or H-(D)-Ala-NH-, Z is other than H or COOH, or, when (iv) R1 is H-Ala-Gly-NH-, Z is other than H, or, when (v) R1 is H-Ala-NH- or R?-CO-NH-(wherein R2 is lower alkyl or unsubstituted phenyl), Z is other than COOH, and with the further proviso that when R1 is H-Cys-NH or H-(D)-Cys-NH and/or X is -Cys- or (D)-Cys, B-B is other than a direct bond, which comprises a) removing at least one protective group from a pro-tected peptide having the sequence indicated in for-mula I, or b) linking together by an amide bond two peptide units, each of which contains at least one amino acid and which is in protected or unprotected form, the pep-tide units being such that the amino acid sequence given in formula I is obtained, and then if necessary carrying out process step a), or c) converting one group Z of an unprotected or protected peptide of formula I into another group Z having the definition indicated above, and if necessary carrying out process step a), or d) oxidizing a peptide of formula I wherein B is hydrogen, to produce a peptide of formula I wherein B-B is a direct bond.
H-Tyr-NH-;
H-Cys-NH-;
H-Val-NH-;
H-Lys-NH-;
H-(.alpha.-amino-isobutyryl)-NH-;
H-Phe-NH-;
(iv) NH2-NH-CO-NH-;
(v) C6H5.NH-CO-Gly-NH-;
H-Ala-Gly-NH-;
H-Val-Gly-NH-;
H-.alpha.-phenyl-Gly-NH-;
(vi) R2-A-CO-NH, wherein R2 is lower alkyl, phenyl, or phenyl substituted by halogen, hydroxy, amino, lower alkyl or lower alkoxy, A is a direct bond, alkylene con-taining up to 6 carbon atoms or -NH-, (vii) R2-Ala-NH-;
R2-Ala-Gly-NH-;
wherein R2 is as defined above, (viii) C6H5.AI.CO-M-NH-, wherein AI is an alkylene chain of up to 6 carbon atoms, and -M- is -(mono- or di-Hal)-Phe, -Gly- or -Ala-, (ix) T-(mono- or di-Hal)-Phe-NH-, wherein T- is H-, H-Val- or benzoyl-, (X) , wherein AI is as defined above, and -L- is -Val-, -Val-(mono- or di-Hal)-Phe-, -.alpha.-phenyl-Gly-, and n is an integer between 4 and 10, each B is hydrogen or the two radicals B form a direct bond, X is -Lys-, -Nle- or -Cys-, and Y is -Asn-, -Gln- or -Thr-, and Z signifies the radicals (i) H; (ii) COOH;
(iii) COOR3 (wherein R3 is lower alkyl);
(iv) -CO-NR4R5 (wherein R4 and R5 independently are hydrogen or lower alkyl); (v) (wherein n is as defined above); (vi) CH2OH;
(vii) -CO-asparaginol; -CO-leucinol; -CO-iso-leucinol; -CO-valinol; -CO-norleucinol;
-CO-glutaminol; -CO-threoninol; (viii) -CO-Leu;
-CO-Ser; -CO-Iso-Leu; -CO-Val, and their corresponding amides, wherein the amide portion signifies the radical -CO-NR4R5 or (wherein n, R4 and R5 are as defined above), or (ix) -CO-ThrOR3 or -CO-SerOR3 (wherein R3 is as defined above);
(x) -CO-NH-(CH2)k-OH (wherein k is an integer between 2 and 6), or wherein l1 and l2 independently signify a whole number from 1 to 6; (xi) ;
(xii) -CO-NH-R6 (wherein R6 is a 5- or 6-membered saturated heterocyclic ring containing an oxygen atom as a ring member, or a 5- or 6-membered lactone ring), wherein in formula I
the unit containing radicals R1, X, Y and Z, as well as in the remaining units or the peptide sequence, at least one unit may be present in D form, with the provisos that when X is Lys and Y is Asn, and all the remaining units of the peptide sequence 3 to 14 are present in the D or L form, and when (i) R1 is H-Ala-Gly-NH- or H-(D)-Ala-Gly-NH-, Z is other than COOH, COOR3, CH2OH or CONR4R5, or, when (ii) R1 is H, NH2 or H-(D)-Ala-Gly-NH-, Z is other than H, COOH, CONR4R5 or or 5' or, when (iii) R1 is H-(.alpha.-amino-isobutyryl)-NH- or H-(D)-Ala-NH-, Z is other than H or COOH, or, when (iv) R1 is H-Ala-Gly-NH-, Z is other than H, or, when (v) R1 is H-Ala-NH- or R?-CO-NH-(wherein R2 is lower alkyl or unsubstituted phenyl), Z is other than COOH, and with the further proviso that when R1 is H-Cys-NH or H-(D)-Cys-NH and/or X is -Cys- or (D)-Cys, B-B is other than a direct bond, which comprises a) removing at least one protective group from a pro-tected peptide having the sequence indicated in for-mula I, or b) linking together by an amide bond two peptide units, each of which contains at least one amino acid and which is in protected or unprotected form, the pep-tide units being such that the amino acid sequence given in formula I is obtained, and then if necessary carrying out process step a), or c) converting one group Z of an unprotected or protected peptide of formula I into another group Z having the definition indicated above, and if necessary carrying out process step a), or d) oxidizing a peptide of formula I wherein B is hydrogen, to produce a peptide of formula I wherein B-B is a direct bond.
2. A compound of formula I as defined in Claim 1, whenever produced by a process as claimed in Claim 1, or by an obvious chemical equivalent thereof.
3. A process according to Claim 1 wherein, in the compound of the formula I, when X is Lys and Y is Asn, Z is selected from the radicals defined under (vii), (viii), (ix) and (x).
4. A compound according to Claim 2 wherein, in the compound of formula I, when X is Lys and Y is Asn, Z
is selected from the radicals defined under (vii), (viii), (ix) and (x), whenever prepared by the process of Claim 3 or by an obvious chemical equivalent thereof.
is selected from the radicals defined under (vii), (viii), (ix) and (x), whenever prepared by the process of Claim 3 or by an obvious chemical equivalent thereof.
5. A process according to Claim 3 wherein,in the compound of the formula I, R1 is H-(HCl)Phe-NH-, H-(3Cl)Phe-NH-, H-(2Cl)Phe-NH- or H-(3,4-diCl)Phe-NH-, each B is hydrogen, X is -Nle, Y is Asn- and Z is CO-Asparaginol.
6. A compound according to Claim 2 wherein, in the compound of formula I, R1 is H-(HCl)Phe-NH-, H-(3Cl)Phe-NH-, H-(2Cl)Phe-NH- or H-(3,4-diCl)Phe-NH-, each B is hydrogen, X is -Nle, Y is Asn- and Z is CO-Asparaginol, whenever prepared by the process of Claim 5 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (18)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH305575 | 1975-03-11 | ||
CH3055/75 | 1975-03-11 | ||
CH3572/75 | 1975-03-20 | ||
CH357275 | 1975-03-20 | ||
CH1061075 | 1975-08-14 | ||
CH10610/75 | 1975-08-14 | ||
CH12282/75 | 1975-09-22 | ||
CH1228275 | 1975-09-22 | ||
CH12586/75 | 1975-09-29 | ||
CH1258675 | 1975-09-29 | ||
CH1511775 | 1975-11-21 | ||
CH15119/75 | 1975-11-21 | ||
CH1511875 | 1975-11-21 | ||
CH15117/75 | 1975-11-21 | ||
CH1511975 | 1975-11-21 | ||
CH15118/75 | 1975-11-21 | ||
CH15252/75 | 1975-11-25 | ||
CH1525275 | 1975-11-25 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1092601A true CA1092601A (en) | 1980-12-30 |
Family
ID=27575775
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA247,515A Expired CA1092601A (en) | 1975-03-11 | 1976-03-10 | Derivatives of somatostatin |
Country Status (13)
Country | Link |
---|---|
JP (1) | JPS51115467A (en) |
AU (1) | AU509661B2 (en) |
CA (1) | CA1092601A (en) |
DE (1) | DE2608336A1 (en) |
FI (1) | FI760539A (en) |
FR (1) | FR2303560A1 (en) |
GB (1) | GB1546517A (en) |
IE (1) | IE44284B1 (en) |
IL (1) | IL49180A (en) |
NL (1) | NL7602395A (en) |
NO (1) | NO760707L (en) |
NZ (1) | NZ180247A (en) |
PT (1) | PT64881B (en) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4104267A (en) * | 1977-02-22 | 1978-08-01 | American Home Products Corporation | Somatostatin analogs |
GB1596329A (en) * | 1977-04-21 | 1981-08-26 | Lilly Co Eli | Tetradeca peptides |
US4100117A (en) * | 1977-04-21 | 1978-07-11 | Eli Lilly And Company | Somatostatin analogs and intermediates thereto |
US4118380A (en) * | 1977-07-25 | 1978-10-03 | Ayerst, Mckenna & Harrison Limited | Decapeptide analogs of somatostatin |
US4244947A (en) * | 1979-08-13 | 1981-01-13 | Ayerst Mckenna And Harrison Inc. | Carba decapeptide derivatives of [TYR6 ]-somatostatin |
DK81082A (en) * | 1981-03-06 | 1982-09-07 | Sandoz Ag | PROCEDURE FOR PREPARING POLYPEPTIDES |
JPS57183797A (en) * | 1981-05-06 | 1982-11-12 | Yamanouchi Pharmaceut Co Ltd | Straight and purely short-chain peptide and its preparation |
EP0084540A4 (en) * | 1981-07-17 | 1985-04-24 | John Trevor Rice | A motor-pump assembly. |
US4485101A (en) * | 1983-10-11 | 1984-11-27 | Administrators Of The Tulane Educational Fund | Peptides |
CN102558001B (en) | 2007-05-22 | 2015-09-23 | 惠氏有限责任公司 | Manufacture the modification method of hydrazides |
CA2870356A1 (en) * | 2012-04-16 | 2013-10-24 | Allergan, Inc. | (2-ureidoacetamido)alkyl derivatives as formyl peptide receptor 2 modulators |
-
1976
- 1976-03-01 DE DE19762608336 patent/DE2608336A1/en not_active Withdrawn
- 1976-03-02 FI FI760539A patent/FI760539A/fi not_active Application Discontinuation
- 1976-03-03 NO NO760707A patent/NO760707L/no unknown
- 1976-03-08 NL NL7602395A patent/NL7602395A/en not_active Application Discontinuation
- 1976-03-09 GB GB9313/76A patent/GB1546517A/en not_active Expired
- 1976-03-09 PT PT64881A patent/PT64881B/en unknown
- 1976-03-09 IE IE493/76A patent/IE44284B1/en unknown
- 1976-03-09 IL IL49180A patent/IL49180A/en unknown
- 1976-03-09 NZ NZ180247A patent/NZ180247A/en unknown
- 1976-03-10 JP JP51025198A patent/JPS51115467A/en active Pending
- 1976-03-10 FR FR7606828A patent/FR2303560A1/en active Granted
- 1976-03-10 CA CA247,515A patent/CA1092601A/en not_active Expired
- 1976-03-11 AU AU11893/76A patent/AU509661B2/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
GB1546517A (en) | 1979-05-23 |
PT64881A (en) | 1976-04-01 |
IL49180A0 (en) | 1976-05-31 |
AU1189376A (en) | 1977-09-15 |
NL7602395A (en) | 1976-09-14 |
FR2303560B1 (en) | 1978-11-17 |
DE2608336A1 (en) | 1976-09-30 |
AU509661B2 (en) | 1980-05-22 |
IE44284L (en) | 1976-09-11 |
PT64881B (en) | 1977-11-17 |
FR2303560A1 (en) | 1976-10-08 |
NO760707L (en) | 1976-09-14 |
IE44284B1 (en) | 1981-10-07 |
NZ180247A (en) | 1978-09-25 |
FI760539A (en) | 1976-09-12 |
IL49180A (en) | 1980-12-31 |
JPS51115467A (en) | 1976-10-12 |
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