DE3937539A1 - Somatostatin and its analogues or derivs. - used for protection against lung damage, esp. respiratory distress syndrome or damage caused by oxygen therapy - Google Patents

Abstract

The use of natural somatostatin (I), or a (I)-analogue or deriv., in free form or as pharmaceutically acceptable salts or complexes, for protecting against acute lung damage is new. Octreolide of formula (Na) is pref. for parenteral admin. Derivs of (IVa) substd. on the N-terminal amino gp. by N-alpha-(alpha-glucosyl(1-4) deoxyfructosyl) or N-alpha-(beta-deoxyfructosyl ) are pref. for oral admin. USE/ADVANTAGE - The cpds. are esp used to prevent, inhibit or treat respiratory distress syndrome in children and adults, and to inhibit or treat lung damage caused by oxygen therapy. Opt. they are formulated with a glucocorticoid steroid, and the dose of (I) is typically 0.05-1mg subcutaneously or 0.3-5mg orally, per day. (I) and derivs. are already known to inhibit release of growth hormone, insulin and glucagon, and to reduce gastric secretions.

Description

The invention relates primarily to a new use of Compounds from the group of natural somatostatin and Somatostatin analogues and derivatives thereof in free form or in the form of a pharmaceutically acceptable salt or Complex, and these connections become collective below referred to as compounds of the invention.

Somatostatin is a tetradecapeptide that is a cyclic dodeca peptide of the structure

contains and has the property of releasing growth Inhibit hormone, insulin and glucagon and gastric secretions to humiliate.

Taking a somatostatin analog or a derivative thereof any straight chain or cyclic polypeptide herein stood, that of the naturally occurring tetradecapeptide Soma tostatin is derived in which one or more amino acid units  omitted and / or by one or more other amino residues are and / or in which one or more functional groups are replaced by one or more other functional groups and / or one or more groups by one or more others isosteric groups are exchanged. The terms analog or derivative also include the corresponding peptides that carry a sugar residue. In general, of these Be attacked all modified derivatives of a biologically active Peptide, which has a qualitatively similar effect to that has unmodified somatostatin peptide, namely the Capable ability to bind to somatostatin receptors and to inhibit Secretion of growth hormone (GH).

Cyclic, bridge cyclic and straight chain somatostatin analogues or derivatives thereof are already known and will be put together with processes for their preparation, for example described in US-A 43 10 518, US-A 42 35 886, EP-A 00 01 295, EP-A 00 29 310, EP-A 00 29 579, EP-A 00 63 308, EP-A 00 70 021, EP-A 02 15 171, EP-A 0 02 03 031, EP-A 02 14 872, EP-A 01 43 307, EP-A 02 98 732, EP-A 02 77 419 and BE-A 9 00 089.

If the compounds of the invention carry a sugar residue, then this is preferably bound to an amino group thereof, the does not correspond to a direct N-glycosidic bond, namely preferably to an N-terminal amino group and / or at least one amino present in a peptide side chain group, in particular an N-terminal amino group. Such ver bindings and their manufacture are described, for example, in WO 88/02756.

The following compounds of the invention are preferred:

A. Natural somatostatin. B. Compounds of formula I to III

wherein
W is S or (CH₂) _s wherein s is 0, 1 or 2;
the symbol X or ZS and the other S or CH₂;
Y is S or (CH₂) _{t is} 0, 1 or 2
R₁ and R₂ each independently of one another alkyl having 1 to 5 carbon atoms, optionally substituted by one or two alkyl having 1 to 5 carbon atoms, halogen, hydroxy, amino, nitro and / or alkoxy having 1 to 5 carbon atoms or benzyl alkyl with 1 to 5 carbon atoms substituted by a 5- or 6-membered heterocyclic ring,
R₃ optionally substituted by alkyl with 1 to 5 carbon atoms, alkoxy with 1 to 5 carbon atoms or halogen 3-indolylmethyl,
R₄ alkyl with 1 to 5 carbon atoms, hydroxyalkyl with 1 to 5 carbon atoms, alkoxycarbonyl with 2 to 6 carbon atoms, amino alkyl with 1 to 5 carbon atoms or optionally by alkyl with 1 to 5 carbon atoms, halogen , Hydroxy, amino, nitro and / or alkoxy with 1 to 5 carbon atoms substituted benzyl and
R₅ is alkyl with 1 to 5 carbon atoms, or benzyl optionally substituted by alkyl with 1 to 5 carbon atoms, halogen, hydroxyl, amino, nitro and / or alkoxy with 1 to 5 carbon atoms.

As examples of alkyl with 1 to 5 carbon atoms, methyl, Ethyl, propyl, isopropyl, butyl, sec-butyl and pentyl in Come into consideration. Alkoxy with 1 to 5 carbon atoms can for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, be tert-butoxy and pentoxy. Halogen turns fluorine, Chlorine, bromine or iodine understood. 5- or 6-membered hetero cyclic rings are preferably those that are 1 or 2 acidic contain substance, nitrogen and / or sulfur atoms, such as for example imidazole, furan, thiazole, pyrazole and pyridine.  

The compounds of formulas I, II and III can be several have asymmetric carbon atoms, which leads to the formation of optical isomers leads. Any asymmetrical center in the Amino acids that can form these cyclic hexapeptides available in D or L configuration.

The following formulas are typical cyclic hexapeptide analogs of somatostatin of formulas I, II and III:

Preferred compounds of formula I are

1) Cyclo- (N-Me-Ala-Tyr-D-Trp-Lys-Thr-Phe)
2) Cyclo- (N-Me-Ala-Phe-D-Trp-Lys-Thr-Phe)
3) Cyclo- (N-Me-Ala-Phe-L-Trp-Lys-Thr-Phe)
4) Cyclo- (N-Me-Ala-Phe-D-Trp-Lys-Thr-p-Cl-Phe)
5) Cyclo- (N-Me-Ala-Phe-D-5-F-Trp-Lys-Thr-Phe)
6) Cyclo- (N-Me-Ala-Phe-L-5-F-Trp-Lys-Thr-Phe)
7) Cyclo- (N-Me-Ala-Phe-D-Trp-Lys-Ser-Phe)
8) Cyclo- (N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe)
9) Cyclo- (N-Me-Ala-Tyr-D-Trp-Lys-Val-Trp)
10) Cyclo- (N-Me-Ala-Tyr-L-Trp-Lys-Val-Phe)
11) Cyclo- (Ser-Ala-N-Me-Phe-His-D-Trp-Lys)

Preferred compounds of formula II are:

12) Cyclo- (Pro-Tyr-D-Trp-Lys-Thr-Phe)
13) Cyclo- (Pro-Phe-D-Trp-Lys-Thr-Phe)
14) Cyclo- (Pro-Phe-L-Trp-Lys-Thr-Phe)
15) Cyclo- (Pro-Phe-D-Trp-Lys-Thr-p-Cl-Phe)
16) Cyclo- (Pro-Phe-D-5-F-Trp-Lys-Thr-Phe)
17) Cyclo- (Pro-Phe-L-5-F-Trp-Lys-Thr-Phe)
18) Cyclo- (Pro-Phe-D-Trp-Lys-Ser-Phe)

Preferred compounds of formula III are:

C. Compounds of Formula IV

wherein
A represents alkyl having 1 to 12 carbon atoms, phenylalkyl having 7 to 10 carbon atoms or a group of the formula RCO-,
in which
i) R is hydrogen, alkyl having 1 to 11 carbon atoms, phenyl or phenylalkyl having 7 to 10 carbon atoms, or
ii) RCO-
a) an L- or D-phenylalanine radical optionally substituted in the ring by fluorine, chlorine, bromine, NO₂, NH₂, OH, alkyl with 1 to 3 C atoms and / or alkoxy with 1 to 3 C atoms,
b) the remainder of a natural or synthetic α -amino acid or a corresponding D-amino acid other than that defined above under a), or
c) a dipeptide residue, in which the individual amino acid residues are identical or different and are selected from the residues defined under a) and / or b) above, where the α- amino group of the amino acid residues a) and b) and the N- terminal amino group of the dipeptide radical c) optionally mono- or di-alkylated by alkyl having 1 to 12 carbon atoms or substituted by alkanoyl having 1 to 8 carbon atoms,
A ′ represents hydrogen or, if A denotes alkyl with 1 to 12 C atoms or phenylalkyl with 7 to 10 C atoms, also stands for alkyl with 1 to 12 C atoms or phenylalkyl with 7 to 10 C atoms,
Y₁ and Y₂ independently of one another for hydrogen, or

where m is an integer from 1 to 4
R _a CH₃ or C₂H₅ and
R _{b is} H, CH₃ or C₂H₅, or

wherein n is an integer from 1 to 5, or

3) -CO-NHR _c

wherein R _{c is} a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, or

wherein
R _{d is} the residue of the α -C atom of a natural or synthetic α- amino acid (incl. Hydrogen) and
R _{e represents} an alkyl radical with 1 to 5 carbon atoms,

wherein R ' _a and R' _{b are} independently hydrogen, CH₃ or C₂H₅
R₈ and R₉ independently of one another hydrogen, halogen, alkyl with 1 to 3 C atoms or alkoxy with 1 to 3 C atoms
p is 0 or 1, q is 0 or 1 and r is 0, 1 or 2,
or Y₁ and Y₂ together represent a bond,
B for Phe or in the phenyl radical substituted by halogen, NO₂, NH₂, OH, alkyl having 1 to 3 C atoms or alkoxy having 1 to 3 C atoms, or naphthyl ala
C for L- or D-Trp optionally substituted in the benzene ring by halogen, NO₂, NH₂, OH, alkyl having 1 to 3 C atoms or alkoxy having 1 to 3 C atoms, it being possible for the α- amino group to be substituted by methyl
D for Lys, Lys which contains O or S in the β position in the side chain, ThiaLys, γ F-Lys or δ F-Lys, where the α- amino group can be substituted by methyl, or 4-aminocyclohexylAla or 4-aminocyclohexylGly
E for Thr, Ser, Val, Phe, Tyr, Ile or an amino butter acid or amino isobutyric acid residue
F for COOR₇, CH₂OR₁₀, CO-NR₁₁R₁₂ or

R₇ for hydrogen or alkyl with 1 to 3 carbon atoms
R₁₀ for hydrogen or the rest of a physiologically acceptable, physiologically hydrolyzable ester
R₁₁ represents hydrogen, alkyl having 1 to 3 C atoms, phenyl or phenylalkyl having 7 to 10 C atoms, but if R₁₂ represents -CH (R₁₃) -X₁, only hydrogen or methyl
R₁₂ for hydrogen, alkyl with 1 to 3 carbon atoms or

R₁₃ for the residue of the α -C atom of a natural union or synthetic amino acid (including hydrogen) or for a CH₂OH, HO-CH₂-CH₂-, HO (CH₂) ₃- or -CH (CH₃) OH residue,
X₁ for COOR₇, CH₂OR₁₀ or

R₁₄ for hydrogen or alkyl having 1 to 3 carbon atoms
R₁₅ for hydrogen, alkyl with 1 to 3 carbon atoms, phenyl or phenylalkyl with 7 to 10 carbon atoms, and
R₁₆ represent hydrogen or hydroxy,
where the radicals B, D and E in L-form and the radicals in positions 2 and 7 and the radicals Y₁4) and Y₂4) can be in D- or L-form,
as well as the salts and complexes of these polypeptide derivatives.

In the present formula IV, "halogen" stands for fluorine, Chlorine or bromine.

In the compounds of formula IV, the following are interpretations either individually or in any combination or sub-combination preferred:

• 1. The radical A is C₇-C₁₀-phenylalkyl, especially phenethyl, or a group of the formula RCO. A is preferably a group of the formula RCO.
  • 1.1. The radical R is preferably C₁-C₁₁-alkyl or C₇-C₁₀-phenylalkyl, in particular C₇-C₁₀-phenylalkyl, especially phen ethyl or RCO has the meanings given above under a), b) or c).
  • 1.2. If RCO has the meanings a), b) or c), then the α- amino group of the amino acid residues a) and b) and the N-terminal amino group dipeptide residues c) are preferably not alkylated or monoalkylated by C₁-C₁₂-alkyl, in particular by C₁ -C₈ alkyl monoalkylated and preferably monoalkylated by methyl. Above all, the N-terminal amino group is not alkylated.
  • 1.3. If RCO has the meaning a) above, then this is preferably a ') an L- or D-phenylalanine or L- or D-tyrosine residue, which is optionally monoalkylated by C₁-C₁₂-alkyl. In particular, a ') is an L- or D-phenylalanine residue or an L- or DN- (C₁-C₈-alkyl) - phenylalanine residue. Above all, a ') represents a D-phenylalanine residue or DN- (C₁-C₈-alkyl) -phenylalanine residue, and primarily a D-phenylalanine residue or D- (N-methyl) -phenyl alanine residue.
  • 1.4. If RCO has the meanings b) or c), the respective radical is preferably lipophilic. Preferred radical b) are therefore b ′) a -amino acid residues with a hydrocarbon side chain, such as an alkyl group with 3, preferably with 4, and in particular with more carbon atoms, such as with up to 7 carbon atoms, a naphthylmethyl group or a heteroaryl group, for example a 3- (2-Naphthyl) alanine residue, 3- (1-naphthyl) alanine residue or tryptophan residue, these residues having the L configuration or the D configuration, and preferred residues c) are dipeptide residues in which the individual amino acid residues are identical or are different and selected from the radicals defined above under a ′) and b ′).
    An example of a residue c) is the 3- (2-naphthyl) alanine residue.
  • 1.5. In particular, RCO has the meaning a), and above all the meaning a ′).
• 2. B represents B ′, where B ′ means Phe or Tyr.
• 3. C represents C ', where C' represents (D) Trp.
• 4. D is D ', where D' stands for Lys, MeLys or Lys ( ε -Me), and especially Lys.
• 5. E is E ', where E' is Val or Thr, especially Thr.
• 6. F is F ', where F' is a group of the formula means and in particular a group of the formula represents (where R₁₁ is H or CH₃).
  In this case, the rest -CH (R₁₃) -X₁ preferably has the L configuration.
  • 6.1. The rest R₁₁ is preferably hydrogen.
  • 6.2. As a substituent which is attached to the α- carbon atom of a natural amino acid (namely an amino acid of the formula H₂N-CH (R₁₃) -COOH), R₁₃ is preferably -CH₂OH, -CH (CH₃) -OH, isobutyl or butyl, or is R₁₃ for - (CH₂) ₂-OH or - (CH₂) ₃-OH. The rest R₁₃ mainly means -CH₂OH or -CH (CH₃) OH.
  • 6.3. The radical X₁ is preferably a group of the formula or -CH₂-OR₁₀, and in particular of the formula -CH₂OR₁₀, wherein R₁₀ is preferably hydrogen or has the meaning given below under 7. R₁₀ mainly represents hydrogen.
• 7. As the rest of a physiologically acceptable and physio logically hydrolyzable ester, R₁₀ is preferably HCO, C₂-C₁₂-alkylcarbonyl, C₈-C₁₂-phenylalkylcarbonyl or Bezoyl.
• 8. The residues in positions 2 and 7 are preferred the L configuration.
• 9. The radicals Y₁ and Y₂ together preferably form a direct bond.

Examples of preferred compounds of the formula IV are the following:

Suitable derivatives that have at least one sugar residue have, for example compounds of formula IV below Inclusion of the compound also called octreotide, as described for example in WO 88/02756, the content of which is hereby introduced.

The compounds are preferred sugar somatostatin derivatives of the formula IV, the one on the N-terminal amino group Have sugar residue, for example a residue of the formula

which is the deoxy residue of an aldose, for example, by Amadori rearrangement from one natural or synthetically accessible monosaccharide, Disaccharide or oligosaccharide available residue, or a residue of the formula

which is the deoxy residue of ketosis, for example, by a Heyns rearrangement from a natural or synthetically accessible monoketosis, Diketose or oligoketose available rest, or a remainder of the formula

G₃-CO-

wherein
G₃CO the rest of a uronic acid, e.g. B. the glucuronic acid or galacturonic acid, a polyhydroxymonocarboxylic acid or a polyhydroxydicarboxylic acid such as gluconic acid, glucaric acid, quinic acid, acetylmuramic acid, acetylneuraminic acid or D-glucosamic acid
or a radical of the formula (d 1) to (d 4)

wherein
Q, Q ', Q''andQ''' represent groups that connect the somatostatin peptide to the sugar residue, e.g. B. is preferably the rest of a dicarboxylic acid, -C _b H _{2 b} -CO- (where b is 1 to 6), CO or CS, Q 'is preferably -C _b H _{2 b} -CO- or the rest of a dicarboxylic acid, -NHQ '' and -NHQ '''each is the residue of an ω- amino carboxylic acid, for. B. -NH-C _b H _{2 b} -CO-, and
G₄, G′₄, G′′₄ and G ′ ′ ′ ₄ have a meaning as given for G₁ and G₂
or a radical of the formula (e 1) or (e 2)

wherein
one symbol Y stands for hydrogen and the other for hydrogen or hydroxy, and
c is 2, 3 or 4,
wherein any of the free hydroxyl groups in the polyol residue of formula (e 1) or (e 2) is optionally glycosyl-linked to the reducing monosaccharide, disaccharide or oligosaccharide or an amino sugar.

A preferred connection is

(also referred to as compound IVb), and

(also called Compound IVc).  

D. Compounds of formulas V to IX

[see Vale et al., Metabolism, 27, Supplement 1, Page 139 (1978)]

[see EP-A 00 01 295 and application 78 100 994.9]

[see R. F. Nutt et al. Clin. Weekly 64 (supplementary volume VII), pages 71 to 73 (1966)].

(see EP-A 02 00 188)

Cyclo- (DTrp-Lys-Val-Phe-NMeAla-Tyr) (IX)

(see EP-A 00 70 021)

The content of all of the above publications including the compounds mentioned therein are hereby introduced.

For example, the compounds of the invention can be used in free Form, in salt form or in the form of complexes thereof. Acid addition salts can, for example, with organic acids, polymeric acids and inorganic acids are formed. To such acid addition salts include, for example, the hydro  chloride and acetates. Complexes are made from the compounds of the Invention, for example, by adding inorganic substances, such as inorganic salts or hydroxides, for example from Calcium salts and zinc salts, and / or by adding polymer organic substances.

Somatostatin and the somatostatin analogs and the derivatives of this, they are characterized primarily by the fact that they Inhibit growth hormone, glucagon and insulin secretion.

According to the invention it has now been found that the compounds of Invention have a lung protective effect.

According to this particular knowledge of the invention The invention initially relates to the following subjects:

• 1. A method for protecting the lungs against acute lung damage in a patient in need of such treatment, which involves the administration of a therapeutically effective amount of a compound according to the invention in free form or in a pharmaceutically acceptable salt or complex form, to said patient includes.
  • 1.1. A method of preventing, preventing, or treating respiratory distress syndrome in a patient in need of such treatment, which comprises administering a therapeutically effective amount of a compound of the invention in free form or in a pharmaceutically acceptable salt or complex form on the patient mentioned.
  • 1.2. A method of preventing or treating lung damage caused by oxygen therapy in a patient in need of such treatment, which comprises administering a therapeutically effective amount of a compound of the invention in free form or in a pharmaceutically acceptable salt or complex form to said patient includes.
  • 1.3. A method of improving oxygen tolerance in a patient in need of such treatment which comprises administering to the patient a therapeutically effective amount of a compound of the invention in free form or in a pharmaceutically acceptable salt or complex form.
  • 1.4. A method of treatment with oxygen at a concentration of <40% in a patient in need of such treatment, which involves administering a therapeutically effective amount of a compound of the invention in free form or in a pharmaceutically acceptable salt or complex form to the same Patient includes.
    A particular embodiment of the invention includes a method as described in 1. and 1.1 above. until 1.4. Defined type, for example the use of the compounds according to the invention for the treatment of acute shortness of breath, e.g. B. the treatment of children and adults with respiratory distress syndrome, of premature and newborn children with hyaline (membrane) disease, the treatment of severe pneumonia, oxygen pneumonitis, pulmonary edema and other conditions where artificial respiratory support for a long time , for example over 60 hours with <40% oxygen, for example in the case of post-operative anesthesia.
    Another preferred embodiment of the invention includes the use of the compounds according to the invention for preventing, preventing the development or for treating the respiratory distress syndrome in children and adults (ARDS). This respiratory distress syndrome can be caused by various acute procedures that directly or indirectly damage the lungs, e.g. septicemia, sepsis syndrome, bacterial or viral pneumonia, gastric contents aspiration, massive trauma, brain trauma, direct chest trauma, prolonged or deep shock, burns, almost Drowned, fat embolism, massive blood transfusion, cardiopulmonary bypass, oxygen toxicity, acute hemorrhagic pancreatitis or endotoxin shock.
• The following subjects form an alternative to the above invention:
• 2. A compound of the invention for use in any a procedure of the type defined above.
• 3. A compound of the invention for use in manufacture Provision of a pharmaceutical composition application in any method of the type defined above.
• 4. A pharmaceutical composition for use in any method of the type defined above, the one A compound of the invention together with one or more pharma tacitically acceptable diluents or carriers contains for this.

The utility of the compounds of the invention in loading treatment of diseases and conditions of the type described above can be performed using standard pharmacological tests and clinical examinations are also shown, namely for example  wise using procedures as detailed below to be discribed.

A. Oxygen toxicity

In 6 non-premedited mixed breed dogs, an Anaes initiated with 5 mg / kg sodium thiopental and after Maintain intubation with thiopental and pancuronium bromide. The rectal temperature is between 37.5 and 38.5 degrees hold. The internal jugular vein is cannulated and a swan Whole catheter and another catheter in the femoral artery placed. The following parameters are logged:

• - heart rate
• - Right atrial pressure
• - systolic, diastolic and mean arterial print
• - Wedge printing
• - pulmonary artery pressure
• - tidal volume
• - Minute ventilation
• - end expiratory pressure
• - End-expiratory CO₂ concentration
• - arterial and venous blood gases or oxygen saturation
• - Serum hemoglobin, electrolytes and glucose.

Cardiac output is achieved using the thermodilution method determined. The shunt volume and the physiological dead space are calculated from the above parameters. In the contralateral V. jugularis becomes a catheter for fluid replacement placed.  

After half an hour to stabilize the anesthesia the experiment is started and the basal values are no animals. The dogs are divided into 2 groups: one group receives one with 5 L oxygen / min atomized saline containing an inventive Connection over 48 hours, the other group one with 5 L Oxygen / min of saline atomized over 48 hours (Control group). The parameters are proto every 4 hours collides.

The observed differences between the baseline and the subsequent evaluation are carried out with the control animals like. At the end of the experiment, the lung tissues become the Animals examined histologically.

In this experiment, by administering the invention Compounds, for example somatostatin or a verbin IVa, IVb or IVc, in a dose of about 0.001 to 2 mg / pc. there is a significant lowering of the Oxygen caused lung lesions compared to that Control groups. For example, in the above experiment oxygen toxicity by administration of 1 mg / h. Somatostatin decreased. No lung exudate becomes special in the treated animals compared to the control animals observed.

B. Respiratory distress syndrome

5 groups of guinea pigs (20 months old, 750 g to 1.250 kg) are used for the study:

Group 1:
Control group receiving iv administration of 2 ml saline.

Group 2:
Septic control group receiving iv administration of 2 × 10⁹ Escherischia coli.

Group 3:
the animals receive an iv bolus administration of the test compound 5 minutes before an E. coli injection.

Group 4:
The test compound is administered continuously by infusion starting with an iv bolus injection (the same dose as in group 3) 60 minutes before an E. coli injection.

Group 5:
the test compound is administered continuously by infusion starting with an iv bolus injection, control group.

The mean arterial blood pressure is measured every hour. Before the experiment and 0.5, 1, 2, 4 and 8 hours afterwards, 0.2 ml of blood are drawn and the total whole blood (WBC) and differential number are determined. Arterial blood is collected in glass syringes and frozen immediately: the blood gases (Pa₀₂, Pa _CO2 ) and the pH are measured with a blood gas determination device. The resistance and ductility of the trachea, minute ventilation, heart rate, oxygen consumption and lung volume are determined regularly over 8 hours. The animals are administered 10 µCi ¹²⁵I-labeled albumin after 5 hours and 5 µCi ⁵¹Cr-labeled erythrocytes in 3 ml of blood after 7 hours. To treat hypotension and dehydration during septicemia, animals in the 5 groups are given 25 ml / kg saline per hour iv. After 8 hours, 30 mg of Nembutal and 2000 IU heparin are administered to the animals. The animals are killed 5 minutes later. 8 ml of blood for plasma preparations are taken and frozen in small amounts at -20 ° C. The chest is opened and each lung hilus is clamped twice and cut between the clamps. The lungs are drained free of blood and the caudal lobes are placed in a tared container to determine the lung water.

The dry-to-wet lung weight ratio is calculated. In addition, the concentration ratio of ¹²⁵I- labeled albumin in the bronchoalveolar washing liquid to that in the plasma (albumin index) and the accumulation of ¹²⁵I-labeled albumin in the lung interstitium and lymphatic values (AIMS) determined. Lung tissue becomes histo logically examined to be the neutrophil accumulation vote.

In this experimental model, the connections of the Erfin show an effect if used in a dose of 0.01 µg / kg to 2 mg / kg i. v. be administered. For example, for compound IVa a decrease in septic Shock caused lung damage in one bolus dose of 100 µg / kg i. v. or by infusing a dose of 0.01 µg / kg / pc.

Comparable results are also likely to be found in tests let that get related to other diseases and conditions of the type described above using Compounds of the invention, especially the compounds IVa, IVb or IVc with the same or comparable dose height as above. For example a clinical trial will be conducted, e.g. B. with patients who suffer from irreversible brain damage and be artificially ventilated with pure oxygen. The experimental connection becomes s. c. or I. v. administered. Arterial blood gases, cardiac output, intrapulmonary shunt, the ratio from the dead space to the tidal volume and the lung-thorax expansion  Availability are determined regularly. By administering the compounds of the invention, for example the Ver binding IVa, IVb or IVc, in a dose of 0.002 to 20 mg / day i. v. or S. c. there is a decrease in the Oxygen toxicity compared to the control group.

The suitable dose of active ingredient in the process according to the invention depends on, for example, the connection used, the respective recipient, the mode of administration and the strength of the condition to be treated. The appropriate active ingredient doses can be in the range of doses used for treatment gastroenteropancreactive endocrine tumors (GI), such as from Vipom, or from acromegaly, and up to about that 10 times these doses are enough.

For the treatment of GI tumors, the compound of formula IVa for example, initially by subcutaneous injection of 0.05 mg Active ingredient applied once or twice a day. The dose can be increased to 0.2 mg of active ingredient, which ge three times a day will give. For the treatment of acromegaly, for example as a daily dose of active ingredient from 100 to 300 µg subcutaneously be enough. The compound of formula IVa is used in an amount tolerated by at least up to 1 mg.

The compound of formula IVa is according to the invention Process in a daily dose of generally 0.025 mg to 1 mg, and preferably from 0.1 to 1 mg, applied, the Administration expediently in divided doses up to four times a day or in a form that is persistent Enables release of the active ingredient. The connections of the Er can be administered by any conventional route, in particular enterally, for example in the form of Tablets or capsules, or preferably parenterally, for example as injectable solutions or suspensions, such as  subcutaneously, intramuscularly or i. v. The compound of formula IVa is preferably parenteral in the form of an injectable formulation Administration administered, for example, based on lactic acid. The Compound of Formula IVa is the preferred compound. she will expediently in a daily dose of 50 µg to 1 mg administered subcutaneously. The compound of formula IVb (namely Octreotide with a sugar residue) is preferably in an oral Form, for example in a oral dose of 2 µg to 20 mg and preferably in a oral dose of 300 µg to 5000 µg, administered. Oral unit dosages can be, for example Contain 0.5 µg to about 10 mg of the compound of formula IVb.

The present invention also relates to pharmaceutical Preparations, especially inhalation or insufflation preparations, which compounds according to the invention in free form or in a pharmaceutically acceptable salt or complex form hold. These preparations can, for example, as a powder or in liquid form, together with pharmaceutically acceptable diluents nern and / or carriers. You can also allow that Compounds according to the invention in the form of a powder or in the form of drops of a solution or suspension, for example a Aerosol. These preparations can be a propellant contain or together with oxygen, for example as for artificial respiration is used.

The compositions to be used according to the invention can be prepared be made by an inventive compound intimately with suitable pharmaceutically acceptable diluents or Carriers mixed and the mixture obtained is then formulated in this way or is presented to be a convenient form of administration results.  

The compounds of the invention can also where ge desires or is appropriate as an adjunct or adjuvant to one other therapy can be used, e.g. B. an active substance as in Emergencies used, such as glucocorticoid steroids, or monoclonal antibodies to LPS.

Are the compounds of the invention together, for example wise as an adjuvant, with another therapeutic treatment administered, such as a treatment of specific diseases or Conditions of the type described above, then the doses fluctuate for the co-administered agent, of course, depending on the species the agent used, the special active ingredient used, of the condition to be treated, of the desired therapy, etc. Im In general, however, satisfactory results can be obtained achieve when the co-administered drug in cans in the the same order of magnitude or in cans of 80%, for example of 50% of the doses that are usually required if the active ingredient co-administered as monotherapy is applied. For example, hydrocortisone is in an emergency situation in a dose of 500 mg to 1 g i. v. adult Administered to patients.

Accordingly, the invention also belongs

• 5. the use of a compound according to the invention a second active pharmaceutical ingredient, for example a Glucocorticoid steroid, used to treat respiratory Distress syndrome;
• 6. A composition for use as above give a compound of the invention and a second active pharmaceutical ingredient, for example a gluco corticoid steroid.

The following example makes the production more solid compositions according to the invention explained.

1. ampoules

The compositions are made by conventional techniques as in batches of 50 l to form about 43,000 ampoules 1 ml each or to form 8400 vials with fumigation with carbon dioxide. The compositions are filtered (at for example through filters with a pore size of 0.2 µm at one Pressure of 0.5 bar) and under aseptic conditions Bottled ampoules or vials.

The compounds of the invention are well tolerated in cans that are to be used according to the invention. For example, the ver bindings VIa and IVb have the same tolerance, e.g. B. at the Mouse, on. For example, an i. p. Injection of 100 mg / kg to no increase in the GOT and also not to death. For the Ver Binding IVb is the maximum non-lethal dose in rats after 2 weeks of administration in the order of 2000 mg / kg body weight. The pharmaceutically acceptable salts of the compounds of the invention show the same or similar Degree of tolerability and / or effectiveness like the free one Links.

Claims (9)

1. Using natural somatostatin or soma tostatin analogs or derivatives in free form or in form a pharmaceutically acceptable salt or complex as Lung protective agent against acute lung damage. 2. Using natural somatostatin or a soma tostatin analogs or derivatives in free form or in form a pharmaceutically acceptable salt or complex for Prevent, prevent or treat respira toric distress syndrome in children or adults. 3. Use natural somatostatin or soma tostatin analogs or derivatives in free form or in form a pharmaceutically acceptable salt or complex for Prevent or treat through oxygen therapy caused lung damage. 4. Use according to one of the preceding claims, characterized in that the somatostatin analog or derivative is a compound of the following formulas I, II or III, wherein
W is S or (CH₂) _s wherein s is 0.1 or 2;
the symbol X or ZS and the other S or CH₂;
Y is S or (CH₂) _t where t is 0, 1 or 2
R₁ and R₂ each independently of one another alkyl having 1 to 5 carbon atoms, optionally substituted by one or two alkyl having 1 to 5 carbon atoms, halogen, hydroxy, amino, nitro and / or alkoxy having 1 to 5 carbon atoms or benzyl alkyl with 1 to 5 carbon atoms substituted by a 5- or 6-membered heterocyclic ring,
R₃ optionally substituted by alkyl with 1 to 5 carbon atoms, alkoxy with 1 to 5 carbon atoms or halogen 3-indolylmethyl,
R₄ alkyl with 1 to 5 carbon atoms, hydroxyalkyl with 1 to 5 carbon atoms, alkoxycarbonyl with 2 to 6 carbon atoms, amino alkyl with 1 to 5 carbon atoms or optionally by alkyl with 1 to 5 carbon atoms, halogen , Hydroxy, amino, nitro and / or alkoxy with 1 to 5 carbon atoms substituted benzyl and
R₅ is alkyl with 1 to 5 carbon atoms, or benzyl optionally substituted by alkyl with 1 to 5 carbon atoms, halogen, hydroxy, amino, nitro and / or alkoxy with 1 to 5 carbon atoms,
or that the somatostatin analog or derivative is a compound of the formula IV, wherein
A represents alkyl having 1 to 12 carbon atoms, phenylalkyl having 7 to 10 carbon atoms or a group of the formula RCO-,
in which
i) R is hydrogen, alkyl having 1 to 11 carbon atoms, phenyl or phenylalkyl having 7 to 10 carbon atoms, or
ii) RCO-
a) an L- or D-phenylalanine radical optionally substituted in the ring by fluorine, chlorine, bromine, NO₂, NH₂, OH, alkyl with 1 to 3 C atoms and / or alkoxy with 1 to 3 C atoms,
b) the remainder of a natural or synthetic α -amino acid or a corresponding D-amino acid other than that defined above under a), or
c) a dipeptide residue, in which the individual amino acid residues are identical or different and are selected from the residues defined under a) and / or b) above, where the α- amino group of the amino acid residues a) and b) and the N- terminal amino group of the dipeptide radical c) optionally mono- or di-alkylated by alkyl having 1 to 12 carbon atoms or substituted by alkanoyl having 1 to 8 carbon atoms,
A ′ represents hydrogen or, if A denotes alkyl with 1 to 12 C atoms or phenylalkyl with 7 to 10 C atoms, also stands for alkyl with 1 to 12 C atoms or phenylalkyl with 7 to 10 C atoms,
Y₁ and Y₂ independently of one another for hydrogen, or where m is an integer from 1 to 4
R _a CH₃ or C₂H₅ and
R _{b is} H, CH₃ or C₂H₅, or wherein n is an integer from 1 to 5, or
3) -CO-NHR _c
wherein R _{c is} a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, or wherein
R _{d is} the residue of the α -C atom of a natural or synthetic α- amino acid (incl. Hydrogen) and
R _{e represents} an alkyl radical with 1 to 5 carbon atoms, wherein
R ′ _a and R ′ _b independently of one another are hydrogen, CH₃ or C₂H₅
R₈ and R₉ independently of one another hydrogen, halogen, alkyl with 1 to 3 C atoms or alkoxy with 1 to 3 C atoms
p 0 or 1,
q 0 or 1 and
r is 0, 1 or 2,
or Y₁ and Y₂ together represent a bond,
B for Phe or in the phenyl radical substituted by halogen, NO₂, NH₂, OH, alkyl having 1 to 3 C atoms or alkoxy having 1 to 3 C atoms, or naphthyl ala
C for L- or D-Trp optionally substituted in the benzene ring by halogen, NO₂, NH₂, OH, alkyl having 1 to 3 C atoms or alkoxy having 1 to 3 C atoms, it being possible for the a -amino group to be substituted by methyl
D for Lys, Lys which contains 0 or S in the β position in the side chain, ThiaLys, γ F-Lys or δ F-Lys, where the α- amino group can be substituted by methyl, or 4-aminocyclohexylAla or 4-aminocyclohexylGly
E for Thr, Ser, Val, Phe, Tyr, Ile or an amino butter acid or amino isobutyric acid residue
F for COOR₇, CH₂OR₁₀, CO-NR₁₁R₁₂ or R₇ for hydrogen or alkyl with 1 to 3 carbon atoms
R₁₀ for hydrogen or the rest of a physiologically acceptable, physiologically hydrolyzable ester
R₁₁ represents hydrogen, alkyl having 1 to 3 C atoms, phenyl or phenylalkyl having 7 to 10 C atoms, but if R₁₂ represents -CH (R₁₃) -X₁, only hydrogen or methyl
R₁₂ for hydrogen, alkyl with 1 to 3 carbon atoms or R₁₃ for the residue of the α -C atom of a natural union or synthetic amino acid (including hydrogen) or for a CH₂OH, HO-CH₂-CH₂-, HO (CH₂) ₃- or -CH (CH₃) OH residue,
X₁ for COOR₇, CH₂OR₁₀ or R₁₄ for hydrogen or alkyl having 1 to 3 carbon atoms
R₁₅ for hydrogen, alkyl with 1 to 3 carbon atoms, phenyl or phenylalkyl with 7 to 10 carbon atoms, and
R₁₆ represent hydrogen or hydroxy,
where the radicals B, D and E in L-form and the radicals in positions 2 and 7 and the radicals Y₁4) and Y₂4) can be in D- or L-form,
wherein the respective somatostatin analog or derivative can be in free form or in the form of a pharmaceutically acceptable salt or complex. 5. Use according to claim 4, characterized in that the somatostatin analog or derivative is in free form or in the form of a pharmaceutically acceptable salt or complex. 6. Use according to any one of claims 1 to 4, characterized records that the somatostation analog or derivative is a A compound of formula IV as defined in claim 4 is a sugar residue on the N-terminal amino group contains. 7. A composition for use according to any one of claims 1 to 3, characterized in that they are natural Soma tostatin or a somatostatin analog or derivative in free form or in the form of a pharmaceutically acceptable Contains salt or complex. 8. The composition according to claim 7, characterized in that the somatostation analog or derivative connects to Claim 4, 5 or 6. 9. A composition for use according to any one of claims 1 to 3, characterized in that they are natural Soma tostatin or a somatostatin analog or derivative in free Form or in the form of a pharmaceutically acceptable salt or complex and contains a glucocorticoid steroid.