Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the invention relates to the use of compounds of the formula I, disclosed in EP 0 738 715 A2,
• R 1 and R 2 each independently of one another H or A
• R 3 and R 4 each independently of one another -OH, -OR 10 , -SR 10 ,
• R 5 is an unsubstituted or mono- or disubstituted by R 6 and / or R 7 substituted phenyl radical
• Q is absent or alkylene with 1-6 C atoms
• R 6 and R 7 each independently of one another -NH 2 , -NR 8 R 9 , -NHR 10 ,
• R 8 and R 9 each independently of one another H, acyl with 1-8 C atoms, which is replaced by 1-5 F and / or Cl atoms can be substituted, -COOA, -SO-A, -S0 2 A, -CONH 2l -CONHA, -CONA 2 , -CO-COOH, -CO-COOA, -CO-CONH 2 , - CO-CONHA or -CO-CONA 2 , A alkyl with 1 to 6 carbon atoms, which by 1-5 F and / or
• Cl atoms can be substituted, R 10 and R 11 each independently of one another A, cycloalkyl with 3-7 C atoms, methylene cycloalkyl with 4-8 C atoms or alkenyl with 2-8 C atoms and Hal F, Cl, Br or I mean
• R 1 and R 2 are each independently H or A
• R 3 and R 4 each independently of one another -OH, -OR 10 , -SR 10 ,
• R 5 is an unsubstituted or mono- or disubstituted phenyl radical R 6 and / or R 7 , Q is absent or alkylene with 1 -6 C atoms,
• R 6 and R 7 each independently of one another -NH 2) -NR 8 R 9 , -NHR 10 , -NR 10 R 11 , -N0 2 , shark, -CN, -OA, -COOH or -COOA, R 8 and R 9 each independently of one another H, acyl with 1 -8 C-
• Atoms which can be substituted by 1-5 F and / or Cl atoms, -COOA, -SO-A, -S0 2 A, -CONH 2) -CONHA, -CONA 2 , -CO-COOH, -CO -COOA, -CO-CONH 2l -CO-CONHA or -CO-CONA 2 ,
• a alkyl with 1 to 6 carbon atoms which is represented by 1 -5 F and / or
• Cl atoms can be substituted, R 10 and R 1 each independently of one another A, cycloalkyl with 3-7 C atoms, methylene cycloalkyl with 4-8 C atoms or alkenyl with 2-8 C atoms and
• B is an aromatic heterocycle with 1 to 4 N, O and / or S atoms, bonded via N or C, which may be unsubstituted or substituted once, twice or three times by shark, A and / or OA, and can also be fused to a benzene or pyridine ring,
• Q is absent or alkylene with 1 -6 C atoms
• R 1 and R 2 are each independently H or A
• R 3 and R 4 each independently of one another -OH, OR 5 , -SR 5 , -SO-R 5 , -S0 2 -R 5 , shark, methylenedioxy, -N0 2l -NH 2 , -NHR 5 or -NR 5 R 6 ,
• R 5 and R 6 each independently of one another A, cycloalkyl with 3-7 C atoms, methylene cycloalkyl with 4-8 C atoms or alkenyl with 2-8 C atoms,
• a alkyl having 1 to 10 carbon atoms, which can be substituted by 1 to 5 F and / or Cl atoms and Hal F, Cl, Broder I mean
• R 1 and R 2 each independently of one another H or A, R 3 H, OA or O-C m H 2m + 1-n X n ,
• A is alkyl with 1-6 C atoms, m is 1, 2, 3, 4, 5 or 6 and n is 1,2,3,4,5,6,7,8,9, 10, 11, 12 or 13 .
• R 1 and R 2 are each independently H or A, R 3 and R 4 each independently of one another OH, OA, SA, SOA, S0 2 A, shark, methylenedioxy, cycloalkyloxy with 3-7 C atoms or 0-C m H 2m + 1-k F k ,
• R 6 and R 7 each independently of one another H or A, Q alkylene with 1 -6 C atoms,
• R 1 and R 2 are each independently H or A
• R 3 and R 4 each independently of one another -OH, OA, -SA,
• Atoms that are substituted by 1 to 5 F and / or Cl atoms can be tuiert, cycloalkyl with 3-7 C-atoms or methylene cycloalkyl with 4-8 C-atoms,
• Q is absent or alkylene with 1 -4 C atoms
• Y is absent or alkylene with 1 -10 C atoms
• NHA NHA
• NAA an unsubstituted or simply substituted by A or OH saturated 3-8-membered heterocycle with at least one N atom, in which further CH 2 groups have been replaced by NH, NA, S or O.
• the object of the invention was to find new uses of the compounds of the formulas I, in particular those which can lead to the production of medicaments.
• the compounds according to the invention can be used for the treatment of asthmatic diseases.
• the anti-asthmatic effect of the PDE IV inhibitors is e.g. by T.J. Torphy et al. in Thorax, 46, 512-523 (1991) and can e.g. B. by the method of T. Olson, Acta allergologica 26, 438-447 (1971) can be determined.
• the compounds also show an inhibitory effect on the formation of TNF (tumor necrosis factor) and are therefore suitable for the treatment of allergic and inflammatory diseases, autoimmune diseases and graft rejection reactions.
• TNF tumor necrosis factor
• PDE IV inhibitors in the treatment of asthma, inflammatory diseases, diabetes mellitus, atopic dermatitis, psoriasis, AIDS, tumor growth or tumor metastases is e.g. described in EP 779 291.
• the anti-inflammatory effect of the substances according to the invention and their effectiveness for the treatment of, for example, autoimmune diseases, Multiple sclerosis or rheumatoid arthritis can be analogous to the methods of N. Sommer et al., Nature Medicine, 1, 244-248 (1995) or L. Sekut et al., Clin. Exp. Immunol., 100, 126-132 (1995).
• the invention furthermore relates to the use of the compounds of the formulas I and their physiologically acceptable salts and / or solvates for the production of a medicament for inhibiting the growth of neoplastic cells.
• Neoplastic cells are understood to mean cancer cells.
• the invention relates in particular to the use of the compounds of the formulas I and their physiologically acceptable salts and / or solvates for the production of a medicament for the treatment and / or prophylaxis of cancer.
• the invention furthermore relates to the use of the compounds of the formulas I and their physiologically acceptable salts and / or solvates for the production of a medicament for the treatment of neoplastic damage.
• the invention furthermore relates to the use of the compounds of the formulas I and their physiologically acceptable salts and / or solvates for the production of a medicament for the treatment of precancerogenic damage.
• Precancerogenic damage means, for example, benign growths in the intestine that can lead to colon cancer.
• Precancerogenic damage includes in particular those in US
• Irregularities in apoptosis play a role in the formation of precancerogenic damage. Regulation of apoptosis is also known to play an important role in diseases associated with abnormal cell growth, such as e.g. benign prostatic hyperplasia, neurodegenerative diseases, e.g. Parkinson's, autoimmune diseases including multiple sclerosis and rheumatoid arthritis or infectious diseases such as AIDS.
• diseases associated with abnormal cell growth such as e.g. benign prostatic hyperplasia, neurodegenerative diseases, e.g. Parkinson's, autoimmune diseases including multiple sclerosis and rheumatoid arthritis or infectious diseases such as AIDS.
• the compounds of the formula I modulate apoptosis and are used in the treatment or prophylaxis of cancer.
• the invention thus relates to the use of the compounds of the formulas I and their physiologically acceptable salts and / or solvates for the production of a medicament for regulating apoptosis in human cells.
• the compounds of the formulas I can be used as active pharmaceutical ingredients in human and veterinary medicine. They can also be used as intermediates for the production of further active pharmaceutical ingredients.
• the compounds of the formulas I can have a chiral center and can therefore occur in several stereoisomeric forms. All of these forms (e.g. R and S forms) and their mixtures (e.g. the R, S-
• parenteral or topical application and do not react with the new compounds, e.g. water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly.
• Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used in particular for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for which topical application ointments, creams or powder.
• the new compounds can also be lyophilized and the resulting lyophilisates e.g. can be used for the production of injectables.
• the specified preparations can be sterilized and / or contain auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or one or more further active ingredients, eg one or more vitamins.
• the compounds of the formulas I and their physiologically acceptable salts can be used in combating diseases in which an increase in the cAMP (cyclo-adenosine monophosphate) level leads to inhibition or prevention of inflammation and muscle relaxation.
• cAMP cyclo-adenosine monophosphate
• Particular use can be made of the invention
• the substances according to the invention are generally preferably used in doses between about 1 and 500 mg, in particular between see 5 and 100 mg administered per dosage unit.
• the daily dosage is preferably between about 0.02 and 10 mg / kg body weight.
• the specific dose for each patient depends on a wide variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of excretion and on the combination of drugs and severity of the respective disease to which the therapy applies. Oral application is preferred.
• Compounds of the formula I can contain one or more centers of asymmetry. In this case, they are usually in racemic form. Racemates obtained can be separated into their enantiomers mechanically or chemically by methods known per se. Diastereomers are preferably formed from the racemic mixture by reaction with an optically active release agent.
• the invention relates in particular to the use of a) compounds, disclosed in EP 0 738 715 A2, selected from the

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• 2001
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