Guanidine derivatives, methods of preparing them and their...

Details Guanidine derivatives, methods of preparing them and their... Guanidine derivatives, methods of preparing them and their...

1999-10-18

2001-09-04

Vollano, Jean F. (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C514S631000, C564S277000, C564S227000

Reexamination Certificate

active

06284798

ABSTRACT:

The present invention relates to new guanidine derivatives, processes for preparing them and their use as sphingomyelinase inhibitors and pharmaceutical compositions which contain these compounds. The guanidine derivatives of the present invention correspond to the general formula I:
wherein
X denotes R
1
, —NHR
1
, —NH—NH—CHR
1
R
2
, —NH—N═CR
1
R
2
,
R
1
and R
2
independently of each other denote hydrogen, a straight-chained or branched C
3-20
-alkyl, C
3-20
-cycloalkyl group, an adamantyl, norbornyl, tricyclodecyl, benzyl, furyl, pyridyl, indolyl, quinolyl, anthracenyl, phenanthryl, perinaphthyl or quinuclidinyl group, wherein the above-mentioned straight-chained or branched C
3-20
-alkyl group may be substituted by a hydroxy or C
1-4
-alkoxy group, a halogen atom or an amino group and the above-mentioned C
3-20
-cycloalkyl group may be substituted by a hydroxy, C
1-4
-alkoxy, C
1-4
-alkyl group or by a halogen atom or an amino group, and wherein, if X denotes —NH—N═CR
1
R
2
, only one of the substituents R
1
and R
2
may represent hydrogen
optionally in the form of individual optical isomers, mixtures of the individual isomers or racemates, tautomers or geometrical isomers e.g. cis/trans-isomers as well as in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids.
Preferred compounds of general formula I are those wherein
X denotes —NH—NH—CH
2
R
1
and —NH—N═CHR
1
R
1
denotes C
8-20
-alkyl (branched or unbranched).
Particularly preferred compounds of general formula I are those wherein
X denotes —NH—NH—CH
2
R
1
and —NH—N═CHR
1
and
R
1
denotes an unbranched decyl group.
The compounds according to the invention have valuable pharmacodynamic and biochemical properties and can therefore be used advantageously in research and in human and veterinary medicine.
Surprisingly it has been found that the aminoguanidines and amidines according to the invention have beneficial sphingomyelinase-inhibiting, antimicrobial, antiviral, anti-inflammatory (e.g. anti-shock) activities and effects on cell growth.
The compounds according to the invention are prepared by reacting an aldehyde or ketone of formula R
1
CHO or R
1
COR
2
with aminoguanidine. The reaction is usually carried out in an inert organic solvent, e.g. a chlorinated hydrocarbon, such as dichloromethane or chloroform, or an aromatic hydrocarbon such as benzene or toluene. The reaction is preferably carried out by removing the water formed from the equilibrium, e.g. using a water separator. The reaction may be carried out over a wide temperature range but is generally performed at elevated temperature, particularly at a temperature in the range from about 60° C. up to the boiling point of the reaction mixture. In addition, the compounds according to the invention may be prepared by methods known from the prior art.
The starting compounds are known or may be prepared by known methods.
The pharmaceutical compositions according to the invention contain one of the above-mentioned compounds of general formula I in a conventional solid or liquid pharmaceutical carrier. The compounds according to the invention may also be combined with known active substances.
The compounds according to the invention are characterised by anti-inflammatory (e.g. anti-shock), antimicrobial, antitumoral and, in particular, antiviral effects. The antiviral spectrum of activity includes, for example, herpes, vesicular stomatitis, HIV and papilloma viruses. It has also been found that the compounds according to the invention influence the growth of tumour cells. They may be used to treat carcinomas, e.g. carcinoma of the large intestine, sarcomas or leukaemias.
In general, it is found that these substances according to the invention bring about an NF-kappaB-dependent immunosuppression.
The compounds according to the invention can therefore be used to treat the following diseases:
A. Systemic inflammatory reactions
sepsis-causing diseases
gram-positive sepsis
gram-negative sepsis
fungal sepsis
agranulocytosis (neutropenic fever)
urinary infections (urosepsis)
general infections with meningococci (meningococcaemia)
trauma/haemorrhage
burns
injuries caused by ionising radiation
acute pancreatitis
adult respiratory distress syndrome (ARDS)
B. Reperfusion syndrome
post pump syndrome
ischaemia-induced reperfusion injury
C. Cardiovascular disease:
cardiac stun syndrome
myocardial infarction
congestive heart failure
arteriosclerosis
D. Infectious diseases:
papilloma virus infection
herpes virus infection
HIV infection/HIV neuropathy
meningitis
hepatitis
septic arthritis
peritonitis
pneumonia
bronchitis
epiglottitis
E. coli
0157:H7 infection
haemolytic uremic syndrome/thrombolytic thromocytopenic purpura
malaria
Dengue haemorrhagic fever
Leishmaniasis
leprosy
toxic shock syndrome
Streptococcal myositis
gas gangrene
myobacterium tuberculosis infections
myobacterium avium intracellular infections
pneumocystosis
pelvic inflammatory disease
orchitis/epidydimitis
Legionella
lyme disease
influenza A virus infection
diseases caused by Epstein-Barr virus
viral-associated haemaphagocytic syndrome
viral encephalitis/aseptic meningitis
E. Gynaecological applications
premature labour
miscarriage
infertility
F. Inflammatory diseases/autoimmune diseases:
rheumatoid arthritis/seronegative arthropathy
emphysema bronchitis (chronic obstructive pulmonary disease COPD)
osteoarthritis
inflammatory bowel disease
Crohn's disease
systemic lupus erythematosis
iridocyclitis/uveitis/optic neuritis
idiopathic pulmonary fibrosis
systemic vasculitis/Wegner's granulomatosis
sarcoidosis
orchitis/vasectomy reversal procedures
H. Allergic/atopic diseases:
asthma
allergic rhinitis
eczema
allergic contact dermatitis
allergic conjunctivitis
hypersensitive pneumonitis
I. Malignant disease:
tumour therapy in combination with chemotherapy, radiotherapy and cytokine treatment such as TNF-&agr; treatment of sarcomas, carcinomas and leukaemias
ALL
AML
CML
CLL
breast cancer
small-cell and non-small-cell bronchial carcinoma
squamous cell carcinoma
Hodgkin's disease, non-Hodgkin's lymphoma
multiple melanoma
Kaposi's sarcoma
colorectal carcinoma
nasopharyneal carcinoma
malignant histiocytosis
paraneoplastic syndrome/hypercalcaemia of malignancy
J. Transplant complications
rejection reactions after transplant
graft versus host reactions
K. Cachexia
L. Congenital diseases:
cystic fibrosis
familial hematophagocytic lymphohistiocytosis
sickle cell anaemia
M. Skin diseases:
psoriasis
alopecia
N. Neurological diseases/chronic and acute neurodegeneration
multiple sclerosis
Parkinson's disease
Down's syndrome
stroke
skull/brain trauma
migraine
O. Diseases of the kidneys:
nephrotic syndrome
haemodialysis
uraemia
P. Various toxicities:
OKT3 therapy
anti-CD3 therapy
cytokine therapy
chemotherapy
radiation therapy
chronic salicylate intoxication
Q. Metabolic/idiopathic diseases:
Wilson's disease
haemachromatosis
alpha-1-antitrypsin deficiency
diabetes
Hashimoto's thyroiditis
osteoporosis
hypothalamic pituitary adrenal axis evaluation
primary biliary cirrhosis
In vitro investigations in plaque reduction tests using different viruses showed an inhibition of growth at substance concentrations of from 0.1 to 1000/&mgr;g/ml. The toxicity of the substances according to the invention is relatively low. They may be used in particular as effective preventative or therapeutic agents against influenza, AIDS or herpes diseases of the skin and mucous membranes. The daily dose for adults during the disease is of the order of about 5 to 1000 mg of active substance per day.
The compounds according to the invention may be administered by parental, subcutaneous, intravenous, intramuscular and intraperitoneal route. In this case, the carrier substance is a sterile liquid such as water or oil, the oil being of vegetable, animal or synthetic origin. Conventional glucose solutions are used as the injectable solutions. The liquid carriers for the injectable solutions generally contain 0.5 to 26% by weight of active s

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