Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-11-01
2001-02-20
Raymond, Richard L. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S230500, C544S006000, C544S051000, C544S052000, C544S071000, C544S105000
Reexamination Certificate
active
06191127
ABSTRACT:
The invention relates to substituted heterocycles, the process for their production and their use in pharmaceutical agents.
In human cells, there exist 3 specific forms of nitrogen monoxide synthases, which convert arginine into nitrogen monoxide (NO) and citrulline. Two constitutive NO-synthases (NOS) were identified that are present as Ca
++
/calmodulin-dependent enzymes in the brain (bcNOS or NOS 1) or in the endothelium (ecNOS or NOS 3). The third isoform is the inducible NOS (iNOS or NOS 2), which is a Ca
++
-independent enzyme and is induced after activation of different cells by endotoxin and cytokines.
NOS-inhibitors and especially specific inhibitors of NOS 1, NOS 2 or NOS 3 are therefore suitable for treatment of different diseases, which are induced or aggravated by pathological concentrations of NO in cells (Clin. Neuropharmac. 18, 1995 page 482).
As NOS-inhibitors, different compounds are described, such as, for example, cyclic amidine derivatives (WO 96/14844) or guanidine derivatives (WO95/05363).
It has now been found that the heterocycles that are substituted according to the invention can be used especially advantageously as pharmaceutical agents.
The invention relates to the compounds of Formula I, their tautomeric and isomeric forms and salts
in which
is a double bond,
X is —O— or —S(O)
m
—,
R
1
and R
2
, independently of one another, are hydrogen, halogen, S(O)
n
—R
7
, OR
7
, COOR
7
, NR
7
R
8
, C(═NR
7
)—NHR
8
, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl or —S—C(═NR
7
)—NHR
8
,
R
3
and R
4
, independently of one another, are hydrogen, C
1-12
alkyl, phenyl, CO—NR
9
R
10
, CSNR
9
R
10
, COR
9
, CSR
9
, COOR
9
, OH, O—C
1-6
alkyl, and
R
5
is halogen, C
1-8
alkoxy, S(O)
p
—C
1-6
alkyl, C
1-8
alkylcarbonyl, C
1-8
alkyl, C
3-10
cycloalkyl, phenyl or a C
1-8
alkyl radical, which is substituted with phenyl, halogen, hydroxy, S(O)
n
R
11
, NO
2
, OR
11
, COOR
11
, NR
11
R
12
, cyano, —C(═NR
11
)—NHR
12
or —S—C(═NR
11
)—NHR
12
,
R
6
is hydrogen or C
1-3
alkyl, which optionally together with R
5
forms a 3-, 4- or 5-membered spirocyclic compound,
R
7
, R
8
and R
11
, R
12
, the same or different, are hydrogen, C
1-6
alkyl, phenyl or C
3-7
cycloalkyl,
R
9
and R
10
, independently of one another, are hydrogen, phenyl, benzyl, C
3-7
cycloalkyl or C
1-6
alkyl,
m, n, or p is 0, 1 or 2.
The compounds of Formula I, in which R
3
or R
4
means hydrogen, can be viewed as a preferred embodiment. Compounds in which R
5
is C
1-8
alkyl are another preferred embodiment. R
6
is preferably hydrogen. Especially preferred are compounds in which R
3
, R
4
and R
6
mean hydrogen. The definition of m, n and p is preferably zero.
The compounds of Formula I can be present as tautomers, stereoisomers or geometric isomers. The invention also comprises all possible isomers, such as E- and Z-isomers, S- and R-enantiomers, diastereomers, racemates and mixtures thereof, including the tautomeric compounds of Formulas Ia and Ib
The physiologically compatible salts can be formed with inorganic and organic acids, such as, for example, oxalic acid, lactic acid, citric acid, fumaric acid, acetic acid, maleic acid, tartaric acid, phosphoric acid, HCl, HBr, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, i.a.
For salt formation of acid groups, the inorganic or organic bases are also suitable, which are known for the formation of physiologically compatible salts, such as, for example, alkali hydroxides, such as sodium and potassium hydroxide, alkaline-earth hydroxides, such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, tris-(hydroxymethyl)-methylamine, etc.
In each case, alkyl means a straight-chain or branched alkyl group, such as, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, tert-pentyl, neopentyl, n-hexyl, sec-hexyl, heptyl, octyl, preferably alkyl radicals with 1-4 C atoms. The alkenyl and alkynyl substituents are in each case straight-chain or branched. For example, the following radicals can be mentioned: vinyl, 2-propenyl, 1-propenyl, 2-butenyl, 1-butenyl, 2-butenyl, 1-methyl-1-propenyl, 2-methyl-2-propenyl, 3-methyl-2-propenyl, ethinyl, 1-propinyl, 2-propinyl, 1-butinyl, 2-butinyl.
Cycloalkyl is defined respectively as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
Halogen means respectively fluorine, chlorine, bromine or iodine.
Aryl is defined respectively as naphthyl or phenyl.
For example, the following spirocyclic compounds can be mentioned: spiropropyl, spirobutyl, spiropentyl.
Alkyl radical R
5
can be substituted in one or more places with the above-mentioned substituents.
The invention also relates to the use of the compounds according to the invention for the production of a pharmaceutical agent for treating diseases, which are induced by the action of nitrogen monoxide at pathological concentrations. These include neurodegenerative diseases, inflammatory diseases, auto-immune diseases, and cardiovascular diseases.
For example, there can be mentioned:
Cerebral ischemia, hypoxia and other neurodegenerative diseases, which are brought into contact with inflammations, such as multiple sclerosis, amyotrophic lateral sclerosis and comparable sclerotic diseases, Parkinson's Disease, Huntington's Disease, Korksakoff's Disease, epilepsy, sleep disorders, schizophrenia, depression, migraine, hypoglycemia, dementia, such as, e.g., Alzheimer's Disease, HIV-dementia and presenile dementia.
They are also suitable for treating diseases of the cardiovascular system and for treating auto-immune and/or inflammatory diseases, such as hypotension, ARDS (adult respiratory distress syndrome), sepsis or septic shock, rheumatoid arthritis, osteoarthritis, insulin-dependent diabetes mellitus (IDDM), inflammatory disease of the pelvis/intestine (bowel disease), meningitis, glomerulonephritis, acute and chronic liver diseases, diseases by rejection (for example allogenic heart, kidney or liver transplants) or inflammatory skin diseases such as psoriasis, etc. Based on their profile of action, the compounds according to the invention are very well suited for specific inhibition of the neuronal NOS and can therefore be used for treating neurodegenerative diseases such as strokes.
To use the compounds according to the invention as pharmaceutical agents, they are brought into the form of a pharmaceutical preparation, which in addition to the active ingredient contains vehicles, adjuvants and/or additives that are suitable for enteral or parenteral administration. The administration can be done orally or sublingually as a solid in the form of capsules or tablets or as a liquid in the form of solutions, suspensions, elixirs, aerosols or emulsions or rectally in the form of suppositories or in the form of injection solutions that can also optionally be used subcutaneously, intramuscularly or intravenously, or topically or intrathecally. As adjuvants for the desired pharmaceutical agent formulation, the inert organic and inorganic support media that are known to one skilled in the art are suitable, such as, e.g., water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, plant oils, polyalkylene glycols, etc. Moreover, preservatives, stabilizers, wetting agents, emulsifiers or salts for changing the osmotic pressure or buffers can optionally be contained.
For parenteral administration, especially injection solutions or suspensions, especially aqueous solutions of the active compounds in polyhydroxyethylated castor oil, are suitable.
As vehicle systems, surface-active adjuvants such as salts of bile acids or animal or plant phospholipids, but also mixtures thereof as well as liposomes or their components can also be used.
For oral administration, especially tablets, coated tablets or capsules with talc and/or hydrocarbon vehicles or binders, such as, for example, lactose, corn or potato starch, are suitable. The administration can also be done in liquid form, such as, for exa
Burton Gerardine
Davey David Daniel
Hillmann Margrit
Holscher Peter
Pribilla Iris
Millen White Zelano & Branigan P.C.
Raymond Richard L.
Schering Aktiengesellschaft
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