Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1994-09-27
2001-05-01
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S573000, C560S121000, C562S503000
Reexamination Certificate
active
06225347
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to new 9-halogen (Z) prostaglandin derivatives, a process for their product and their use as pharmaceutical agents.
Form the very extensive prior art of prostaglandins and their analogs it is known that this class of substances because of its biological and pharmacological properties is suitable for treating mammals, including man. However, its use as a pharmaceutical agent often runs into difficulties. Most natural prostaglandins have too short a duration of effect for therapeutic purposes, since they are metabolically broken down too quickly be various enzymatic processes. All structural changes have the aim of increasing the duration of effect and the selectivity of the effectiveness.
SUMMARY OF THE INVENTION
An object of the invention is to provide novel 9-halogen-(Z) prostaglandin derivatives having outstanding specificity of action, better effectiveness and prolonged duration of effect as compared to natural prostaglandins and their derivatives and which are especially suitable for oral application.
Upon further study of the specification and appended claims, further objects and advantages of this invention will become apparent to those skilled in the art.
The invention relates to 9-halogen-(Z) prostaglandin derivatives of the formula I
in which Z represents the radicals
Hal represents a chlorine or fluorine atom in the alpha or beta position,
R
1
represents the radical CH
2
OH or
with R
2
meaning a hydrogen atom, an alkyl, cycloalkyl, aryl or heterocyclic radical or R
1
represents the radical
with R
3
meaning an acid residue or the radical R
2
and
A represents a —CH
2
—CH
2
—, a trans-CH═CH or —C≡C group,
W represents a free or a functionally modified hydroxymethylene group or a free or functionally modified
group, and the respective OH groups can be in the alpha or beta position,
D and E together represent a direct bond or
D represents a straight-chain alkylene group with 1-10 C atoms, a branched-chain alkylene group with 2-10 C atoms or an annular alkylene group with 3-10 C atoms, which optionally can be substituted by fluorine atoms, and
E represents an oxygen or sulfur atom, a direct bond, a —C≡C bond or a —CR
6
═CR
7
group, and R
6
and R
7
are different and mean a hydrogen atom, a chlorine atom or a C
1
-C
4
alkyl group,
R
4
represents a free or functionally modified hydroxy group,
R
5
means a hydrogen atom, an alkyl, a halogen-substituted alkyl, a cycloalkyl, an optionally substituted aryl or a heterocyclic group, and if R
2
means a hydrogen atom, its salts with physiologically compatible bases or its cyclodextrin chlathrates.
Straight-chain or branched-chain alkyl groups with 1-10 C atoms such as, for example, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, decyl are suitable as alkyl groups R
2
. Alkyl groups R
2
can optionally be substituted singly to multiply by halogen atoms, alkoxy groups, optionally substituted aryl or aroyl groups, dialkylamino and trialkylammonium, and a single substitution is to be preferred. As substituents there can be mentioned. e.g., fluorine, chlorine or bromine, phenyl, dimethylamino, diethylamino, methoxy, ethoxy. As preferred alkyl groups R
2
are to be mentioned those with 1-4 C atoms such as, e.g., methyl, ethyl, propyl, dimethylaminopropyl, isobutyl, butyl.
Suitable as aryl groups R
2
are both substituted and unsubstituted aryl groups such as, for example, phenyl, 1-naphthyl and 2-naphthyl, which in each case can be substituted by 1-3 halogen atoms, a phenyl group, 1-3 alkyl groups with 1-4 C atoms in each case, a chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, hydroxy or alkoxy group with 1-4 C atoms. Substituents in the 3 and 4 position on the phenyl ring, for example, by fluorine, chlorine, alkoxy or trifluoromethyl or in the 4 position by hydroxy are preferred.
The cycloalkyl group R
2
can contain 3-10, preferably 5 and 6, carbon atoms in the ring. The rings can be substituted alkyl groups with 1-4 carbon atoms. For example, there can be mentioned cyclopentyl, cyclohexyl or methylcyclohexyl.
Suitable as heterocyclic groups R
2
are 5- and 6-membered heterocycles, which contain at least one heteroatom, preferably nitrogen, oxygen or sulfur. For example, there can be mentioned 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, 3-furyl, 3-thienyl, 2-tetrazolyl, etc.
Suitable as acid radicals are physiologically compatible acid radicals. Organic carboxylic acids and sulfonic acids with 1-15 carbon atoms are suitable, which belong to the aliphatic, cycloaliphatic, aromatic, aromatic aliphatic and heterocyclic series. These acids can be saturated, unsaturated and/or polybasic and/or substituted in a conventional manner. Alkyl, hydroxy, alkoxy, oxo or amino groups or halogen atoms can be mentioned as examples for the substituents. For example, the following carboxylic acids can be mentioned: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valerianic acid, isovalerianic acid, caproic acid, heptanoic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myrisitic acid, pentadecylic acid, trimethylacetic acid, diethylacetic acid, tert-butylacetic acid, cyclopropylacetic acid, cyclopentylacetic acid, cyclohexylacetic acid, cyclopropanecarboxylic acid, cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid, ethoxyacetic acid, mono-, di and tri-chloroacetic acid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoic acid, with halogen, trifluoromethyl, hydroxy, alkoxy or carboxy groups substituted benzoic acids, nicotinic acid, isonicotinic acid, furan-2-carboxylic acid, cyclopentylpropionic acid. As preferred acyl radicals those are suitable with up to 10 carbon atoms. Sulfonic acids are, for example, alkanesulfonic acids with 1-10 C atoms are suitable such as, e.g., methanesulfonic acid, ethanesulfonic acid, isopropanesulfonic acid and butanesulfonic acid as well as beta-chloroethanesulfonic acid, cyclopentanesulfonic acid, cyclohexanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzene-sulfonic acid, N,N-dimetbylaminosulfonic acid, N,N-diethylamino-sulfonic acid, N,N-bis(beta-chloroethyl)-aminosulfonic acid, N,N-diisobutylaminosulfonic acid, N,N-dibutylaminosulfonic acid, pyrrolidino-, piperidino-, piperazino-, N-methylpiperazino- and morpholino-sulfonic acid. Acyl radicals and alkanesulfonic acids with 1-4 C atoms are preferred.
The hydroxy groups in W and R
4
can be functionally modified, for example, by etherification or esterification, and also the modified hydroxy group in W can be in the alpha or beta position, and free hydroxy groups are preferred.
Radicals known to those of ordinary skill in the art are suitable as ether and acyl radicals. Preferred are easily cleavable ether radicals such as, for example, the tetrahydropyranyl, tetrahydrofuranyl, alpha-ethoxyethyl, trimethylsilyl, dimethyl tert-butylsilyl, dimethyl thexylsilyl, diphenyl tert-butylsilyl and tribenzylsilyl radical. As suitable acyl radicals the same ones are suitable as mentioned for R
3
under organic carboxylic acids, namely, there can be mentioned, for example, acetyl, propionyl, butyryl and benzoyl.
As alkyl and alkenyl groups R
5
suitable are straight-chain or branched-chain alkyl radicals with 1-10 C atoms and alkenyl radicals with 2-10 C atoms, especially 1-6 and 2-6 C atoms, which optionally can be substituted by substituents phenyl, alkyl with 1-4 C atoms or halogen. There can be mentioned, for example, methyl, ethyl, propyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, butenyl, isobutenyl, propenyl, pentenyl, hexenyl as well as benzyl, and for the case, that D and E together mean a direct bond, optionally alkinyl with 2-6 C atoms substituted in the 1 position by fluorine or C
1
-C
4
alkyl. Suitable as alkinyl radicals are: ethinyl, propin-1-
Buchmann Bernd
Elger Walter
Loge Olaf
Raduechel Bernd
Skuballa Werner
Gerstl Robert
Millen White Zelano & Branigan P.C.
Schering Aktiengesellschaft
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