Pyrimidinyl methyl indole derivatives with antibacterial...

Details Pyrimidinyl methyl indole derivatives with antibacterial... Pyrimidinyl methyl indole derivatives with antibacterial...

2002-10-25

2004-03-09

Rao, Deepak (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S228200, C514S235200, C514S235800, C544S062000, C544S122000, C544S324000

Reexamination Certificate

active

06703397

ABSTRACT:

This invention relates to indole derivatives of the general formula:
wherein
R
1
is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkylsulfonyl, cycloalkylsulfonyl, cycloalkylalkylsulfonyl, dialkylsulfamoyl, N-cycloalkyl-N-alkylsulfamoyl, heterocyclylalkyl or phenylalkyl;
R
2
is hydrogen, halogen, alkyl, alkanoyl, phenyl, phenylalkyl or heterocyclylalkyl;
R
3
is hydrogen, alkyl; and
R
4
is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkylsulfonyl, cycloalkylsulfonyl, cycloalkylalkylsulfonyl, dialkylsulfamoyl, N-cycloalkyl-N-alkylsulfamoyl, heterocyclylalkyl, or phenylalkyl;
and pharmaceutically acceptable acid addition salts of these compounds.
The above compounds are novel and possess valuable antibiotic properties. They can be used in the control and prevention of infectious diseases. In particular, they exhibit a pronounced antibacterial activity, including multi-resistant gram-positive strains, such as
Streptococcus pneumoniae
and
Staphylococcus aureus
. These compounds can also be administered in combination with known antibacterially active substances and then exhibit a synergistic effect. Typical combination partners are, e.g., sulfonamides, which can be admixed with the compounds of formula I or their salts in various ratios.
Objects of the present invention are compounds of formula I and their pharmaceutically acceptable salts per se and their use as therapeutically active substances; medicaments based on these substances, optionally in combination with sulfonamides, and their production; the use of these substances as medicaments and for the production of antibacterially active medicaments; as well as the manufacture of the compounds of formula I and their pharmaceutically acceptable salts and intermediates for their manufacture.
The residues named above are defined below. In combined residues such as cycloalkylalkyl etc. the exemplification is to be understood accordingly.
The term “Halogen” denotes fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
The term “Alkyl” denotes a straight chained or branched group which carries up to and including 6, preferably 4 carbon atoms, if not otherwise specified. Such groups are, e.g., methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl or t-butyl.
“Alkenyl ” and “alkynyl” denote unsaturated straight chain or branched hydrocarbon groups which carry up to and including 6, preferably 4 carbon atoms, having at least one double or one triple bond, respectively, e.g., vinyl, 2-propenyl, 1,3-butadienyl, isopropenyl, 1-propynyl, 2-propynyl, 1-butynyl, 3-butynyl.
“Cycloalkyl” denotes a cyclic hydrocarbon group which carries 3 to 6 carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
“Cycloalkylalkyl” denotes the combination of cycloalkyl and alkyl as defined above, e.g., cyclopropylmethyl, 2-cyclopropylethyl, cyclopentylmethyl.
“Alkanoyl” denotes the formyl group or an alkyl-CO-group, where “alkyl” is as defined above.
“Heterocyclyl” refers to heterocyclic, saturated 3 to 6 membered rings containing one or two heteroatoms selected from nitrogen, oxygen and sulfur, e.g., aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, piperidyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxolanyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, pyrazolidinyl, or 1,4-dioxo-8-aza-spiro[4.5]decan-8-yl etc., the heterocyclic group may be substituted by one or more substituents such as alkyl, alkoxy, halogen, alkanoyl or phenyl. “Phenyl” refers to unsubstituted phenyl and phenyl substituted by one or more substituents such as alkyl, alkoxy, halogen, alkanoyl or phenyl.
Preferred compounds of formula I are the compounds wherein R
1
is alkylsulfonyl, cycloalkylsulfonyl, or cycloalkylalkylsulfonyl, particularly isopropylsulfonyl, isobutyl-sulfonyl, sec-butylsulfonyl, cyclopropylsulfonyl or cyclopropylmethylsulfonyl. Preferred meanings for R
2
are hydrogen or alkyl, particularly methyl. Preferred meanings for R
3
are hydrogen or methyl. Preferred meanings for R
4
is alkyl, particularly ethyl.
Preferred compounds of formula I are:
cyclopropyl-methanesulfonic acid 6-(2,4-diamino-pyrimidin-5-ylmethyl)-1-ethyl-1H-indol-4-yl ester;
2-methyl-propane-1-sulfonic acid 6-(2,4-diamino-pyrimidin-5-ylmethyl)-1-ethyl-1H-indol-4-yl ester;
rac-butane-2-sulfonic acid 6-(2,4-diamino-pyrimidin-5-ylmethyl)-1-ethyl-1H-indol-4-yl ester;
cyclopropyl-methanesulfonic acid 6-(2,4-diamino-pyrimidin-5-ylmethyl)-1-ethyl-3-methyl-1H-indol-4-yl ester; and
rac-butane-2-sulfonic acid 6-(2,4-diamino-pyrimidin-5-ylmethyl)-1-ethyl-2-methyl-1H-indol-4-yl ester;
and pharmaceutically acceptable acid addition salts of these compounds.
The compounds of formula I form pharmaceutically acceptable acid addition salts with organic and inorganic acids. Examples of acid addition salts of compounds of formula I are salts with mineral acids, for example hydrohalic acids such as hydrochloric acid, hydrobromic acid and hydriodic acid, sulphuric acid, nitric acid, phosphoric acid and the like, salts with organic sulfonic acids, for example with alkyl- and arylsulfonic acids such as methanesulfonic acid, p-toluene sulfonic acid, benzenesulfonic acid and the like as well as salts with organic carboxylic acids, for example with acetic acid, tartaric acid, maleic acid, citric acid, benzoic acid, salicylic acid, ascorbic acid and the like.
The compounds of formula I and their pharmaceutically acceptable salts can be manufactured in accordance with the invention by
i) reacting a compound of the general formula:
 in which R
1
-R
4
have the above significance, and X represents a leaving group, with guanidine or a salt thereof, or
ii) introducing at least one of the groups R
1
, R
2
and R
4
in a compound of the general formula:
 in which R
3
is as above and R
1A
, R
2A
and R
4A
are as R
1
, R
2
and R
4
but at least one, thereof is hydrogen,or
iii) converting a compound of formula I into a pharmaceutically acceptable salt.
The cyclization of the starting materials II (where the ═CHX group can be either in (E)- or (Z)-configuration) with guanidine or a salt thereof in accordance with variant i) of the process in accordance with the invention is preferably carried out in an inert organic solvent, preferably in a lower alkanol, e.g., ethanol, or in dimethyl sulfoxide, tetrahydrofuran or dioxane, and at about 50 to 100° C. The guanidine is preferably used as a salt, e.g.) as the hydrochloride, in which case the reaction is preferably carried out in the presence of a base, e.g., potassium t-butylate. The leaving group X is preferably bromine, iodine, methylsulfonyloxy, trifluoromethylsulfonyloxy, phenylsulfonyloxy or p-tolylsulfonyloxy.
Variant ii) of the process in accordance of the invention contains several alternatives. A phenyl or heterocyclyl group R
2
can be introduced by reacting a compound of the general formula:
with a compound of the general formula:
R
21
—Y  IV
in which
R
1
, R
3
and R
4
have the above significance,
R
21
is phenyl (which may be substituted)
one of the symbols X and Y represent a leaving group and the other is a group which is eliminated with this leaving group.
In this reaction groups X and Y can be:
X=bromine, iodine, methylsulfonyloxy, trifluoromethylsulfonyloxy, phenyl-sulfonyloxy or p-tolylsulfonyloxy; and
Y=(OH)
2
B—.
This reaction with a boronic acid derivative IV, also known as a “Suzuki coupling”, is preferably effected in an inert organic solvent such as, e.g., dioxane, tetrahydrofuran or dimethyl sulfoxide at a temperature between about 20° C. and the boiling point of the reaction mixture. Preferably, a base such as an alkali metal carbonate, e.g., potassium carbonate, is preferably added as well as a catalyst, preferably a palladium complex such as tetrakistriphenylphosphine-palladium.
A compound IV with Y=—Sn(lower-alkyl)
3
, e.g., —Sn(CH
3
)
3
or —Sn(n-butyl)
3
(“Stille reaction”); —MgHal (“Grignard coupling”); o

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