Alkylsulfonamido heterocyclic thrombin inhibitors

Details Alkylsulfonamido heterocyclic thrombin inhibitors Alkylsulfonamido heterocyclic thrombin inhibitors

1994-03-16

2003-03-18

Chang, Ceila (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S212010, C514S261100, C514S303000, C514S345000, C514S350000, C514S354000, C540S604000, C540S605000, C540S607000, C544S264000, C546S119000, C546S216000, C546S220000, C546S221000, C546S223000, C546S226000, C548S537000, C548S538000

Reexamination Certificate

active

06534536

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to alkylsulfonamido heterocyclic compounds which are thrombin inhibitors and thus useful in inhibiting formation of thrombi.
BACKGROUND OF THE INVENTION
U.S. application Ser. No. 146,714 filed Nov. 10, 1993, discloses sulfonamido heterocyclic thrombin inhibitors of the invention have the structure
wherein G is an amido moiety which is
including all stereoisomers thereof; and including all pharmaceutically acceptable salts thereof; wherein
R is hydrogen, hydroxyalkyl, aminoalkyl, amidoalkyl, alkyl, cycloalkyl, aryl, arylalkyl, alkenyl, alkynyl, arylalkoxyalkyl, or an amino acid side chain, either protected or unprotected;
R
1
and R
2
are independently hydrogen, lower alkyl, cycloalkyl, aryl, hydroxy, alkoxy, oxo, thioxo thioalkyl, thioaryl, amino or alkylamino; or R
1
and R
2
together with the carbons to which they are attached form a cycloalkyl, aryl, or heteroaryl ring; and
R
3
is lower alkyl, aryl, arylalkyl, heteroaryl, quinolinyl or tetrahydroquinolinyl;
n is 0, 1 or 2;
m is 0, 1, 2 or 3;
Y is NH or S;
p is 0, 1 or 2;
Q is a single bond or
A is aryl or cycloalkyl, or an azacycloalkyl ring
A of 4 to 8 carbons in the ring or an azaheteroalkyl ring a of 4 to 8 carbons in the ring, A
 where
X is CH
2
, O, S or NH;
q is 0, 1, 2, 3 or 4 if x is CH
2
;
q is 2, 3 or 4 if X is O, S or NH;
Y
1
and Y
2
are independently H, lower alkyl, halo or keto; and
R
4
is guanidine, amidine or aminomethyl;
where A is aryl or cycloalkyl, R
4
is guanidine, amidine or aminomethyl;
where A is azacycloalkyl or azaheteroalkyl, R
4
is amidine;
provided that where X is a hetero atom (that is, A is azaheteroalkyl), then there must be at least a 2-carbon chain between X and any N atom in the ring A or outside ring A;
and provided that where G is Gl, then if R
3
is alkyl, the alkyl must contain at least 3 carbons.
DESCRIPTION OF THE INVENTION
The alkylsulfonamido heterocyclic thrombin inhibitors of the invention have the structure I
wherein G is an amido moiety which is
including all stereoisomers thereof; and including all pharmaceutically acceptable salts thereof; wherein
R is hydrogen, hydroxyalkyl, aminoalkyl, amidoalkyl, alkyl, cycloalkyl, aryl, arylalkyl, alkenyl, alkynyl, arylalkoxyalkyl, or an amino acid side chain, either protected or unprotected;
R
1
and R
2
are independently hydrogen, lower alkyl, cycloalkyl, aryl, hydroxy, alkoxy, oxo, thioketal, thioalkyl, thioaryl, amino or alkylamino; or R
1
and R
2
together with the carbons to which they are attached form a cycloalkyl, aryl, or heteroaryl ring; and
n is 0, 1 or 2;
m is 0, 1, 2 or 3;
Y is NH or S; and
Alkyl
1-2
is methyl or ethyl.
The term “lower alkyl” or “alkyl” as employed herein by itself or as part of another group includes both straight and branched chain radicals of up to 18 carbons, preferably 1 to 8 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, and the like as well as such groups including 1, 2 or 3 halo substituents (for example, to form CF
3
or CF
3
CH
2
) and/or 1 or 2 of the following substituents: an aryl substituent (for example, to form benzyl or phenethyl), an alkyl-aryl substituent, a haloaryl substituent, a cyclo-alkyl substituent, an alkylcycloalkyl substituent, an alkenyl substituent, an alkynyl substituent, hydroxy or a carboxy substituent. It will be appreciated that the same “alkyl” group may be substituted with one or more of any of the above substituents.
The term “cycloalkyl” by itself or as part of another group includes saturated cyclic hydrocarbon groups containing 3 to 12 carbons, preferably 3 to 8 carbons, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, any of which groups may be substituted with substituents such as halogen, lower alkyl, alkoxy and/or hydroxy groups.
The term “aryl” or “Ar” as employed herein by itself or as part of another group refers to mono-cyclic or bicyclic aromatic groups containing from 6 to 10 carbons in the ring portion, such as phenyl, or naphthyl. Aryl (or Ar), phenyl or naphthyl may include substituted aryl, substituted phenyl or substituted naphthyl, which may include 1 or 2 substituents on either the Ar, phenyl or naphthyl such as lower alkyl, cyano, amino, alkylamino, dialkylamino, nitro, carboxy, carboalkoxy, trifluoromethyl, halogen (Cl, Br, I or F), lower alkoxy, arylalkoxy, hydroxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfinyl and/or arylsulfonyl.
The term “aralkyl”, “aryl-alkyl” or “aryl-lower alkyl” as used herein by itself or as part of another group refers to lower alkyl groups as discussed above having an aryl substituent, such as benzyl.
The term “lower alkoxy”, “alkoxy” or aralkoxy” includes any of the above lower alkyl, alkyl or aralkyl groups linked to an oxygen atom.
The term “halogen” or “halo” as used herein by itself or as part of another group refers to chlorine, bromine, fluorine or iodine with chlorine being preferred.
The term “lower alkenyl” or “alkenyl” as employed herein by itself or as part of another group includes a carbon chain of up to 16 carbons, preferably 3 to 10 carbons, containing one double bond which will be separated from “N” by at least one saturated carbon moiety such as —(CH
2
)
q
— where q can be 1 to 14, such as 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 4-pentenyl and the like, and may include a halogen substituent such as I, Cl, or F.
The term “lower alkynyl” or “alkynyl” as employed herein by itself or as part of another group includes a carbon chain of up to 16 carbons, preferably 3 to 10 carbons, containing one triple bond which will be separated from “N” by at least one saturated carbon moiety such as —(CH2)
q′
— where q′ can be 1 to 14, such as 2-propynyl, 2-butynyl, 3-butynyl and the like.
The term “heteroaryl” or heteroaromatic by itself or as part of another group refers to a 5-10-membered aromatic ring which includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygen or sulfur, such as
and the like. The heteroaryl rings may optionally be fused to aryl rings defined previously. The heteroaryl rings may optionally include 1 or 2 substituents such as halogen (Cl, Br, F or CF
3
), lower alkyl, lower alkoxy, carboxy, amino, lower alkylamino and/or dilower alkylamino.
The term “amino acid side chain” refers to any of the known alpha-amino acids such as arginine, histidine, alanine, glycine, lysine, glutamine, leucine, valine, serine, homoserine, allothreonine, naphthylalanine, isoleucine, phenylalanine and the like.
Preferred are compounds of formula I wherein n is 0 or 1; m is 2; Alkyl
1-2
is methyl; R is arylalkyl; R
1
and R
2
are independently hydrogen or lower alkyl such as methyl or ethyl; and Y is —NH—.
The compounds of formula I of the invention wherein Y is NH may be prepared according to the following Reaction Sequence I.
The compounds of formula I of the invention wherein Y is NH may also be prepared according to the following Reaction Sequence II
As seen in the above Reaction Sequence I, compounds of formula I wherein Y is —NH—, are prepared as follows. The ester II is made to undergo a carbodiimide coupling reaction with protected amino acid III in the presence of ethyl 3-(3-dimethylamino)propyl carbodiimide hydrochloride (WSC) or dicyclohexylcarbodiimide (DCC), and 1-hydroxybenzotriazole monohydrate (HOBT), and N-methylmorpholine (NMM), and in the presence of an inert organic solvent such as dimethylformamide (DMF), THF or N-methylpyrrolidone, to form the amide IV. Amide IV is deprotected by treatment with trifluoroacetic acid with or without the presence of dry inert organic solvent such as dichloromethane, chloroform or THF at temperatures within the range of from about −15° to about 20° C. Sulfonyl chloride V is added followed by organic base such as triethylamine, pyridine or N,N-diisopropylethylamine to form the sulfonamide VI. Sulf

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