Orally-active elastase inhibitors

Details Orally-active elastase inhibitors Orally-active elastase inhibitors

2000-01-28

2001-07-24

Jones, Dwayne C. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C530S330000, C530S331000

Reexamination Certificate

active

06265381

ABSTRACT:

This invention relates to orally-active elastase inhibitors useful for a variety of physiological end-use applications.
In its broad aspects, this invention relates to analogs of peptidase substrates in which the carboxy terminal carboxyl group has been replaced by a pentafluoroethylcarbonyl (—C(O)C
2
F
5
)group and in which the amino terminal amino acid is protected by various heterocycle-containing groups such as a 4-morpholinecarbonyl group. These elastase inhibitors exert valuable pharmacological activities and therefore have useful physiological consequences in a variety of disease states.
In its more specific aspects, this invention relates to pentafluoroethylcarbonyl analogs of certain elastase substrates which have various heterocyclic containing protecting groups which are useful in inhibiting elastase, the inhibition of which will have useful physiological consequences in a variety of disease states.
The contemplated elastase inhibitors are selected from the generic formulae
K—B—P
4
—P
3
—P
2
—P
1
—CF
2
CF
3
1  (SEQ. ID NO. 1)
wherein
P
1
is Ala, bAla, Leu, Ile, Val, Nva, bVal, Met, Nle, or an N-methyl derivative;
P
2
is Ala, bAla, Leu, Ile, Val, Nva, bVal, Met, Nle, Gly, Phe, Tyr, Trp, or Nal(1) where the nitrogen of the alpha-amino group can be substituted with an R group where R is a (C
1-6
)alkyl, (C
3-12
)cycloalkyl, (C
3-12
)cycloalkyl(C
1-6
)alkyl, (C
4-11
)bicycloalkyl, (C
4-11
)bicycloalkyl(C
1-6
)alkyl, (C
6-10
)aryl, (C
6-10
)aryl(C
1-6
)alkyl, (C
3-7
)heterocycloalkyl, (C
3-7
)heterocycloalkyl(C
1-6
)alkyl, (C
5-9
)heteroaryl, (C
5-9
)heteroaryl(C
1-6
)alkyl, fused (C
6-10
)aryl-(C
3-12
)cycloalkyl, fused (C
6-10
)aryl(C
3-12
)cyclo-alkyl(C
1-6
)alkyl, fused (C
5-9
)heteroaryl(C
3-12
)cycloalkyl, or fused (C
5-9
)heteroaryl(C
3-12
)cycloalkyl-(C
1-6
)alkyl, or P
2
is Pro, 1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid (Tic), thiazolidine-4-carboxylic acid (Tca), or Ind;
P
3
is Ala, bAla, Leu, Ile, Val, Nva, bVal, Met, or Nle or an N-methyl derivative, Pro, Ind, Tic or Tca, Lys or Orn each substituted on its omega amino group with a morpholino-B-group;
P
4
is Ala, bAla, Leu, Ile, Val, Nva, bVal, Met, or Nle or an N-methyl derivative or a bond;
B is a group of the formulae
R′ is a hydrogen or a C
1-6
branched or straight chain alkyl group;
n is zero or the integers 1 or 2;
K is
X is N or CH;
or a hydrate, isostere, or pharmaceutically acceptable salt thereof;
Isosteres of the compounds of formula 1 include those wherein (a) one or more of the &agr;-amino residues of the P
1
-P
4
substituents are in its unnatural configuration (when there is a natural configuration) or (b) when the normal peptidic amide linkage is modified, such as for example, to form —CH
2
NH— (reduced), —COCH
2
— (keto), —CH(OH)CH
2
— (hydroxy), —CH(NH
2
)CH
2
— (amino), —CH
2
CH
2
— (hydrocarbon), —CH═CH— (alkene). Preferably a compound of the invention should not be in an isosteric form; particularly it is preferred that there be no modified peptidic amide group, but if there is, it is preferable to keep the isosteric modifications to a minimum. Of course, it is also understood that in those instances wherein the carbonyl moiety of P
1
is in its reduced form, then such compounds are not hydrates.
As used herein the term “(C
1-6
)alkyl” means a straight or branched alkyl group of from 1 to 6 carbon atoms, such as, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, sec-pentyl, iso-pentyl, and n-hexyl. The term “(C
3-12
)cycloalkyl” means a cyclic alkyl group consisting of a 3 to 8 member ring which can be substituted by a lower alkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 4-ethylcyclohexyl, cycloheptyl, and cyclooctyl. The term “(C
3-12
)cycloalkyl(C
1-6
)alkyl” means a (C
1-6
)alkyl group substituted by a (C
3-12
)cycloalkyl group, such as a cyclohexylmethyl or cyclopentylethyl group. The term “(C
4-11
)bicycloalkyl” means an alkyl group containing one pair of bridgehead carbon atoms, such as 2-bicyclo[1.1.0]-butyl, 2-bicyclo[2.2.1]hexyl, and 1-bicyclo[2.2.2]octane. The term “(C
4-11
)bicycloalkyl(C
1-6
)alkyl” means a (C
1-6
)alkyl substituted by a (C
4-11
)bicycloalkyl, such as 2-bicyclohexlymethyl. The term “(C
6-10
)aryl” means a cyclic, aromatic assemblage of conjugated carbon atoms, for example, phenyl, 1-naphthyl, and 2-naphthyl. The term “(C
6-10
)aryl(C
1-6
)alkyl” means a (C
1-6
)alkyl substituted by a (C
6-10
)aryl, such as benzyl, phenethyl, and 1-naphthylmethyl. The term “(C
3-7
)heterocycloalkyl” means a nonaromatic, carbon containing cyclic group which contains from 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, such as morpholinyl and piperidinyl. The term “(C
3-7
)heterocycloalkyl(C
1-6
)alkyl” means a (C
1-6
)alkyl group substituted by a (C
3-7
)heterocycloalkyl group, for example, morpholinomethyl. The term “(C
5-9
)heteroaryl” means a cyclic or bicyclic, aromatic assemblage of conjugated carbon atoms and from 1 to 3 nitrogen, oxygen, and sulfur atoms, for example, pyridinyl, 2-quinoxalinyl, and quinolinyl. The term “(C
5-9
)heteroaryl(C
1-6
)alkyl” means (C
1-6
)alkyl group substituted by a (C
5-9
)heteroaryl group, such as, 3-quinolinylmethyl. The term “fused (C
6-10
)aryl(C
3-12
)cycloalkyl” means a “(C
3-12
)cycloalkyl” group which has one or more sides shared with a “(C
6-10
)aryl” group and can, for example, include groups derived by the fusion of benzene and cyclopentane, that is 2-indanyl. The term “fused (C
6-10
)aryl(C
3-12
)cycloalkyl(C
1-6
)alkyl” means a (C
1-6
)alkyl substituted by a fused (C
6-10
)aryl(C
3-12
)cycloalkyl group. The term “fused (C
5-9
)heteroaryl(C
3-8
)cycloalkyl” means a (C
5-9
)heteroaryl group which has one or more sides shared with a (C
3-8
)cycloalkyl group and can, for example, include groups derived by the fusion of cyclohexane and pyridine, that is tetrahydroquinoline. Finally the term “fused (C
5-9
)heteroaryl(C
3-8
)cycloalkyl(C
1-6
)alkyl” means a (C
1-6
)alkyl substituted by a fused (C
5-9
)heteroaryl(C
3-8
)cycloalkyl group.
Unless otherwise stated, the &agr;-amino acids of these peptidase substrate analogs are preferably in their L-configuration; however, applicants contemplate that the amino acids of the formula 1 compounds can be of either the D- or L-configurations or can be mixtures of the D- and L-isomers, including the racemic mixture. Also, the carbon adjacent to the carboxy terminal —C(═O)CF
2
CF
3
moiety can also be the D- or the L-optical isomer and can also be a mixture of such isomers. The recognized abbreviations for the &agr;-amino acids are set forth in Table I.
TABLE I
AMINO ACID
SYMBOL
Alanine
Ala
Glycine
Gly
Isoleucine
Ile
Leucine
Leu
Lysine
Lys
Phenylalanine
Phe
Proline
Pro
Tryptophan
Trp
Tyrosine
Tyr
Valine
Val
Norvaline
Nva
Norleucine
Nle
1-Naphthylalanine
Nal (1)
2-Indolinecarboxylic acid
Ind
Sarcosine
Sar
beta-Alanine
bAla
beta-Valine
bVal
Methionine
Met
1,2,3,4-Tetrahydro-3-
Tic
isoquinoline carboxylic
acid
Thiazolidine-4-carboxylic
Tca
acid
Ornithine
Orn
Some of the preferred compounds of this invention are also morpholino urea derivatives by virtue of the fact that the amino terminal amino group of the peptide chain is protected by a 4-morpholinecarbonyl group. The 4-morpholinecarbonyl protecting group of the formula
is abbreviated throughout as MC. Other preferred compounds of this invention are 4-morpholinecarbonylbenzoyl, abbreviated throughout as MCBz, derivatives wherein the morpholine-B group is of the formula
Yet other preferred copounds of this invention are 4-morpholine sulfonylbenzoyl derivatives wherein the morpholine-B group is of the formula
Still other preferred compounds of this invention are 2-(N-morpholinocarbonyl)-3-methyl-butanoyl derivatives wherein the morpholine-B group is of the formula
Of the compounds of formula 1 applicants also prefer those compounds wherein P
1
is norvaline or valine. Also preferred are those formula 1 compounds wherein P
2
is a proline or glycine; wherein P
3
is isoleucine, valine, or alanine; an

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