Note: Descriptions are shown in the official language in which they were submitted.
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Description
Novel sulfonamide derivatives as inhibitors of bone resorption and as
inhibitors
of cell adhesion
The present invention relates to sulfonamide derivatives of the formula I,
O
O
O N ~ ~ N-R'
~~H
R4 O / \NH H ' 2
N-R
S02 Rs
Rs/
in which R', R2, R4, R5 and Rg have the meanings indicated below, their
physiologically tolerable salts and their prodrugs. The compounds of the
formula
I are valuable pharmaceutical active compounds. They are vitronectin receptor
antagonists and inhibitors of cell adhesion and inhibit bone resorption by
osteoclasts. They are suitable, for example, for the therapy and prophylaxis
of
diseases which are caused at least partially by an undesired extent of bone
resorption, for example of osteoporosis. The invention furthermore relates to
processes for the preparation of compounds of the formula I, their use, in
particular as pharmaceutical active ingredients, and pharmaceutical
preparations comprising them.
Human bones are subject to a constant dynamic renovation process comprising
bone resorption and bone formation. These processes are controlled by types of
cell specialized for these purposes. Bone resorption is based on the
destruction
of bone matrix by osteoclasts. The majority of bone disorders are based on a
disturbed equilibrium between bone formation and bone resorption.
Osteoporosis is a disease characterized by low bone mass and enhanced bone
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2
fragility resulting in an increased risk of fractures. It results from a
deficit in new
bone formation versus bone resorption during the ongoing remodelling process.
Conventional osteoporosis treatment includes, for example, the administration
of
bisphosphonates, estrogens, estrogen/progesterone (hormone replacement
therapy or HRT), estrogen agonists/antagonists (selective estrogen receptor
modulators or SERMs), calcitonin, vitamin D analogues, parathyroid hormone,
growth hormone secretagogues, or sodium fluoride (Jardine et al., Annual
Reports in Medicinal Chemistry 1996, 31, 211).
Activated osteoclasts are polynuclear cells having a diameter of up to 400 Nm,
which remove bone matrix. Activated osteoclasts become attached to the
surface of the bone matrix and secrete proteolytic enzymes and acids into the
so-called "sealing zone", the region between their cell membrane and the bone
matrix. The acidic environment and the proteases cause the destruction of the
bone. The compounds of the formula I inhibit bone resorption by osteoclasts.
Studies have shown that the attachment of osteoclasts to the bones is
controlled
by integrin receptors on the cell surface of osteoclasts. Integrins are a
superfamily of receptors which include, inter alia, the fibrinogen receptor
anb(~3
on the blood platelets and the vitronectin receptor a~(i3. The vitronectin
receptor
a~/33 is a membrane glycoprotein which is expressed on the cell surface of a
number of cells such as endothelial cells, cells of the vascular smooth
musculature, osteoclasts and tumor cells. The vitronectin receptor a"~i3,
which is
expressed on the osteoclast membrane, controls the process of attachment to
the bones and bone resorption and thus contributes to osteoporosis. a"(i3 in
this
case binds to bone matrix proteins such as osteopontin, bone sialoprotein and
thrombospontin, which contain the tripeptide motif Arg-Gly-Asp (or RGD).
Horton and coworkers describe RGD peptides and an anti-vitronectin receptor
antibody (23C6) which inhibit tooth destruction by osteoclasts and the
migration
of osteoclasts (Horton et al., Exp. Cell. Res. 1991, 195, 368). In J. Cell
Biol.
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3
1990, 111, 1713, Sato et al. describe echistatin, an RGD peptide from snake
venom, as a potent inhibitor of bone resorption in a tissue culture and as an
inhibitor of osteoclast adhesion to the bones. Fischer et al. (Endocrinology
1993,
132, 1411 ) were able to show in the rat that echistatin also inhibits bone
resorption in vivo.
It was furthermore shown that the vitronectin a~(33 on human cells of the
vascular
smooth musculature of the aorta stimulates the migration of these cells into
the
neointima, which finally leads to arteriosclerosis and restenosis after
angioplasty
(Brown et al., Cardiovascular Res. 1994, 28, 1815).
Brooks et al. (Cell 1994, 79, 1157) showed that antibodies against a"~i3 or
a"(3s
antagonists sari cause a shrinkage of tumors by inducing the apoptosis of
blood
vessel cells during angiogenesis. The vitronectin receptor oc"(i3 is also
involved
in the progression of a variety of other types of cancer, and is overexpressed
in
malignant melanoma cells (Engleman et al., Annual Reports in Medicinal
Chemistry 1996, 31, 191). The melanoma invasiveness correlated with this
overexpression (Stracke et al., Encylopedia of Cancer, volume III, 1855,
Academic Press, 1997; Hillis et al., Clinical Science 1996, 91, 639). Carron
et al.
(Cancer Res. 1998, 58, 1930) describe the inhibition of tumor growth and the
inhibition of hypercalcemia of malignancy using an a~p3 antagonist.
Cheresh et al. (Science 1995, 270, 1500) describe anti-a"p3 antibodies or
a"~i3
antagonists which inhibit the bFGF-induced angiogenesis processes in the rat
eye, a property which can be used therapeutically in the treatment of
retinopathies. Influencing of the vitronectin receptor or of the interactions
in
which it is involved thus offers the possibility of influencing different
disease
states for whose therapy and prophylaxis there continues to be a need for
suitable pharmaceutical active ingredients.
WO-A-94/12181 describes substituted aromatic or nonaromatic ring systems,
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4
and WO-A-94/08577 describes substituted heterocycles as fibrinogen receptor
antagonists and inhibitors of platelet aggregation. EP-A-528586 and EP-A-
528587 disclose aminoalkyl-substituted or heterocyciyl-substituted
phenylalanine derivatives, and WO-A-95132710 discloses aryl derivatives as
inhibitors of bone resorption by osteoclasts. WO-A-96/00574 describes
benzodiazepines, and WO-A-96/00730 describes fibrinogen receptor antagonist
templates, in particular benzodiazepines which are linked to a nitrogen-
bearing
5-membered ring, as vitronectin receptor antagonists. WO-A-98/00395 (DE-A-
19654483) describes vitronectin receptor antagonists derived from a tyrosine
scaffold. EP-A-820991 (German patent application 19629816.4) describes
cycloalkyl derivatives and European patent application 97122520.6 describes
carbamic ester derivatives which are vitronectin receptor antagonists. Further
investigations have shown that the sulfonamide derivatives of the formula I
are
particularly strong inhibitors of the vitronectin receptor and of bone
resorption by
osteoclasts.
The present invention relates to compounds of the formula I,
O
O
O N ~ ~ N-R'
~~H
R4 O/I \NH H ' z
N-R
SOz Rs
Rs/
in which
R' and RZ independently of one another are hydrogen or (C,-Cs)-alkyl which is
unsubstituted or substituted by R3,
or in which the radicals R'- and R2- together are a saturated or unsaturated
bivalent (C2-Cs)-alkylene radical, for example the group -(CH2)P , in which p
is 2,
3, 4, 5, 6, 7, 8 or 9, which is unsubstituted or is substituted by one or more
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groups from the group consisting of halogen, (C,-Cs)-alkyl, (C,-Cg)-alkoxy,
(Ce-
C,4)-aryl, (Cs-C,4)-aryl-(C,-Cs)-alkyl-, (C5-C,4)-heteroaryl, (Cg-C,4)-
heteroaryl-(C,-
CB)-alkyl-, (C3-C,z)-cycloalkyl, (C3-C,z)-cycloalkyl-(C,-Cg)-alkyl- and oxo,
where a
5-membered to 7-membered saturated or unsaturated ring which is
5 unsubstituted or is substituted by R3, in particular by one or two radicals
R3, and
which is a carbocyclic ring or a heterocyclic ring containing one or two ring
nitrogen atoms, can be fused to a carbon-carbon bond in the (Cz-Cs)-alkylene
radical;
R3 is (C,-C,o)-alkyl, (C3-Czo)-monocycloalkyl, (CS-Czo)-bicycloalkyl, (C$-Czo)-
tricycloalkyl, (C,-C8)-alkoxy, (C~-C,4)-aryl, (Cs-C,4)-aryl-(C,-C4)-alkyl-,
(C~-C,4)-
heteroaryl, (Cs-C,4)-heteroaryl-(C,-C4)-alkyl-, halogen, trifluoromethyl,
cyano,
hydroxyl, oxo, nitro, amino, -NH-(C,-C4)-alkyl, -N((C,-C4)-alkyl)z, -NH-CO-(C,-
C4)-alkyl, -CO-(C,-C4)-alkyl;
R4 is hydrogen, (C,-Cs)-alkyl-CO-O-(C,-C4)-alkyl- or (C,-Cg)-alkyl which is
unsubstituted or is substituted by a radical from the group consisting of
hydroxyl,
(C,-C4)-alkoxy, (C,-C4)-alkyl-S(O)z-, -NR'R'~ and -N+R'R'~R'~~ Q-, where R',
R'
and R'~~ independently of one another are hydrogen, (C,-Cs)-alkyl, (Cs-C,4)-
aryl
or (Cs-C,4)-aryl-(C,-Cs)-alkyl- and Q- is a physiologically tolerable anion,
or in
which R4 is one of the radicals
-- N-CH --
O ~ ~ ~.,/ O 'w/~
OH
CH3 CH3 __
N O ~ ~~OH
~ \OH ~/ OH
in which the bonds, via which the radicals are bonded, are indicated by dashed
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lines;
R5 is (C,-Czo)-alkyl, (C3-Czo)-monocycloalkyl, (C5-Czo)-bicycloalkyl, (C5-Czo)-
tricycloalkyl, (Ce-C,4)-aryl, (Cs-C,4)-heteroaryl, (Cs-C,4)-aryl-(C,-Ce)-alkyl-
or (C5-
C,4)-heteroaryl-(C,-Ce)-alkyl-, where the aryl radical, the heteroaryl
radical, the
alkyl radical, the monocycloalkyl radical, the bicycloalkyl radical and the
tricycioalkyl radical each is unsubstituted or is substituted by one, two or
three
radicals R3 and wherein in the alkyl radical, the monocycloalkyl radical, the
bicycloalkyl radical and the tricycloalkyl radical one or more carbon atoms,
in
particular one, two, three or four carbon atoms, may be replaced by identical
or
different atoms selected from the series consisting of nitrogen, oxygen and
sulfur;
Rs is hydrogen, (C,-Cs}-alkyl-O-CO-, hydroxyl, (C,-Cs)-alkyl-O-CO-O- or nitro;
in all their stereoisomeric forms and mixtures thereof in all ratios, and
their
physiologically tolerable salts and their prodrugs.
All radicals which can occur several times in the compounds of the formula I,
for
example the radicals R3, can each independently of one another have the
meanings indicated, and can in each case be identical or different. Radicals
which independently of one another can have a meaning indicated, can in each
case be identical or different.
Alkyl radicals can be straight-chain or branched and can be saturated or
monounsaturated or polyunsaturated. This also applies if tfaey carry
substituents
or occur as substituents of other radicals, for example in alkoxy radicals,
alkoxycarbonyl radicals or arylalkyl radicals. The same applies to alkylene
radicals (= bivalent alkyl radicals = saturated or unsaturated aikanediyl
radicals).
Examples of suitable alkyl radicals containing from 1 to 20 carbon atoms are
methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyi, decyl,
undecyl,
dodecyl, tetradecyl, hexadecyl, octadecyl and eicosyl, the n-isomers of all
these
radicals, isopropyl, isobutyl, isopentyl, neopentyl, isohexyl, isodecyl, 3-
methyipentyl, 2,3,4-trimethylhexyl, sec-butyl, tert-butyl, tert-pentyl. A
preferred
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group of alkyl radicals is formed by the radicals methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. The bivalent radicals
corresponding to the abovementioned monovalent radicals, for example
methylene, 1,1-ethylene (= methylmethylene), 1,2-ethylene, 1, 3-propylene, 1,2-
propylene (= 1-methylethylene and 2-methylethylene), 2,3-butylene (= 1,2-
dimethyl-1,2-ethylene), 1,4-butylene, 1,6-hexylene, are examples of alkylene
radicals.
Unsaturated alkyl radicals are, for example, alkenyl radicals such as vinyl, 1-
propenyl, allyl, butenyl, 3-methyl-2-butenyl, or alkynyl radicals such as
ethynyl,
1-propynyl or propargyl. Unsaturated alkylene radicals, i. e. alkenylene and
alkynylene radicals (= alkenediyi and alkynediyl radicals), can likewise be
straight-chain or branched. Examples of alkenylene radicals are vinylene or
propenylene, and examples of alkynylene radicals are ethynylene or
propynylene. Alkyl radicals can also be unsaturated when they are substituted.
An example of an arylalkyl radical unsaturated in the alkyl moiety is styryl
(= 2-
phenylethenyl).
Unless specified otherwise, cycloalkyl radicals can be monocyclic, bicyclic or
tricyclic, i. e. they can be monocycloalkyl radicals, bicycloalkyl radicals
and
tricycloalkyl radical, provided they have a suitable number of carbon atoms.
Monocycloalkyl radicals are, for example, cyclopropyl, cyclobutyl,
cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl,
cyclododecyl, cyclotetradecyl or cyclooctadecyl which, can also be substituted
by, for example, {C,-C4)-alkyl. Examples of substituted cycloalkyl radicals
which
may be mentioned are 4-methylcyclohexyl and 2,3-dimethylcyclopentyl.
Bicycloalkyl radicals and tricycloalkyl radicals can be unsubstituted or
substituted in any desired suitable position, for example by one or more oxo
groups and/or one or more identical or different (C,-C4)-alkyl groups, for
example methyl or isopropyl groups, preferably methyl groups. The free bond
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PCT/EP99/00242
via which the bicyclic or the tricyclic radical is bonded can be located in
any
desired position in the molecule; the radical can thus be bonded via a
bridgehead atom or an atom in a bridge. The free bond can also be located in
any desired stereochemical position, for example in an exo-position or an endo-
position. Examples of bicycloalkyl radicals and tricycloalkyl radicals are,
camphanyl, bornyl, adamantyl, such as 1-adamantyl and 2-adamantyl, caranyl,
epiisobornyl, epibornyl, norbornyl and norpinanyl.
Halogen is, for example, fluorine, chlorine, bromine or iodine.
(C5-C,4)-Aryl includes heterocyclic (CS-C,4)-ary! radicals {_ (CS-C,4)-
heteroaryl
radicals) in which one or more of the 5 to 14 ring carbon atoms are replaced
by
heteroatoms such as nitrogen, oxygen or sulfur, and carbocyclic (CB-C")-aryl
radicals. Examples of carbocyclic (Cs-C,4)-aryl radicals are phenyl, naphthyl,
biphenylyl, anthryl or fluorenyl, where 1-naphthyl, 2-naphthyl and phenyl are
preferred. If not stated otherwise, aryl radicals, in particular phenyl
radicals, can
be unsubstituted or substituted by one or more radicals, preferably one, two
or
three identical or different radicals. In particular aryl radicals can be
substituted
by identical or different radicals from the group consisting of (C,-C8)-alkyl,
in
particular (C,-C4)-alkyl, (C,-C8)-alkoxy, in particular (C,-C4)-alkoxy,
halogen,
such as fluorine, chlorine and bromine, vitro, amino, trifluoromethyl,
hydroxyl,
methylenedioxy, cyano, hydroxycarbonyl, aminocarbonyl, (C,-C4)-
alkoxycarbonyl, phenyl, phenoxy, benzyl and benzyioxy. Generally, only up to
two vitro groups can occur as substituents in the compounds of the formula I
according to the invention.
In monosubstituted phenyl radicals, the substituent can be located in the 2-
position, the 3-position or the 4-position, the 3- and the 4-position being
preferred. If phenyl is disubstituted, the substituents can be in the 2,3-
position,
2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position.
Preferably, in
disubstituted phenyl radicals, the two substituents are arranged in the 3,4
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position, relative to the linkage site. In trisubstituted phenyl radicals, the
substituents can be in the 2,3,4-position, 2,3,5-position, 2,3,6-position,
2,4,5-
position, 2,4,6-position or 3,4,5-position. Similarly, naphthyl radicals and
other
aryl radicals can be substituted in any desired position, for example a 1-
naphthyl
radical in the 2-, 3-, 4-, 5-, 6-, 7- and 8-position, a 2-naphthyl radical in
the 1-,
3-, 4-, 5-, 6-, 7- and 8-position.
Beside carbocyclic systems, (Cs-C,4)-aryl groups can also be monocyclic or
polycyclic, for example bicyclic or tricyclic, aromatic ring systems in which
1, 2,
3, 4 or 5 ring carbon atoms are replaced by heteroatoms, in particular by
identical or different heteroatoms from the group consisting of nitrogen,
oxygen
and sulfur. Examples of heterocyclic (Cs-C,4)-aryl groups and (Cs-C,4)-
heteroaryl
groups are pyridyl like 2-pyridyl, 3-pyridyl and 4-pyridyl, pyrrolyl like 2-
pyrrolyl
and 3-pyrrolyl, furyl like 2-furyl and 3-furyl, thienyl like 2-thienyf and 3-
thienyl,
imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
tetrazolyl,
pyridazinyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, indazolyl,
phthalazinyi,
quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, ~i-carbolinyl,
or benzo-
fused, cyclopenta-fused, cyclohexa-fused or cyclohepta-fused derivatives of
these radicals. The heterocyclic systems can be substituted in all suitable
positions by the same substituents as the abovementioned carbocyclic aryl
systems.
In the series of these heteroaryl groups, monocyclic or bicyclic aromatic ring
systems having 1, 2 or 3 heteroatoms, in particular 1 or 2 heteroatoms, from
the
group consisting of N, O and S, which can be unsubstituted or substituted by
1,
2 or 3 substituents from the group consisting of (C,-Cs)-alkyl, (C,-Cs)-
alkoxy,
fluorine, chlorine, nitro, amino, trifluoromethyl, hydroxyl, (C,-C4)-
alkoxycarbonyl,
phenyl, phenoxy, benzyloxy and benzyl, are preferred. Particularly preferred
here are monocyclic or bicyclic aromatic 5-membered to 10-mernbered ring
systems having 1 to 3 heteroatoms, in particular having 1 or 2 heteroatoms,
from
the group consisting of N, O and S, which can be substituted by 1 to 2
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substituents from the group consisting of (C,-C~)-alkyl, (C,-C4)-alkoxy,
phenyl,
phenoxy, benzyt and benzyloxy. More particularly preferred are 5-membered or
6-membered monocyclic heteroaryl groups and 9- or 10-membered bicyclic he-
teroaryl groups containing 1 or 2, in particular 1, heteroatom from the group
con-
s sisting of N, O and S which are unsubstituted or substituted as described
before.
If the two radicals R'- and RZ- together represent a bivalent saturated or
unsaturated (CZ-Cs)-alkyiene radical, these two radicals together with the two
nitrogen atoms to which they are bonded and the central carbon atom of the
10 guanidino group to which these two nitrogen atoms are bonded, form a
monocyclic 1,3-diazaheterocycle which is bonded to the nitrogen atom in the
group (CH2)Z-CO-NH via its 2-position. Examples of radicals of such 1,3-
diazaheterocycles which can be substituted as indicated in the (Cz-Ca)-
alkylene
radical and also on the guanidino nitrogen atom, are the 2-imidazolyl radical,
the
4,5-dihydro-2-imidazolyl radical, the 1,4,5,6-tetrahydro-2-pyrimidinyl radical
or
the 4,5,6,7-tetrahydro-1 H-1,3-diazepin-2-yl radical. If a 5-membered to 7
membered ring is fused to a carbon-carbon bond in the (C2-C9)-alkylene
radical,
then the two radicals R' and RZ, together with the two nitrogen atoms to which
they are bonded and the central carbon atom of the guanidino group to which
these two nitrogen atoms are bonded form a bicyclic heterocycle which is
bonded to the nitrogen atom in the~group (CH2)Z-CO-NH and which can be
substituted as indicated. The fused (or condensed) 5-membered to 7-membered
ring can be saturated, mono-unsaturated or di-unsaturated or aromatic. Thus,
for example, a cyclopentane ring, cyclohexane ring, cyclohexene ring,
cyclohexadiene ring, cycloheptane ring or benzene ring can be condensed.
Examples of radicals of such bicyclic heterocycles which can be bonded to the
nitrogen atom in the group (CHZ)2-CO-NH are the 1,3a,4,5,6,6a-hexahydro-1,3-
diazapentalen-2-yl radical, the 1 H-benzimidazol-2-yl radical, the
3a,4,5,6,7,7a-
hexahydro-1 H-benzimidazol-2-yl radical, the 4,5,6,7-tetrahydro-1 H-
benzimidazol-2-yl radical, the 4,7-dihydro-1 H-benzimidazol-2-yl radical or
the
1 H-imidazo[4,5-bjpyridin-2-yl radical. If a condensed ring is substituted
and/or if
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the (C2-Cs)-alkylene radical is substituted, they are preferably independently
of
one another monosubstituted or disubstituted by identical or different
radicals
R3. If alkyl groups representing R' and/or R2 are substituted, they are
preferably
independently of one another monosubstitued or disubstituted, in particular
monosubstituted, by identical or different radicals R3.
Optically active carbon atoms present in the compounds of the formula I can
independently of one another have the R configuration or the S configuration.
The compounds of the formula I can be present in the form of pure enantiomers
or pure diastereomers or in the form of enantiomer mixtures, for example in
the
form of racemates, or of diastereomer mixtures. The present invention relates
to
both pure enantiomers and enantiomer mixtures as well as to pure
diastereomers and diastereomer mixtures. The invention comprises mixtures of
two or of more than two stereoisomers of the formula I and all ratios of the
stereoisomers in the mixtures. The compounds of the formula I can optionally
be
present as E isomers or Z isomers. The invention relates to both pure E
isomers
and pure Z isomers and E/Z mixtures in al! ratios. The invention also
comprises
all tautomeric forms of the compounds of the formula I, for example, beside
the
form shown in the formula I, also the form in which the acylguanidine unit is
present as a -CO-N=C(NHR'}-NR2R6 group, and all other forms which differ by
different positions of mobile hydrogen atoms. Diastereomers, including E/Z
isomers, can be separated into the individual isomers, for example, by
chromatography. Racemates can be separated into the two enantiomers by
customary methods, for example, by chromatography on chiral phases or by
resolution. Stereochemically unifom compounds of the formula I can also be
obtained by employing stereochemically uniform starting materials or by using
stereoselective reactions.
Physiologically tolerable salts of the compounds of formula I are nontoxic
salts
that are physiologically acceptable, in particular pharmaceutically utilizable
salts. Such salts of compounds of the formula I containing acidic groups, for
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example carboxyl, are, for example, alkali metal salts or alkaline earth metal
salts such as, for example, sodium salts, potassium salts, magnesium salts and
calcium salts, and also salts with physiologically tolerable quaternary
ammonium
ions and acid addition salts with ammonia and physiologically tolerable
organic
amines, such as, for example, triethylamine, ethanolamine or tris-(2-
hydroxyethyl)amine. Compounds of the formula I containing basic groups form
acid addition salts, for example with inorganic acids such as hydrochloric
acid,
sulfuric acid or phosphoric acid, or with organic carboxylic acids and
sulfonic
acids such as acetic acid, citric acid, benzoic acid, malefic acid, fumaric
acid,
10tartaric acid, methanesulfonic acid or p-toluenesulfonic acid. Compounds of
the
formula I which contain a basic group and an acidic group, for example the
guanidino group and a carboxyl group, can be present as zwitterions
(betaines),
which are likewise included by the present invention.
The physiologically tolerable anion Q- which is contained in the compounds of
the formula I when R" is an alkyl radical which is substituted by a positively
charged ammonium group, is, in particular, a monovalent anion or an eqivalent
of a polyvalent anion of a nontoxic, physiologically utilizable, in particular
also
pharmaceutically utilizable, inorganic or organic acid, for example the anion
or
an anion equivalent of one of the abovementioned acids suitable for the
formation of acid addition salts. Q- can thus be, for example, one of the
anions
(or an anion equivalent) from the group consisting of chloride, sulfate,
phosphate, acetate, citrate, benzoate, maleate, fumarate, tartrate,
methanesulfonate and p-toluenesulfonate.
Salts of compounds of the formula i can be obtained by customary methods
known to those skilled in the art, for example by combining a compound of the
formula 1 with an inorganic or organic acid or base in a solvent or
dispersant, or
from other salts by ration exchange or anion exchange. The present invention
also includes all salts of the compounds of the formula I which, because of
low
physiologically tolerability, are not directly suitable for use in
pharmaceuticals,
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but are suitable, for example, as intermediates for carrying out other
chemical
modifications of the compounds of the formula I or as starting materials for
the
preparation of physiologically tolerable salts.
The present invention moreover includes all solvates of compounds of the
formula I, for example hydrates or adducts with alcohols, and also derivatives
of
the compounds of the formula I, for example esters, prodrugs and other
physiologically tolerable derivatives, as well as active metabolites of the
compounds of the formula I. The invention relates in particular to prodrugs of
the
compounds of the formula I, which can be converted into compounds of the
formula I under physiological conditions. Suitable prodrugs for the compounds
of
the formula I, i. e. chemically modified derivatives of the compounds of the
formula I having properties which are improved in a desired manner, are known
to those skilled in the art. More detailed information relating to prodrugs is
found, for example, in Fleisher et al., Advanced Drug Delivery Reviews 19
(1996) 115-130; Design of Prodrugs, H. Bundgaard, Ed., Elsevier, 1985; H.
Bundgaard, Drugs of the Future 16 (1991 ) 443; Saulnier et al., Bioorg. Med.
Chem. Lett. 4 (1994) 1985; Safadi et al., Pharmaceutical Res. 10 (1993) 1350
which are all incorporated herein by reference. Suitable prodrugs for the
compounds of the formula I are especially ester prodrugs of carboxylic acid
groups, in particular of the COOH group which is present when R" in the group
COOR4 is hydrogen, for example alkyl esters of this group like (C,-Cg)-alkyl
esters or (C,-C,,}-alkyl esters, and also acyl prodrugs and carbamate prodrugs
of
acylatable nitrogen-containing groups such as amino groups and in particular
the guanidino group. In the acyl prodrugs or carbamate prodrugs, one or more
times, for example twice, a hydrogen atom located on a nitrogen atom in these
groups is replaced by an acyl group or carbamate group. Suitable acyl groups
and carbamate groups for the acyl prodrugs and carbamate prodrugs are, for
example, the groups R'°-CO and R"O-CO, in which R'° is hydrogen,
(C,-C,$)-
alkyl, (C3-C,4)-cycloalkyl, (C3-C,4)-cycloaikyl-(C,-C8)-alkyl-, (CS-C,4)-aryl,
in which
1 to 5 carbon atoms can be replaced by heteroatoms such as N, O or S, or (CS-
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14
C,,,)-aryl-(C,-Cs)-alkyl-, in which 1 to 5 carbon atoms in the aryl moiety can
be
replaced by heteroatoms such as N, O or S, and in which R" has the meanings
indicated for R'° with the exception of hydrogen.
In the compounds of the formula I, the radicals R' and Rz are preferably
hydrogen or together are a saturated or unsaturated, in particular a
saturated,
bivalent (Cz-C5)-alkylene radical, in particular a (Cz-C4)-alkylene radical,
especially a (Cz-C3)-alkylene radical, which is unsubstituted or is
substituted by
one or two identical or different radicals from the group consisting of
halogen,
(C,-Ce)-alkyl, (C,-Cs)-alkoxy, (Cs-C,a)-aryl, (Cs-C,,,)-aryl-(C,-Ce)-alkyl-,
(C5-C,a)-
heteroaryl, (CS-C,4)-heteroaryl-(C,-Ce)-alkyl-, (C3-C,z)-cycloalkyl, (C3-C,z)-
cycloalkyl-(C,-Ce)-alkyl- and oxo, where a 5-membered to 7-membered
saturated or unsaturated ring which is unsubstituted or is substituted by R3,
in
particular by one or two radicals R3, and which is a carbocyclic ring or
heterocyclic ring containing one or two ring nitrogen atoms can be fused to a
carbon-carbon bond in the alkylene radical. In the compounds of the formula I,
the radicals R' and Rz are particularly preferably hydrogen or the group -
(CHz)p-,
in which p is the numbers 2, 3, 4 or 5, preferably the numbers 2, 3 or 4,
particularly preferably the numbers 2 or 3, and which is unsubstituted or is
substituted by one or two identical or different radicals from the group
consisting
of halogen, (C,-Cs)-alkyl, (C,-Cg)-alkoxy, (Cs-C,4)-aryl, (Cs-C,4)-aryl-(C,-
CB)-
alkyl-, (Cs-C,4)-heteroaryl, (Cs-C,4)-heteroaryl-(C,-Cs)-alkyl-, (C3-C,z)-
cycloalkyl,
(C3-C,z)-cycloalkyl-(C,-CB)-alkyl- and oxo, where a 5-membered to 7-membered
saturated or unsaturated ring which is unsubstituted or is substituted by R3,
in
particular by one or two radicals R3, and which is a carbocyclic ring or
heterocyclic ring containing one or two ring nitrogen atoms, can be fused to a
carbon-carbon bond in the group -(CHz)P . More particularly preferably the
radicals R' and Rz together are the group -(CHz)p-, in which p is the numbers
2,
3, 4 or 5, preferably the numbers 2, 3 or 4, particularly preferably the
numbers 2
or 3, which preferably is unsubstituted. Especially preferably the radicals R'-
and Rz- together are the bivalent radical -CHz-CHz-CHz-, i. e. R' and Rz
together
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with the nitrogen atoms to which they are bonded and with the central carbon
atom of the guanidino group to which these nitrogen atoms are bonded, form a
1,4,5,6-tetrahydro-2-pyrimidinyl radical.
5 R3 preferably is (C,-C,o)-alkyl, (C3-Czo)-monocycloalkyl, (Cs-Czo)-
bicycloalkyl,
(Cs-Czo)-tricycloalkyl, (C,-C8)-alkoxy, (Cs-C,4)-aryl, (C5-C,4)-heteroaryl,
(Cg-C,4)-
aryl-(C,-C4)-alkyl-, (Cs-C,,,)-heteroaryl-(C,-C4)-alkyl-, halogen,
trifluoromethyl,
cyano, oxo, -N((C,-C,,)-alkyl)z or -NH-CO-(C,-C4)-alkyl. More preferably, R3
is
(C,-C4)-alkyl, {C3-C,o)-monocycloalkyl, (Cs-C,z)-bicycloalkyl, (Cs-C,z)-
10 tricycloalkyl, (C,-C4)-alkoxy, {Cs-C,4)-aryl, (Ce-C,4)-aryl-(C,-C4)-alkyl-,
halogen,
trifluoromethyl, cyano, oxo, -N((C,-C4)-alkyl)z or -NH-CO-(C,-C4)-alkyl.
Particularly preferably R3 is (C,-C4)-alkyl, (C3-C,o)-monocycloalkyl, (C5-C,z)-
bicycloalkyl, (Cs-C,z)-tricycloalkyl, (C,-C4)-alkoxy, (Cs-C,4)-aryl, halogen,
trifluoromethyl, cyano, oxo, -N((C,-C4)-alkyl)z or -NH-CO-{C,-C4)-alkyl.
R4 is preferably hydrogen or unsubstituted or substituted (C,-Cs}-alkyl,
particularly preferably hydrogen or (C,-Cg)-alkyl, which is unsubstituted or
substituted by a radical from the group consisting of (C,-C4)-alkoxy, (C,-C4)-
alkyl-S(O)z- and -NR'R'~, where R' and R'~ independently of one another are
hydrogen or (C,-C4)-alkyl. R" is very particularly preferably hydrogen or
unsubstituted or substituted (C,-C4}-alkyl, moreover preferably hydrogen or
(C,-
C4)-alkyl which is unsubstituted or substituted as indicated before.
R5 preferably is (C,-Czo)-alkyl, (C3-Czo)-monocycloalkyl, (CS-Czo)-
bicycloalkyl,
(CS-Czo)-tricycloalkyl, (Cs-C,4)-aryl, (Cs-C,4)-heteroaryl, (CB-C,4)-aryl-(C,-
Cs)-
aikyl- or (Cs-C,4)-heteroaryl-(C,-Cg)-alkyl-, where the aryl radical, the
heteroaryl
radical, the alkyl radical, the monocycloalkyl radical, the bicycloalkyl
radical and
the tricycloalkyl radical each is unsubstituted or is substituted by one, two
or
three identical or different radicals R3. More preferably R5 is (C,-C,o)-
alkyl, (C3-
C,s)-monocycloalkyl, (Cs-C,5)-bicycloalkyl, (Cs-C,5)-tricycloalkyl, {CB-C,4)-
aryl,
(Cs-C,4)-heteroaryl, (Cs-C,4)-aryl-(C,-Ce)-alkyl- or (Cs-C,4)-heteroaryl-(C,-
CB)-
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1fi
alkyl-, where the aryl radical, the heteroaryl radical, the alkyl radical, the
monocycloalkyl radical, the bicycloalkyl radical and the tricycfoalkyl radical
each
is unsubstituted or is substituted by one, two or three identical or different
radicals R3. Besides these preferences, a preferred group of radicals R5 is
formed by the radicals (C3-Czo)-monocycloalkyl, (C5-Czo)-bicycloalkyl and (C5-
Czo)-tricycloalkyl which can be substituted or otherwise modified as indicated
above and which moreover preferred are (C5-C,s)-monocycloalkyl, (Cs-C,s)-
bicycloalkyt, (C5-C,5)-tricycloalkyl. Another preferred group of radicals R5
is
formed by the radicals (C,-Czo)-alkyl, (Cs-C,4)-aryl, (C5-C,4)-heteroaryl, (C~-
C~4)-
aryl-(C,-Cs)-alkyl- or {C5-C~4)-heteroaryl-{C,-Cs)-alkyl-, of which (Ce-C")-
aryl and
(Cs-C,4)-heteroaryl are preferred, which can be substituted or otherwise
modified
as indicated above. A particularly preferred groups of radicals RS is formed
by
the radicals phenyl and naphthyl, i. e. phenyl, 1-naphthyl and 2-naphthyl,
which
can be unsubstituted or substituted as indicated above.
Rs is preferably hydrogen or (C,-Cs)-alkyl-O-CO-, particularly preferably
hydrogen or (C~-C4)-alkyl-O-CO-, in particular hydrogen.
Preferred compounds of the formula I are those compounds in which one or
more of the radicals have preferred meanings or have one specific or some
specific of their respective denotations, all combinations of such preferred
meanings or specific denotations being a subject of the present invention.
Particularly preferred compounds of the formula I are those compounds in which
R' and Rz are hydrogen or together are a saturated or unsaturated bivalent (Cz-
Cs)-alkylene radical, in particular hydrogen or together the group -(CHz)P ,
in
which p is the numbers 2, 3, 4 or 5, where the (Cz-Cs)-alkylene radical and
the
group -(CHz)p- are unsubstituted or are substituted by a radical from the
group
consisting of halogen, (C,-Cs)-alkyl, (C,-Cs)-atkoxy, {Cs-C,,,)-aryl, (Cg-C,4)-
aryl-
(C,-Cs)-alkyl-, (Cs-C,4)-heteroaryl, (CS-C,4)-heteroaryl-(C,-Cs)-alkyl-, (C3-
C,z)-
cycloalkyl, (C3-C~z)-cyc(oalkyl-(C,-Cs)-alkyl- and oxo, and where a 5-membered
to 7-membered saturated or unsaturated ring which is unsubstituted or
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PCT/EP99/00242
17
substituted by R3, in particular by one or two radicals R3, and which is a
carbocyclic ring or heterocyclic ring containing one or two ring nitrogen
atoms,
can be fused to a carbon-carbon bond in the (CZ-Cs)-alkylene radical and in
the
group -(CHZ)P-;
R3 is (C,-C,o)-alkyl, (C3-C2o}-monocycloalkyl, (Cs-C2o)-bicycloalkyl, (Cs-CZO)-
tricycloalkyl, (C,-Cs)-alkoxy, (C8-C,4)-aryl, (Cs-C,4)-heteroaryl, (CB-C,4)-
aryl-(C,-
C4)-alkyl-, (Cs-C,4)-heteroaryl-(C,-C4)-alkyl-, halogen, trifluoromethyl,
cyano,
oxo, -N((C,-C4)-alkyl)2 or -NH-CO-{C,-C4}-alkyl;
R4 is hydrogen or (C,-Cs)-alkyl which is unsubstituted or is substituted by a
radical from the group consisting of (C,-C4}-alkoxy, (C,-C4)-alkyl-S(O)z- and
NR'R'~, where R' and R'~ independently of one another are hydrogen or (C,-C4)-
alkyl;
Rs is (C,-C2o)-alkyl, (C3-C2o)-monocycloalkyl, (Cs-C2o)-bicycloalkyl, (Cs-C2o)-
tricycloalkyl, (CB-C,4}-aryl, (Cs-C,4)-heteroaryl, (Cs-C,4)-aryl-(C,-Cs)-alkyl-
or (Cs-
C,4)-heteroaryl-(C,-Cs)-alkyl-, where the aryl radical, the heteroaryl
radical, the
alkyl radical, the monocycloalkyl radical, the bicycloalkyl radical and the
tricycioalkyl radical each is unsubstituted or is substituted by one, two or
three
radicals R3.
RB is hydrogen or (C,-CB)-alkyl-O-CO-;
in all their stereoisomeric forms and mixtures thereof in all ratios, and
their
physiologically tolerable salts and their prodrugs. ~ ,
Very particularly preferred compounds of the formula t are those compounds in
which
R' and RZ are hydrogen or together are a saturated or unsaturated bivalent (CZ-
C4)-alkylene radical, in particular hydrogen or together the group -{CHZ)P-,
in
which p is the numbers 2, 3 or 4, where the (C2-C4)-alkylene radical and the
group -(CHz)P are unsubstituted or are substituted by a radical from the group
consisting of halogen, (C,-Cs)-alkyl, (C,-Cs)-alkoxy, (Cs-C,4)-aryl, (Cs-C,4)-
aryl-
(C,-Cs}-alkyl-, (Cs-C,4)-heteroaryl, (Cs-C,4)-heteroaryl-(C,-Cs)-alkyl-, (C3-
C,2)-
cycloalkyl, (C3-C,z)-cycloalkyl-(C,-Cs)-alkyl- and oxo, and where a 5-membered
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PCT/EP99/00242
to 7-membered saturated or unsaturated ring which is unsubstituted or is
substituted by R3, in particular by one or two radicals R3, and which is a
carbocyclic ring or heterocyclic ring containing one or two ring nitrogen
atoms,
can be fused to a carbon-carbon bond in the (C2-C,,)-alkylene radical and in
the
group -(CH2)v-i
R3 is (C,-C4)-alkyl, (C3-C,o)-monocycloalkyl, (C5-C,2)-bicycloalkyl, (C5'C~2)-
tricycloalkyl, (C,-C4)-alkoxy, (C~-C,,,)-aryl, (Cg-C,4)-aryl-(C,-C4)-alkyl-,
halogen,
trifluoromethyl, cyano, oxo, -N((C,-C4)-alkyl)Z or -NH-CO-(C,-C4)-alkyl;
R° is hydrogen or (C,-Cg)-alkyl;
R5 is (C,-C,o)-alkyl, (C3-C,3)-monocycloalkyl, (C5-C,5)-bicycloalkyl, (C5-C,5)-
tricycloalkyl, (Cg-C,4)_aryl, (CS-C,,,)-heteroaryl, (Cs-C,4)-aryl-(C,-Ce)-
alkyl- or (C5-
C,a)-heteroaryl-(C,-Cs)-alkyl-, where the aryl radical, the heteroaryl
radical, the
alkyl radical, the monocycloalkyl radical, the bicycloalkyl radical and the
tricycloalkyl radical each is unsubstituted or is substituted by one, two or
three
radicals R3.
Rs is hydrogen or (C,-C4)-alkyl-O-CO-;
in all their stereoisomeric forms and mixtures thereof in all ratios, and
their
physiologically tolerable salts and their prodrugs.
Especially preferred compounds of the formula I are those in which:
R' and R~ are hydrogen or together are a saturated or unsaturated bivalent (CZ-
C3)-alkylene radical, m particular hydrogen or together the group -(CHZ)P-, in
which p is the numbers 2 or 3, where the (CZ-C3)-alkylene radical and the
group
-(CHZ)P- are unsubstituted or are substituted by a radical from the group
consisting of halogen, (C,-Cg)-alkyl, (C,-Cs)-alkoxy, (Cg-C,4)-aryl, (CB-C,4)-
aryl-
(C,-Cs)-alkyl-, (Cs-C,4)-heteroaryl, (CS-C,4)-heteroaryl-(C,-Cs)-alkyl-, (C3-
C,2)-
cycloalkyl, (C3-C,Z)-cycloalkyl-(C,-Cs)-alkyl- and oxo, and where a 5-membered
to 7-membered saturated or unsaturated ring which is unsubstituted or is
substituted by R3, in particular by one or two radicals R3, and which is a
carbocyclic ring or heterocyclic ring containing one or two ring nitrogen
atoms,
can be fused to a carbon-carbon bond in the (Cz-C3)-alkylene radical and in
the
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19
group -(CHz)P-;
R3 is (C,-C4)-alkyl, (C3-C,o)-monocycloalkyl, (Cs-C,z)-bicycloalkyl, (CS-C,z)-
tricycloalkyl, (C,-C,,)-alkoxy, (Cs-C,4)-aryl, halogen, trifluoromethyl,
cyano, oxo,
-N((C,-C4)-alkyl)z or -NH-CO-(C,-C4)-alkyl;
R" is hydrogen or (C,-Cs)-alkyl;
Rs is (C,-C,a)-alkyl, (C3-C,s)-monocycloalkyl, (C5-C,5)-bicycloalkyl, (CS-C,5)-
tricycloalkyl, (Cs-C,4)-aryl, (C5-C,4)-heteroaryl, (Cs-C,4)-aryl-(C,-Cs)-alkyl-
or (C5-
C,4)-heteroaryl-(C,-Cs)-alkyl-, where the aryl radical, the heteroaryl
radical, the
alkyl radical, the monocycloalkyl radical, the bicycloalkyl radical and the
tricycloalkyl radical each is unsubstituted or is substituted by one, two or
three
radicals R~.
R8 is hydrogen or (C,-C4)-alkyl-O-CO-;
in all their stereoisomeric forms and mixtures thereof in all ratios, and
their
physiologically tolerable salts and their prodrugs.
Moreover preferred compounds of the formula I are those in which RS is (Cg-
C,4)-
aryl or (Cs-C,4)-heteroaryl, preferably (Ce-C,4)-aryl, where the aryl radical
and
the heteroaryl radical each is unsubstituted or is substituted by one, two or
three
identical or different radicals R3 and preferably is unsubstituted or
substituted by
one or two identical or different radicals R3, in all their stereoisomeric
forms and
mixtures thereof in all ratios, and their physiologically tolerable salts and
their
prodrugs. Even more preferred compounds of the formula i are those in which R5
is a naphthyl radical, such as a 1-naphthyl radical or a 2-naphthyl radical,
which
is unsubstituted or is substituted by one, two or three radicals R3, and which
preferably is unsubstituted, such as an unsubstituted 1-naphthyl radical or an
unsubstituted 2-naphthyl radical, in all their stereoisomeric forms and
mixtures
thereof in all ratios, and their physiologically tolerable salts and their
prodrugs.
Preferred compounds of the formula I are additionally those in which the
carbon
atom to which the two groups R°O-CO- and R5-SOz-NH- are bonded has the
S
configuration, in all their stereoisomeric forms and mixtures thereof in all
ratios,
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and their physiologically tolerable salts and their prodrugs.
A specific group of compounds of the formula I is formed by compounds in which
R' and RZ independently of one another are hydrogen or (C,-Cg)-alkyl which is
5 unsubstituted or substituted by R3,
or in which the radicals R'- and RZ- together are a saturated or unsaturated
bivalent (C2-C9)-alkylene radical, for example the group -(CHZ)P-, in which p
is 2,
3, 4, 5, 6, 7, 8 or 9, which is unsubstituted or is substituted by one or more
groups from the group consisting of halogen, (C,-Ce)-alkyl, (C,-Cs)-alkoxy,
(Cg-
10 C,4)-aryl, (Cs-C,4)-aryl-(C,-Cs)-alkyl, (Cs-C,Q)-heteroaryl, (Cs-C,a)-
heteroaryl-(C,-
Cg)-alkyl, (C3-C,Z)-cycloalkyl and (C3-C,2)-cycioalkyl-(C,-CB)-alkyl and oxo,
where
a 5-membered to 7-membered saturated or unsaturated ring which is
unsubstituted or is substituted by R3, in particular by one or two radicals
R3, and
which is a carbocyclic ring or a heterocyclic ring containing one or two ring
15 nitrogen atoms, can be fused to a carbon-carbon bond in the (Cz-Cs)-
alkylene
radical;
R3 is (C,-Ce)-alkyl, (C,-Ce)-alkoxy, (Cs-C,4)-aryl, (Cs-C,4)-aryl-(C,-C4)-
alkyl, (Cs-
C,,,)-heteroaryl, (Cs-C,4)-heteroaryl-(C,-C4)-alkyl, halogen, trifluoromethyl,
hydroxyl, oxo, nitro, amino, NH-(C,-C4)-alkyl, N-((C,-C4)-alkyl)2, NH-CO-(C,-
C4)-
20 alkyl, CO-(C,-C4)-alkyl;
R4 is hydrogen, (C,-Ce)-alkyl-CO-O-(C,-C4)-alkyl or (C,-Ce)-alkyl, which is
unsubstituted or is substituted by a radical from the group consisting of
hydroxyl,
(C,-C4)-alkoxy, (C,-C4)-alkyl-S(O)2, NR'R'~ and N+R'R'~Rr~ Q-, where R', R'~
and
R'~~ independently of one another are hydrogen, (C,-Cs)-alkyl, (Cs-C,4)-aryl
or
(Cs-C,4)-aryl-(C,-Cg)-alkyl and Q- is a physiologically tolerable anion, or in
which
R4 is one of the radicals
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21
N CH _ O ~ ~'~Ow,,/~
OH
CH3 CH3 __ \ ~
~''~OH
~~0~ N I0
OH ~/ OH
in which the free bonds, via which the radicals are bonded, are indicated by
dashed lines;
RS is (C,-CZO)-alkyl, (CS-C2o)-monocycloalkyl, (CS-C2o)-bicycloalkyl, (C5-CZO)-
tricycloalkyl, (CB-C,a)-aryl, (Cs-C,4)-heteroaryl, (Cs-C,4)-aryl-(C,-Cs)-alkyl
or (C5-
C,4)-heteroaryl-(C,-CB)-alkyl, where the aryl radical, the heteroaryl radical,
the
alkyl radical, the monocycloalkyl radical, the bicycloalkyl radical and the
tricycloaikyl radical each is unsubstituted or is substituted by one, two or
three
radicals R3 and wherein in the alkyl radical, the monocycloalkyl radical, the
bicycloalkyl radical and the tricycloalkyl radical one or more carbon atoms,
in
particular one, two, three or four carbon atoms, may be replaced by identical
or
different atoms selected from the series consisting of nitrogen, oxygen and
sulfur;
Re is hydrogen, (C,-Cs)-alkyl-O-C0, hydroxyl, (C,-Cg)-alkyl-O-CO-O or nitro;
in all their stereoisomeric forms and mixtures thereof in all ratios, and
their
physiologically tolerable salts and their prodrugs.
The present invention also relates to processes for the preparation of the
compounds of the formula I. The compounds can generally be prepared, for
example in the course of a convergent synthesis, by linkage of two or more
fragments which can be derived retrosynthetically from the formula I. In the
preparation of the compounds of the formula I it can generally be advantageous
or necessary in the course of the synthesis to introduce functional groups
which
could lead to undesired reactions or side reactions in the respective
synthesis
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PCT/EP99/0024Z
step, in the form of precursors which are later converted into the desired
functional groups, or to temporarily block functional groups by a protective
group
strategy suited to the synthesis problem. Such strategies are well known to
one
skilled in the art (see, for example, Greene and Wuts, Protective Groups in
Organic Synthesis, Wiley, 1991 ). As examples of precursor groups nitro groups
and cyano groups may be mentioned which can later be converted by reduction,
for example by catalytic hydrogenation, into amino groups and aminomethyl
groups, respectively.
The compounds of the formula I can be prepared, for example, by linking in a
manner known per se a carboxylic acid or carboxylic acid derivative of the
formula ll
O
O
O N
~~H
Ra O NH X
Rs/S02
II
in which R4 and RS are defined as indicated for the formula I, or in which
alternatively functional groups are present in the form of precursors which
are
later converted into the groups present in the compounds of the formula I, or
in
which functional groups are present in protected form, and in which X is a
nucleophilically substitutable leaving group, with a guanidine or guanidine
derivative of the formula III
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23
N-R'
H2N
N - RZ III
Rg
in which R', RZ and Rg are defined as indicated for the formula I, or
alternatively
functional groups are present in the form of precursors which are later
converted
into the groups present in the compounds of the formula I, or functional
groups
are present in protected form.
The group COX in the formula.ll is preferably the carboxylic acid group COOH
or an activated carboxylic acid derivative. X, for example, is hydroxyl or
halogen,
in particular chlorine or bromine, alkoxy, preferably methoxy or ethoxy,
aryloxy,
for example phenoxy or pentafluorophenoxy, phenylthio, methylthio, 2-
pyridylthio or a radical of a nitrogen heterocycle bonded via a nitrogen atom,
in
particular of an azole, such as, for example, 1-imidazoiyl. X can furthermore
be,
for example, ((C,-C4)-alkyl)-O-CO-O- or tolylsulfonyloxy and the activated
acid
derivative can thus be a mixed anhydride.
If X is hydroxyl, i. e. if the guanidine of the formula III is reacted with a
carboxylic
acid, then the carboxylic acid is expediently first activated. The activation
can be
carried out, for example, with dicyclohexylcarbodiimide (DCCI) or with O-
((cyano(ethoxycarbonyl)-methylen)amino)-1,1,3,3-tetramethyluronium
tetrafluoroborate (TOTU; K~nig et al., Proc. 21 st Europ. Peptide Symp. 1990
(Eds. Giralt, Andreu), Escom, Leiden 1991, p. 143) or other activating
reagents
customary in peptide chemistry.
Beside the free guanidines of the formula III, guanidinium salts can also be
employed in the reaction with the compounds of the formula II, from which the
free guanidines are then prepared in situ or in a separate step by means of a
base. The reaction of an activated carboxylic acid derivative of the formula
II
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24
with the guanidine (derivative) of the formula III is preferably carried out
in a
manner known per se in a protic or aprotic polar, but inert, organic solvent.
In
this case solvents like methanol, isopropanol, tert-butanol, dimethylformamide
or
tetrahydrofuran at temperatures from 0°C up to the boiling temperature
of these
solvents have proven suitable, for example, in the reaction of methyl esters
(X =
methoxy) or of ethyl esters (X = ethoxy) with guanidines. The reactions of
compounds of the type COX with salt-free guanidines are advantageously
carried out in aprotic inert solvents such as dimethylformamide,
tetrahydrofuran,
dimethoxyethane or dioxane, if appropriate with addition of a base such as,
for
example, potassium tert-butoxide or sodium methoxide. However, water can also
be used as a solvent in the reaction of compounds of the formula ll with
guanidines, for example when using a base such as sodium hdyroxide. It X is,
for example, chlorine the reaction is advantageously carried out with addition
of
an acid scavenger, for example an additional base or in the presence of excess
guanidine (derivative), for binding the resulting hydrohalic acid. The
reaction
mixture is worked up and, if desired, the reaction product is then purified by
the
customary processes familiar to those skilled in the art.
Protective groups optionally still present in the products obtained from the
compounds of the formulae II and Ill are then removed by standard processes.
For example, tart-butyl ester groups are converted into the carboxylic acid
groups by treatment with trifluoroacetic acid, benzyl groups are removed by
hydrogenation or fluorenyimethoxycarbonyl groups are removed by secondary
amines. If desired, further reactions are then carried out by standard
processes,
for example acylation reactions or esterification reactions. In addition, a
conversion into a physiologically tolerable salt or prodrug can then be
carried
out by known processes.
The starting components of the formulae II and lll, which are linked to give
the
compounds of the formula I, are commercially available or can be prepared by
or
analogously to processes described in the literature. The preparation of the
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starting components of the formula II is illustrated by way of example in the
following Scheme 1, the present invention not being restricted to this
synthesis
or these starting components. It does not cause any problems to those skilled
in
the art to carry out the modifications of the synthesis shown, which are
5 necessary for the preparation of other compounds according to the invention.
Thus, the carboxybenzaldehyde of the formula IV can be reacted, for example in
the presence of pyridine and piperidine, with the malonic acid ester salt of
the
formula V to give the cinnamic acid derivative of the formula VI which, after
10 hydrogenation, for example in the presence of palladium on carbon, gives
the
compound of the formula VII. After activation of the carboxylic acid group the
compound of the formula VII can be condensed with the 2,3-diaminopropionic
acid derivative of the formula VIII to give the compound of the formula IX
(Scheme 1 ). The condensation can be carried out, for example, in the presence
15 of TOTU or another customary agent for activating carboxylic acids.
In the formula VIII, Y can be the group RS-SOz- which is present in the final
compounds of the formula I according to the invention and which can then
remain in the molecule, or Y can be a group which temporarily protects the
20 amino group in the 2-position and which in a later stage is removed to give
a
free amino group which can then be converted intp an R5-SOZ-NH group by
standard procedures for the preparation of sulfonamides, for example by
reacting the free amine with a sulfonyl chloride of the formula RS-SOz-CI. An
example of a protecting group representing Y is the benzyloxycarbonyl group (Z
25 group) which can be removed by catalytic hydrogenation. Sulfonyl chlorides
of
the formula R5-S02-CI and other sulfonic acid derivatives suitable for
introducing
the group R5-S02 are commercially available or can be prepared according to or
analogously to procedures described in the literature. Instead of the tert-
butyl
ester present in the compounds of formula VIII and IX other esters can be
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26
Scheme 1
O ~CH3
O
0 H O O K O
HO ~~ ~ O '~ HO ~ ~ ~ O
V
O-CH3
IV VI
O~ /~'~ NH2
CH3
H3C--~-O ~N H
O CH3 Y
O
HO
O-CH3 VIII
VII
O
0
O H ~/
CH3 ~~ O-CH
~ 3
H3C--f--O NH
C~ H3 Y IX
present which either only temporarily protect the acid group or which can also
be present in the final compounds of the formula I according to the invention
and
can remain in the molecule. Compounds analogous to the compound of the
formula VI can also be obtained by other processes for the conversion of a
carbonyl group into an alkene, for example by a Wittig reaction.
The compounds of the formula IX are examples of compounds of the formula II
in which X is methoxy. These compounds and analogous compounds which are
obtained from the synthesis described above and which contain a group that is
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27
an activated carboxylic acid derivative, can be reacted directly with the
compounds of the formula Ill. The compounds obtained in the above synthesis,
however, can also first be converted under standard conditions by cleavage of
the methyl ester group or another ester group present in the position
concerned
in the compounds of the formula IX, into the corresponding carboxylic acids
which are then reacted with the guanidines of the formula I11 after in situ
activation, for example with TOTU or DCCI, or after conversion into an
activated
carboxylic acid derivative. If, as activated acid derivatives, it is intended
to
prepare, for example, the carboxylic acid chlorides (formula II, X = CI), this
conversion can be carried out, for example, by using thionyl chloride. If it
is
intended to prepare, for example, the methyl esters (formula II, X = methoxy)
from the carboxylic acids, this can be carried out by treatment with gaseous
hydrogen chloride in methanol. Other activated acid derivatives can be
prepared
in a manner known per se from the carboxylic acid chlorides or directly from
the
carboxylic acids on which they are based (formula II, X = OH). Example are the
imidazolides (formula II, X = 1-imidazolyl) which are obtained by treating the
acids with carbonyldiimidazole (cf. Staab, Angew. Chem. Int. Ed. Engl. 1, 351-
367 (1962)), or the mixed anhydrides which are obtained, tar example, by
reaction with chloroformic acid esters such as ethyl chloroformate or with
tosyl
chloride in the presence of amines such as triethylamine in an inert solvent.
A
number of suitable methods for the preparation of activated carboxylic acid
derivatives are indicated with details of source literature in J. March,
Advanced
Organic Chemistry, Third Edition, John Wiley & Sons, 1985, p. 350.
The compounds of the formula I are valuable pharmaceutical active ingredients
which are suitable, for example, for the therapy and prophylaxis of bone
disorders, tumor diseases or cardiovascular disorders. The compounds of the
formula I and their physiologically tolerable salts and their prodrugs can be
administered to animals, preferably to mammals, and in particular to humans as
pharmaceuticals for therapy or prophyiaxis. They can be administered on their
own, or in mixtures with one another or in the form of pharmaceutical
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preparations which permit enteral or parenteral administration and which, as
active constituent, contain an efficacious dose of at feast one compound of
the
formuta I and/or its physiologically tolerable salts and/or its prodrugs in
addition
to customary pharmaceutically innocuous carriers and/or additives.
The present invention therefore also relates to the compounds of the formula I
and/or their physiologically tolerable salts and/or their prodrugs for use as
pharmaceuticals, to the use of the compounds of the formula 1 and/or their
physiologically tolerable salts and/or their prodrugs for the production of
pharmaceuticals for the therapy and prophylaxis of the diseases mentioned
above or below, for example for the therapy and prophylaxis of bone disorders,
and also to the use of the compounds of the formula I and/or their
physiologically tolerable salts and/or their prodrugs for the therapy and
prophyiaxis of these diseases. The present invention furthermore relates to
pharmaceutical preparations or pharmaceutical compositions which contain an
efficacious dose of at least one compound of the formula I and/or its
physiologically tolerable salts and/or its prodrugs in addition to a customary
pharmaceutically innocuous carrier.
The pharmaceuticals can be administered orally, for example in the form of
pills,
tablets, lacquered tablets, coated tablets, granules, hard and soft gelatin
capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures.
Administration, however, can also be carried out rectally, for example in the
form
of suppositories, or parenterally, for example intravenously, intramuscularly
or
subcutaneously, in the form of injection solutions or infusion solutions,
microcapsules, implants or rods, or percutaneously or topically, for example
in
the form of ointments, solutions or tinctures, or in other ways, for example
in the
form of aerosols or nasal sprays .
The pharmaceutical preparations according to the invention are prepared in a
manner known per se and familiar to one skilled in the art, pharmaceutically
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inert inorganic or organic carriers being used in addition to the compounds)
of
the formula ! and/or its (their) physiologically tolerable salts and/or its
(their)
prodrugs. For the production of pills, tablets, coated tablets and hard
gelatin
capsules, it is possible to use, for example, lactose, corn starch or
derivatives
thereof, talc, stearic acid or its salts, etc. Carriers for soft gelatin
capsules and
suppositories are, for example, fats, waxes, semisolid and liquid polyols,
natural
or hardened oils, etc. Suitable carriers for the production of solutions, for
example injection solutions, or of emulsions or syrups are, for example,
water,
alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils,
etc.
Suitable carriers for microcapsules, implants or rods are, for example,
copolymers of glycolic acid and lactic acid. The pharmaceutical preparations
normally contain approximately 0.5 to 90% by weight of the compounds of the
formula I and/or their physiologically tolerable salts and/or their prodrugs.
The
amount of the active ingredient of the formula 1 and/or its physiologically
tolerable salts and/or its prodrugs in the pharmaceutical preparations
normally is
0.2 to 500 mg, preferably 1 to 200 mg.
In addition to the active ingredients and carriers, the pharmaceutical
preparations can additionally contain additives, such as, for example,
fillers,
disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers,
preservatives, sweeteners, colorants, flavorings or aromatizers, thickeners,
diluents, buffer substances, and also solvents or solubilizers or agents for
achieving a depot effect, and also salts for altering the osmotic pressure,
coating
agents or antioxidants. They can also contain two or more compounds of the
formula I and/or their physiologically tolerable salts and/or their prodrugs.
Furthermore, in addition to at least one compound of the formula I and/or its
physiologically tolerable salts and/or its prodrugs, they can also contain one
or
more other therapeutically or prophylactically active ingredients.
The compounds of the formula I are antagonists of the vitronectin receptor and
inhibitors of cell adhesion. They have, for example, the ability to inhibit
the
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binding of osteoclasts to the bone surface and thereby inhibit bone resorption
by
osteoclasts. The action of the compounds of the formula I can be demonstrated,
for example, in an assay in which the inhibition of the binding of vitronectin
to
cells which contain the vitronectin receptor is determined. Details of such an
5 assay are given below. As vitronectin receptor antagonists, the compounds of
the formula I and their physiologically tolerable salts and their prodrugs are
generally suitable for the therapy and prophylaxis of diseases which are based
on the interaction between vitronectin receptors and their ligands in cell-
cell
interaction processes or cell-matrix interaction processes, or which can be
10 influenced by an inhibition of interactions of this type, or for their
prevention,
alleviation or cure an inhibition of interactions of this type is desired. As
explained at the beginning, such interactions, for example, play a part in
bone
resorption, in angiogenesis or in the proliferation of cells of the vascular
smooth
musculature. The compounds of the formula I and their physiologically
tolerable
15 salts and their prodrugs are therefore suitable, for example, for the
alleviation or
cure of diseases which are caused at least partially by an undesired extent of
bone resorption, angiogenesis or proliferation of cells of the vascular smooth
musculature.
20 Bone diseases for whose treatment and prevention the compounds of the
formula I according to the invention can be employed are especially
osteoporosis, hypercalcemia, osteopenia, for example caused by metastases,
dental disorders, hyperparathyroidism, periarticular erosions in rheumatoid
arthritis and Paget's disease. In addition, the compounds of the formula i can
be
25 used for the allevation, avoidance or therapy of bone disorders which are
caused by a glucocorticoid, steroid or corticosteroid therapy or by a lack of
sex
hormone(s). All these disorders are characterized by bone loss, which is based
on the inequilibrium between bone formation and bone destruction and which
can be favorably influenced by the inhibition of bone resorption by
osteoclasts.
30 The compounds of the formula I andlor their physiologically tolerable salts
and/or their prodrugs can also favorably be used as inhibitor of bone
resorption,
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for example in the therapy or prophylaxis of osteoporosis, in combination with
conventional osteoporosis treatments, for example in combination with
bisphosphonates, estrogens, estrogenlprogesterone, estrogen
agonists/antagonists, calcitonin, vitamin D analogues, parathyroid hormone,
growth hormone secretagogues, or sodium fluoride. Administration of the
compounds of the formula I and/or their physiologically tolerable salts and/or
their prodrugs and of other active ingredients effective in the treatment or
prophylaxis of osteoporosis like those listed before can take place
simultaneously or sequentially, in any order, and jointly or separately. For
use in
such a combination treatment or prophyiaxis the compounds of the formula I
and/or their physiologically tolerable salts and/or their prodrugs and one or
more
other active ingredients like those listed before can together be present in a
single pharmaceutical preparation, for example tablets or granules, or can be
present in two or more separate pharmaceutical preparations which can be
contained in a single package or in two or more separate packages. The use of
the compounds of the formula I and/or their physiologically tolerable salts
and/or
their prodrugs in such a combination therapy or prophylaxis and their use in
the
production of pharmaceuticals for such a combination therapy or prophylaxis
are
also subjects of the present invention. The invention furthermore relates to
pharmaceutical preparations which comprise efficacious amounts of at least one
compound of the formula I and/or its physiologically tolerable salts and/or
its
prodrugs together with at least one other active ingredient effective in the
treatment or prophylaxts of osteoporosis or in the inhibition of bone
resorption
like those listed before, together with a customary pharmaceutically innocuous
carrier. The above explanations on pharmaceutical preparations
correspondingly apply to such pharmaceutical combination preparations.
Apart from use as inhibitors of bone resorption by osteoclasts, the compounds
of
the formula I and their physiologically tolerable salts and their prodrugs can
be
used as inhibitors of tumor growth and tumor metastasis, as
antiinflammatories,
for the therapy or prophylaxis of cardiovascular disorders such as
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32
arteriosclerosis or restenosis, or for the therapy or prophylaxis of
nephropathies
or retinopathies, such as, for example, diabetic retinopathy. As inhibitors of
tumor growth or tumor metastasis the compounds of the formula I and/or their
physiologically tolerable salts and/or their prodrugs can also favorably be
used
in combination with conventional cancer therapy. Examples of conventional
cancer therapy are given in Bertino (Editor), Encyclopedia of Cancer, Academic
Press, 1997 which is incorporated herein by reference. All the above
statements
relating to the use of the compounds of formula I in combination with
conventional osteoporosis therapy like, for example, possible modes of
administration and pharmaceutical combination preparations, correspondingly
apply to the use of the compounds of formula I in combination with
conventional
cancer therapy.
When using the compounds of the formula I, the dose can vary within wide
limits
and, as is customary, is to be suited to the individual conditions in each
individual case. It depends, for example, on the compound employed or on the
nature and severity of the disease to be treated and on whether an acute or
chronic condition is treated or whether prophylaxis is carried out. In the
case of
oral administration, the daily dose is in general 0.01 to 100 mg/kg,
preferably 0.1
to 50 mg/kg, in particular 0.1 to 5 mg/kg, for example 0.3 to 0.5 mg/kg to
achieve
effective results in an adult weighing about 75 kg (in each case in mg per kg
of
body weight). Also in the case of intravenous administration the daily dose is
in
general approximately 0.01 to 100 mg/kg, preferably 0.05 to 10 rng/kg (in each
case per kg of body weight). The daily dose can be divided, in particular in
the
case of the administration of relatively large amounts, into several, for
example
2, 3 or 4, part administrations. As usual, depending on individual behavior it
may
be necessary to deviate upwards or downwards from the daily dose indicated.
Apart from use as pharmaceutical active ingredients, the compounds of the
formula I can also be used as vehicles or carriers of active ingredients in
order
to transport the active ingredient specifically to the site of action (= drug
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targeting; see, for example, Targeted Drug Delivery, R. C. Juliano, Handbook
of
Experimental Pharmacology, Voi. 100, Ed. Bom, G. V. R. et al., Springer Verlag
which is incorporated herein by reference). The active ingredients to be
transported are in particular those which can be used for the treatment of the
abovementioned diseases.
The compounds of the formula ! and their salts can furthermore be employed for
diagnostic purposes, for example in in vitro diagnoses, and as auxiliaries in
biochemical investigations in which blocking of the vitronectin receptor or
influencing of cell-ce1! or cell-matrix interactions is desired. They can
furthermore be used as synthesis intermediates for the preparation of other
compounds, in particular of other pharmaceutical active ingredients, which are
obtainable from the compounds of the formula l, for example by modification or
introduction of radicals or functional groups.
Examples
The products were identified via mass spectra (MS) and/or NMR spectra.
Depending on how the last synthesis step and/or workup procedures, for
example freeze-drying, were carried out, in some cases the compounds were
obtained partially or completely in the form of a salt, for example in the
form of
an acetic acid salt, trifluoroacetic acid salt or hydrochloric acid salt.
Example 1
(2S)-2~(Naphthalene-1-sulfonylamino)-3-{4-(2-(1,4,5,6-tetrahydropyrimidin-2-
ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid
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O
O
~-- N ~~ ~~ O
' H '..=/ N OH
H H NH
I
O=S=O
a) 4-(2-Methoxycarbonyl-vinyl)benzoic acid
18.74 g (0.12 mol) of monomethyl malonate potassium salt were suspended in
18 ml of pyridine. 15.01 g (0.1 mol) of 4-carboxybenzaldehyde and 0.85 g (0.01
mol) of piperidine were added at room temperature with stirring. The mixture
was
refluxed until the evolution of C02 was complete (about 2 hours), then a
further
60 ml of pyridine were added and the mixture was stirred under reflux for a
further 1 hour. The reaction mixture was treated with stirring with 500 ml of
ice
and 110 ml of conc. hydrochloric acid. After addition was complete, the
mixture
was stirred for a further 20 minutes, and the product was filtered off with
suction,
washed with water and recrystallized from isopropanol. Yield 12.85 g.
'H-NMR (200 MHz, dg-DMSO) : 8 = 3.75 (s, 3H, OCHs); 6.76 (d, J = 15 Hz, 1H,
CHCOOCH3); 7.73 (d, J = 15 Hz, 1 H, Ar-CH); 7.84 (d, J = 9 Hz, 2H, Ar-H); 7.98
(d, J = 9 Hz, 2H, Ar-H); 13.11 (s, broad, 1 H, COOH).
MS (CI+): m/e = 207.2 (M+H+).
HPLC: RP18, Nucleosil 300-5-C18, 250 x 4 mm; buffer A: HZO, 0.1
trifluoroacetic acid (TFA); buffer B: acetonitrile (80% v/v)/H20 (20 % v/v),
0.1
TFA; gradient: first 5 min 90% buffer A/10 % buffer B, then during 20 min to
90%
buffer B, then 5 min 90% buffer B; flow rate 1 ml/min; Rt = 18.05 min.
b) 4-{2-Methoxycarbonyl-ethyl)benzoic acid
8 g (38.8 mmol) of 4-(2-methoxycarbonyl-vinyl)benzoic acid were suspended in
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250 ml of dioxane and hydrogenated for 7 hours at room temperature over Pd/C
(10% strength) at 1 bar of hydrogen. The mixture was filtered and the solvent
was removed in vacuo. Yield 8.05 g.
'H-NMR (200 MHz, ds-DMSO): 8 = 2.67 (t, J = 8 Hz, 2H, CH -COOCH3); 2.93 (t,
5 J = 8 Hz, 2H, Ar-CH ); 3.59 (s, 3H, OCH3); 7.35 (d, 2H, Ar-H); 7.86 (d, J =
9 Hz,
2H, Ar-H); 12.80 (s, broad, 1 H, COOH).
MS (Cl+): m/e = 209.2 (M+H+).
HPLC: RP18, Nucleosil 300-5-C18, 250 x 4 mm; buffer A: H20, 0.1 % TFA; buffer
B: acetonitrile (80% v/v)/H20 {20% v/v), 0.1 % TFA; gradient: first 5 min
90°~
10 buffer A, 10°~ buffer B, then during 20 min to 90% buffer B, then 5
min 90°~
buffer B; flow rate 1 ml/min; Rt = 17.03 min.
c) tart-Butyl (2S)-2-benzyloxycarbonylamino-3-(4-(2-methoxycarbonyl-ethyl)-
benzoylamino)propionate
354 mg (1.7 mmol) of 4-(2-methoxycarbonyl-ethyl)benzoic acid and 500 mg (1.7
mmol) of tent-butyl (2S)-3-amino-2-benzyloxycarbonylaminopropionate were
dissolved in 3 ml of dimethylformamide and treated with 557 mg (1.7 mmol) of 0-
((cyano-{ethoxycarbonyl)-methylidene)amino)-1,1,3,3-tetramethyluronium
tetrafluoroborate (TOTU) and 204 mg (1.7 mmol) of diisopropylethylamine, and
the mixture was stirred at room temperature for 7 hours at pH 7-8. The solvent
was removed in vacuo, the residue was dissolved in ethyl acetate and the
solution was washed three times each with KHS04 solution and NaHC03
solution until neutral. The organic phase was separated off and dried and the
solvent was removed by distillation in vacuo. Yield 770 mg. MS (ES'): m/e =
485.2 (M+H~).
d) (2S)-2-Amino-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-propionic acid
tert-butyl ester
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6.88 g (14.2 mmol) of tert-butyl (2S)-2-benzyloxycarbonylamino-3-(4-(2-
methoxycarbonyl-ethyl)-benzoylamino)propionate was dissolved in 200 ml of
methanol and 852 mg (14.2 mmol) of acetic acid was added. The mixture was
hydrogenated for 7 hours at room temperature over Pd/C (5% strength) at 1 bar
of hydrogen. The mixture was filtered and the solvent was removed in vacuo.
The residue was washed with n-heptane and dried in vacuo. Yield 6.9 g. MS
(ES+): m/e = 351.2 (M+H+).
e) (2S)-3-(4-(2-Methoxycarbonyl-ethyl)-ben2oylamino)-2-(naphthalene-1-
sulfonylamino)-propionic acid tert-butyl ester
0.123 g (0.35 mmol) of (2S)-2-amino-3-(4-(2-methoxycarbonyl-ethyl)-
benzoylamino)-propionic acid tert-butyl ester was dissolved in 2 ml of
dimethylformamide and treated with 0.196 ml (1.4 mmol) of triethylamine and
0.159 g (0.7 mmol) of 1-naphthalenesulfonyl chloride. The solution was stirred
for 4 hours at room temperature. The solvent was removed in vacuo, the residue
was dissolved in dichloromethane and the solution was washed three times with
water. The organic phase was dried with sodium sulfate, filtered and the
solvent
was removed in vacuo. The residue was chromatographed on silica gel eluting
with n-heptane/ethyl acetate (1/1 ). Yield 47 mg. MS (ES+): m/e = 541.3
(M+H+).
f) (2S)-2-(Naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-
ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid tert-butyl ester
47 mg (0.087 mmol) of (2S)-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-2-
(naphthalene-1-sulfonylamino)-propionic acid tert-butyl ester was dissolved in
2
ml of dimethylformamide and 86 mg (0.87 rnmol) of 2-amino-1,4,5,6-
tetrahydropyrimidine was added. The reaction was stirred at room temperature
for 20 hours. The solvent was removed in vacuo and the residue was
chromatographed on silica gel eluting with dichloromethane/methanol (1/1),
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followed by dichloromethanelmethanol/acetic acid/water (85/15/1.5/1.5). Yield
46 mg. MS (ES'): m/e = 608.3 (M+H+).
g) (2S)-2-(Naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-
ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid
45 mg (0.074 mmol) of (2S)-2-(naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-
tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid tert-
butyl ester was dissolved in 2 ml of dichloromethane and 2 ml of
trifluoroacetic
acid was added. The solution was stirred at room temperature for 3 hours. The
solvent was removed in vacuo and toluene was added to the residue and then
removed in vacuo. The residue was dissolved in acetonitrileJwater (1/1 ) and
lyophilized. Yield 50 mg. MS (ES+): m/e = 552 (M+H+),
Example 2
(2S)-2-(Quinoline-8-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-
ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid
O
O
~-- N ~ ~ O
' H ~N OH
H H NH
I
O=S=O
'N
a) (2S)-3-(4-(2-Methoxycarbonyl-ethyl)-benzoylamino)-2-(quinoline-8-
sulfonylamino)-propionic acid tart-butyl ester
0.123 g (0.35 mmol) of (2S)-2-amino-3-(4-(2-methoxycarbonyl-ethyl)-
benzoylamino)-propionic acid tert-butyl ester was dissolved in 2 ml of
dimethylformamide and treated with 0.196 ml (1.4 mmol) of triethylamine and
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0.159 g (0.7 mmol) of 8-quinolinesulfonyl chloride. The solution was stirred
for 4
hours at room temperature. The solvent was removed in vacuo, the residue was
dissolved in dichloromethane and the solution was washed three times with
water. The organic phase was dried with sodium sulfate, filtered and the
solvent
was removed in vacuo. The residue was chromatographed on silica gel eluting
with n-heptane/ethyl acetate (1/1 ). Yield 67 mg. MS (ES+): m/e = 542.2
(M+Fi+).
b) (2S)-2-(Quinoline-8-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-
ylcarbamoyi)-ethyl)-benzoylamino)-propionic acid tert-butyl ester
65 mg (0.12 mmol) of (2S)-3-{4-(2-methoxycarbonyl-ethyl)-benzoylamino)-2-
(quinoline-8-sulfonylamino)-propionic acid tart-butyl ester was dissolved in 1
ml
of dimethylformamide and 59 mg (0.6 mmol) of 2-amino-1,4,5,6-
tetrahydropyrimidine was added. The reaction was stirred at room temperature
for 20 hours. The solvent was removed in vacuo and the residue was
chromatographed on silica gel eluting with dichloromethane/methanol {1/1 ),
followed by dichloromethane/methanol/acetic acid/water (85/15/1.5/1.5). Yield
72 mg. MS (ES''): m/e = 609.3 (M+H'').
c) (2S)-2-(Quinoline-8-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-
ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid
72 mg (0.11 mmol) of (2S)-2-(quinoiine-8-sulfonylamino)-3-(4-{2-(1,4,5,6-
tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid tert-
butyl ester was dissolved in 2 ml of dichloromethane and 2 ml of
trifluoroacetic
acid was added. The solution was stirred at room temperature for 3 hours. The
solvent was removed in vacuo and toluene was added to the residue and then
removed in vacuo. The residue was dissolved in acetonitrile/water {111 ) and
lyophilized. Yield 54 mg. MS (ES''): m/e = 553 (M+H'').
Example 3
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(2S)-2-(4-Acetylamino-benzenesulfonylamino)-3-(4-(2-( 1,4, 5,6-
tetrahydropyrimidin-2- ylcarbamoyl)-ethyl)-benzoyiamino)-propionic acid
O
O
N ~ ~ O
~H ~~N OH
NH
I
O=S=0
\/NH
~O
a) (2S)-2-(4-Acetylamino-benzenesulfonylamino)-3-(4.-{2-methoxycarbonyl-
ethyl)-benzoylamino)-propionic acid tert-butyl ester
0.123 g (0.35 mmol) of (2S)-2-amino-3-(4-(2-metho~cycarbonyl-ethyl)-
benzoylamino)-propionic acid tert-butyl ester was dissolved in 2 ml of
dimethylformamide and treated with 0.196 ml (1.4 mmol) of triethylamine and
0.164 g (0.7 mmol) of 4-acetylamino-benzenesulfonyl chloride. The solution was
stirred for 4 hours at room temperature. The solvent was removed in vacuo, the
residue was dissolved in dichloromethane and the solution was washed three
times with water. The organic phase was dried with sodium sulfate, filtered
and
the solvent was removed in vacuo. The residue was chromatographed on silica
gel eluting with n-heptane/ethyl acetate (1/2). Yield 90 mg. MS (ES+): m/e =
548
(M+H').
b) (2S)-2-(4-Acetylamino-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-
tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid tert-
butyl ester
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87 mg (0.16 mmol) of (2S)-2-(4-acetylamino-benzenesulfonylamino)-3-(4-(2-
methoxycarbonyl-ethyl)-benzoylamino)-propionic acid tart-butyl ester was
dissolved in 1 ml of dimethylformamide and 79 mg (0.8 mmol) of 2-amino-
1,4,5,6-tetrahydropyrimidine was added. The reaction was stir-ed at room
5 temperature for 20 hours. The solvent was removed in vacuo and the residue
was chromatographed on silica gel eluting with dichloromethane/methanol (1/1
),
followed by dichloromethane/methanol/acetic acid/water (85/15/1.5/1.5). Yield
57 mg. MS (ES''): m/e = 615.3 (M+H').
10 c) (2S)-2-(4-Acetylamino-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-
tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid
57 mg (0.09 mmol) of (2S)-2-(4-acetylamino-benzenesulfonylamino)-3-(4-(2-
(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic
acid
15 tert-butyl ester was dissolved in 2 ml of dichloromethane and 2 ml of
trifluoroacetic acid was added. The solution was stirred at room temperature
for
3 hours. The solvent was removed in vacuo and toluene was added to the
residue and then removed in vacuo. The residue was dissolved in
acetonitrile/water (1/1) and lyophilized. Yield 42 mg. MS (ES+): m/e = 559.2
20 (M+Fi+).
Example 4
(2S)-2-(2-(1,4,5,6-Tetrahydropyrimidin-2-ylcarbamoyl)-benzenesulfonylamino)-
3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-
25 propionic acid
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O
O
N N ~ ~ O
' H N OH
H H NH
I
~N O O=S=O
I
N~N
H H ~
a) 2-((1S)-1-tart-Butoxycarbonyl-2-(4-{2-methoxycarbonyl-ethyl)-benzoylamino)-
ethylsulfamoyl)-benzoic acid methyl ester
0.123 g (0.35 mmol) of (2S)-2-amino-3-(4-(2-methoxycarbonyl-ethyl)-
benzoylamino}-propionic acid tart-butyl ester was dissolved in 2 ml of
dimethylformamide and treated with 0.196 ml (1.4 mmol) of triethylamine and
0.164 g (0.7 mmol) of 2-(methoxycarbonyl)-benzenesulfonyl chloride. The
solution was stirred for 4 hours at room temperature. The solvent was removed
in vacuo, the residue was dissolved in dichloromethane and the solution was
washed three times with water. The organic phase was dried with sodium
sulfate, filtered and the solvent was removed in vacuo. The residue was
chromatographed on silica gel eluting with n-heptane/ethyl acetate (1/1 ).
Yield
75 mg. MS (ES+): m/e = 549 (M+H+)
b) (2S)-2-{2-(1,4,5,6-Tetrahydropyrimidin-2-ylcarbamoyl)-
benzenesulfonylamino)-3-(4-(2-( 1, 4, 5,6-tetrahydropyrimidin-2-ylcarbamoyl)-
ethyl)-benzoylamino)-propionic acid tert-butyl ester
75 mg (0.13 mmol) of 2-{(1S)-1-tert-butoxycarbonyl-2-(4-(2-methoxycarbonyl-
ethyl)-benzoylamino)-ethylsulfamoyl)-benzoic acid methyl ester was dissolved
in
1 m) of dimethylformamide and 68 mg (0.69 mmol) of 2-amino-1,4,5,6-
tetrahydropyrimidine was added. The reaction was stirred at room temperature
for 20 hours. The solvent was removed in vacuo and the residue was
chromatographed on silica gel eluting with dichloromethane/methanol (1/1),
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followed by dichloromethane/methanol/acetic acid/water (85/15/1.5/1.5). Yield
54 mg. MS (ES+): m/e = 683.3 (M+H+).
c) (ZS)-2-(2-(1,4,5,6-Tetrahydropyrimidin-2-ylcarbamoyl)-
benzenesulfonyiamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-
ethyl)-benzoylamino)-propionic acid
54 mg (0.08 mmol) of (2S)-2-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-
benzenesulfonylamino)-3-(4-(2-( 1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-
ethyl)-benzoylamino)-propionic acid tert-butyl ester was dissolved in 2 ml of
dichloromethane and 2 ml of trifluoroacetic acid was added. The solution was
stirred at room temperature for 3 hours. The solvent was removed in vacuo and
toluene was added to the residue and then removed in vacuo. The residue was
dissolved in acetonitrile/water (1/1) and lyophilized. Yield 34 mg. MS (ES'):
m/e
= 627 (M+H+).
General procedure 1 (synthesis of the compounds of examples 5 to 24)
Step a: Reaction with the sulfonyl chloride
0.2 g of (2S)-2-amino-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-propionic
acid tert-butyl ester was dissolved in 2 ml of dimethylformamide and treated
with
4 molar equivalents of triethylamine and 2 molar equivalents of the
appropriate
sulfonyl chloride. The solution was stirred for 4 hours at room temperature.
The
solvent was removed in vacuo, the residue was dissolved in dichloromethane
and the solution was washed three times with water. The organic phase was
dried with sodium sulfate, filtered and the solvent was removed in vacuo. The
residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate
(1/1 ).
Step b: Formation of the acyl guanidine
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The product of step a was dissolved in 1 mi of dimethylformamide and 5 molar
equivalents of 2-amino-1,4,5,6-tetrahydropyrimidine was added. The reaction
mixture was stirred at room temperature for 20 hours. The solvent was removed
in vacuo and the residue was chromatographed on silica gel eluting with
dichloromethane/methanol (1/1), followed by dichloromethane/methanol/acetic
acid/water (85/15/1.5/1.5).
Step c: Cleavage of the tert-butyl ester
The product of step b was dissolved in 2 ml of dichloromethane and 2 ml of
trifluoroacetic acid was added. The solution was stirred at room temperature
for
3 hours. The solvent was removed in vacuo, and toluene was 'added to the
residue and then removed in vacuo. The residue was dissolved in
acetonitrile/water (1/1) and lyophilized.
Example 5
(2S)-2-(4-tert-Butyl-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-
tetrahydropyrimidin-
2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid
O
N N ~~ \ O O
H ~~N OH
N H
NH
I
O=S=O
The title compound was synthesized according to general procedure 1, using 4-
tert-butyl-benzenesulfonyl chloride in step a.
Yield MS (ES+): m/e
Product of step a 83 mg 547.2 (M+H)i
Product of step b 85 mg 614.3 (M+H)+
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Product of step c (title compound) 75 mg 558.3 (M+H)+
Example 6
(2S)-2-(Propane-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-
ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid
O
O
~-- N ~ ~ O
' H N OH
NH
I
O=S=O
The title compound was synthesized
according to general procedure
1, using
propane-1-sulfonyl chloride in step
a.
Yield MS (ES+): m/e
Product of step a 54 mg 457.3 (M+H)+
Product of step b 55 mg 524.3 (M+H)~
Product of step c (title compound) 45 mg 468.3 (M+H)+
Example 7
(2S)-2-(2-Phenyl-ethenesulfonylamino)-3-(4-(2-( 1,4, 5,6-tetrahydropyrimidin-2-
ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid
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O
O
~-- N ~-- ~~ ~~ O
' H ~~N OH
H H NH
I
O=S=O
I
The title compound was synthesized according to general procedure 1, using
trans-beta-styrenesulfonyl chloride in step a.
Yield MS (ES+): m/e
5 Product of step a 49 mg 517.1 (M+H)+
Product of step b 45 mg 584.3 (M+H),.
Product of step c (title compound) 37 mg 528.3 (M+H)'
Example 8
10 (2S)-2-(4-Propyl-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-
2-
ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid
O
N~- N ~ ~ O
' H ~N OH
H H NH
I
O=S=O
The title compound was synthesized according to general procedure 1, using 4-
15 (n-propyf)-benzenesulfonyl chloride in step a.
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Yield MS (ES+): m/e
Product of step a 78 mg 533.2 (M+H)+
Product of step b 73 mg 600.4 (M+H)+
Product of step c {title compound) 55 mg 544.3 (M+H);
Example 9
(2S)-2-(2-Methyl-propane-1-sulfonylamino)-3-(4-{2-{1,4,5,6-tetrahydropyrimidin-
2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid
O
N~-- N ~ ~ O
' H ~N OH
H NH
I
O=S=O
The title compound was synthesized according to general procedure 1, using
2-methyl-propane-1-sulfonyl chloride in step a.
Yield MS (ES+): m/e
Product of step a 21 mg 471.3 (M+H),.
Product of step b 10 mg 538.4 (M+H)+
Product of step c (title compound) 13 mg 482.3 (M+H)+
Example 10
(2S)-2-(4-Butoxy-benzenesulfonylamino)-3-(4-(2-( 1,4, 5,6-tetrahydropyrimidin-
2-
ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid
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O
O
~- N ~-- ~~ ~ O
' H ~~N OH
H H NH
I
O=S=O
~~O
The title compound was synthesized according to general procedure 1, using 4-
(n-butoxy)-benzenesulfonyl chloride in step a.
Yield MS (ES+): m/e
Product of step a 83 mg 563.2 (M+H)+
Product of step b 83 mg 630.4 (M+H)+
Product of step c (title compound) 63 mg 574.3 (M+H)+
Example 11
(2S)-2-(2-Cyano-benzenesulfonyiamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-
ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid
O
O
N~- N ~--~ ~
' H ~~N ~ OH
H H NH
I
O=S=O
CN
The title compound was synthesized according to general procedure 1, using
2-cyano-benzenesulfonyl chloride in step a.
Yield MS (ES+): m/e
Product of step a 91 mg 516.2 {M+H)'
Product of step b 71 mg 583.3 (M+H);
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Product of step c (title compound) 73 mg 527.3 (M+H)i
Example 12
(2S)-2-(7, 7-Dimethyl-2-oxo-bicyclo[2.2.1 Jhept-1-ylmethanesulfonylamino)-3-(4
(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)-benzoylamino)-propionic
acid
O
O O
/ ~
N N ~ OOH
H
NH
O=S=O
O
The title compound was synthesized according to general procedure 1, using
70 10-camphorsulfonyl chloride in step a.
Yield MS (ES'): m1e
Product of step a 85 mg 565.3 (M+H)'
Product of step b 88 mg 632.4 (M+H)*
Product of step c (title compound) 77 mg 576.4 (M+H)'
Example 13
(2S)-2-(4-Chioro-benzenesulfonylamino)-3-(4-(2-( 1,4,5,6-tetrahydropyrimidin-2-
ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid
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O
O
N~- N ~ ~ O
' H N OH
H H NH
I
O=S=O
CI
The title compound was synthesized according to general procedure 1, using
4-chloro-benzenesuifonyl chloride in step a.
Yield MS (ES+): m/e
Product of step a 91 mg 525.1 {M+H)'"
Product of step b 82 mg 592.3 (M+H)'
Product of step c (title compound) 64 mg 536.3 (M+H)''
Example 14
(2S)-2-(3-Chloro-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-
ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid
O
O
~.-N
H H ~ ~' OH
NH.
O=S=O
CI
The title compound was synthesized according to general procedure 1, using
3-chioro-benzenesulfonyl chloride in step a.
Yield MS (ES'): m/e
Product of step a 65 mg 525.2 (M+H)''
Product of step b 58 mg 592.3 (M+H)'"
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Product of step c (title compound) 52 mg 536.3 (M+H)'
Example 15
(2S)-3-(4-(2-(1,4,5,6-Tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-
5 2-(3-trifluoromethyl-benzenesulfonylamino)-propionic acid
O
O
N ~ ~ O
N H ~/ N ~ -OH
H H NH
I
O=S=O
F
~F
F
The title compound was synthesized according
to general procedure 1, using
3-trifluoromethyl-benzenesulfonyl chloride
in step a.
10 Yield MS (ES+): m/e
Product of step a 86 mg 559.2 (M+H)+
Product of step b 94 mg 626.3 (M+H)+
Product of step c (title compound) 84 mg 570.3 (M+H)+
15 Example 16
(2S)-2-{4-Methoxy-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-
2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid
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0
O
~-- N C~ ~~ 0
' H ''=.J N OH
H H NH
I
O=S=O
O~
The title compound was synthesized according to general procedure 1, using
4-methoxy-benzenesulfonyl chloride in step a.
Yield MS (ES+): m/e
Product of step a 66 mg 521.1 (M+H)'
Product of step b 71 mg 588.3 (M+H)'
Product of step c (title compound) 49 mg 532.3 (M+H)''
Example 17
(2S)-2-Benzenesulfonylamino-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-
ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid
O
O
~-- N C~ ~ 0
' H ~~:~N OH
H H NH
I
O=S=0
The title compound was synthesized according to general procedure 1, using
benzenesulfonyi chloride in step a.
Yield MS (ES+): m/e
Product of step a 76 mg 491.2 (M+H)+
Product of step b 77 mg 558.3 (M+H)+
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Product of step c (title compound) 64 mg 502.3 (M+H)+
Example 18
(2S)-3-(4-(2-{1,4,5,6-Tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-
2-(thiophene-2-sulfonylamino)-propionic acid
O
O
N~-- N ~ ~ O
' H N OH
H H NH
I
0=S=O
/.
S
The title compound was synthesized
according to general procedure
1, using
2-thiophenesulfonyl chloride in
step a.
Yield MS (ES+): m/e
Product of step a 87 mg 497.1 {M+H)+
Product of step b 74 mg 564.2 (M+H)''
Product of step c (title compound) 64 mg 508.2 (M+H)+
Example 19
{2S)-2-(Biphenyl-4-sulfonylamino)-3-{4-(2-(1,4,5,6-tetrahydropyrimidin-2-
ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid
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O
N ~ \ O O
H ~N OH
N H
H NH
i
O=S=O
The title compound was synthesized according to general procedure 1, using
4-biphenylsulfonyl chloride in step a.
Yield MS (ES+): m/e
Product of step a 39 mg 567.1 (M+H)''
Product of step b 40 mg 634.4 (M+H)+
Product of step c (title compound) 33 mg 578.3 (M+H);
Example 20
(2S)-2-(Naphthalene-2-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-
ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid
0
N N ~ \ O
I-I N OH
N H.
H NH
I
0=S=O
The title compound was synthesized according to general procedure 1, using 2-
naphthalenesulfonyl chloride in step a.
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Yield MS (ES+): m/e
Product of step a 76 mg 541.2 (M+H),.
Product of step b 74 mg 608.3 (M+H);
Product of step c (title compound) 62 mg 552.3 (M+H)+
Example 21
(2S)-3-(4-(2-(1,4,5,6-Tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-
2-(2,4,6-trimethyl-benzenesulfonylamino)-propionic acid
O
O
N ~ ~ O
N H U N '~ -OH
H H NH
I
O=S=O
The title compound was synthesized according to general procedure 1, using
2,4,6-trimethylbenzenesulfonyl chloride in step a.
Yield MS (ES+): m/e
Product of step a 68 mg 533.2 (M+H)+
Product of step b 71 mg 600.4 (M+H)+
Product of step c (title compound) 54 mg 544.3 (M+H)'
Example 22
(2S)-3-(4-(2-(1,4,5,6-Tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-
2-(4-trifluoromethyl-benzenesulfonylamino)-propionic acid
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O
O
~-- N ~ ~ O
' H ~N OH
H H NH
I
O=S=O
F F
F
The title compound was synthesized according to general procedure 1, using
4-trifluoromethyl-benzenesulfonyl chloride in step a.
Yield MS (ES'): m/e
5 Product of step a 105 mg 559.3 (M+H)+
Product of step b 93 mg 626.4 (M+H)+
Product of step c (title compound) 70 mg 570.3 (M+H)~
Example 23
10 (2S)-2-(Butane-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-
ylcarbamoyl)-ethyl)-benzoylamino}-propionic acid
O
O
N~-- N
' H N OH
H H NH
I
O=S=0
The title compound was synthesized according to general procedure 1, using
15 butane-1-sulfonyl chloride in step a.
Yield MS (ES+): m/e
Product of step a 87 mg 471.4 (M+H)+
Product of step b 60 mg 538.4 (M+H)''
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Product of step c (title compound) 57 mg 482.3 (M+H)'
Example 24
(2S)-2-Methanesulfonylamino-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-
ylcarbamoyi)-ethyl)-benzoylamino)-propionic acid
O
~- N ~ ~ O
' H ~N OH
H H NH
I
O=S=O
The title compound was synthesized
according to general procedure
1, using
methanesulfonyl chloride in step
a.
Yield MS (ES+): m/e
Product of step a 87.8 mg 429.3 {M+H)'
Product of step b 98 mg 496.4 (M+H)''
Product of step c (title compound) 74 mg 440.3 (M+H)+
General procedure 2 (synthesis of the compounds of examples 25 to 27)
Step a: Reaction with the sulfonyl chloride
0.1 g of (2S)-2-amino-3-(4-(2-carboxy-ethyl)-benzoylamino)-propionic acid tert-
butyl ester hydrochloride was dissolved in 3 ml of dimethylformamide and
treated with 3 molar equivalents of diisopropylethylamine and 2 molar
equivalents of the appropriate sulfonyi chloride at 0°C. The solution
was stirred
for 3 hours at 0°C. The reaction mixture was diluted by the addition of
ethyl
acetate and the solution was washed twice with aqueous potassium
hydrogensulfate solution and once with saturated aqueous sodium chloride
solution. The organic phase was dried with magnesium sulfate, filtered and the
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solvent was removed in vacuo. The residue was chromatographed on silica gel
eluting with dichloromethane/methanol/acetic acid/water (97.5/2.5/0.25/0.25).
Step b: Formation of the acyl guanidine
The product of step a was dissolved in 2 mI of tetrahydrofuran and 1.2 molar
equivalents of 2-amino-1,4,5,6-tetrahydropyrimidine, 4 molar equivalents of
diisopropylethylamine, and 1.1 molar equivalents of 0-(7-azabenzotriazol-1-yi)-
1,1,3,3-tetramethyluronium hexafluorophosphate were added. The reaction was
stirred at room temperature for 20 hours. The solvent was removed in vacuo and
the residue was dissolved in ethyl acetate and the solution was washed twice
with saturated aqueous sodium bicarbonate solution and once with saturated
aqueous sodium chloride solution. The organic phase was dried with
magnesium sulfate, filtered and the solvent was removed in vacuo. The residue
was chromatographed on silica gel eluting with dichloromethane/methanol/acetic
acid/water (85/15/1.5/1.5) followed by dichioromethane/methanol/acetic
acid/water (9/1 /0.1 /0.1 ).
Step c: Cleavage of the tent-butyl ester
The product of step b was dissolved in 1.5 ml of trifluoroacetic acidlwater
(95/5).
The solution was stirred at room temperature for 1 hour. The solvent was
removed in vacuo and toluene was added to the residue and then removed in
vacuo. The residue was dissolved in acetonitrile/water (1/1) and lyophilized.
Example 25
(2S)-2-(Propane-2-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-
ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid
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O
~- N ~ ~ O
' H N OH
H H NH
I
O=S=O
The title compound was synthesized according to general procedure 2, using
propane-2-sulfonyl chloride in step a.
Yield MS: m/e
Product of step a 17 mg 443.2 (M+H)' (FAB+)
Product of step b 7 mg 524.2 (M~H)+ (ES+)
Product of step c (title compound) 7.2 mg 468.2 (M+H)+ (ES'')
Example 26
{2S)-2-Chloromethanesulfonylamino-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-
ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid
O
O
--N
N H N ~ _OH
H H NH
I
O=S=O
CI
The title compound was synthesized according to general procedure 2, using
chloromethanesulfonyl chloride in step a.
Yield MS: m/e
Product of step a 94 mg 449.1 (M+H)+ (FAB')
Product of step b 28 mg 530.2 (M)+ (ES+)
Product of step c (title compound) 34 mg 474.2 (M+H)~ (ES'')
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Example 27
(2S)-3-(4-(2-( 1,4,5,6-Tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-
2-(2,2,2-trifluoro-ethanesulfonylamino)-propionic acid
O
O
N~--N
' H ~N OH
H H NH
I
O=S=O
F
F F
The title compound was synthesized according to general procedure 2, using
2,2,2-trifluoroethanesulfonyl chloride in step a.
Yield MS: m/e
Product of step a 43 mg 483.2 (M+H)'' (FAB'}
Product of step b 24 mg 564.2 (M+H)+ {ES')
Product of step c (title compound) 22 mg 508.2 (M+H)+ (ES')
Example 28
(2S)-2-(4-tart-Butyl-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-
tetrahydropyrimidin-
2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid ethyl ester
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O
~--N ~ ~ O O
' H N O--
H H NH
I
O=S=O
700 mg of (2S)-2-(4-tert-butyl-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-
tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid was
dissolved in 100 ml of ethanol and 15 drops of concentrated sulfuric acid was
5 added. The reaction solution was boiled for 3.5 hours. The solvent was
removed
in vacuo, the residue was dissolved in dichloromethane and washed three times
with saturated aqueous sodium bicarbonate solution. The aqueous phase was
extracted once with dichloromethane and the combined organic phase was
washed twice with saturated aqueous sodium chloride solution. The organic
10 phase was dried with sodium sulfate, filtered and the solvent was removed
in
vacuo. The residue was dissolved in 2N aqueous hydrochloric acid. The
hydrochloric acid was removed in vacuo, the residue was dissolved in
acetonitrile and added to water. This mixture was lyophilized. Yield 480 mg.
MS
(ES+): mle = 586.4 (M+H)+.
Example 29
(2S)-2-{4-tert-Butyl-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-
tetrahydropyrimidin-
2- ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid isopropyl ester
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O
O
~-- N ~ ~ O
' H N O
H H NH
1
O=S=O
700 mg of (2S)-2-(4-tert-butyl-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-
tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid was
dissolved in 100 ml of isopropanol and 15 drops of concentrated sulfuric acid
was added. The reaction solution was boiled for 2.5 days. The solvent was
removed in vacuo, the residue was dissolved in dichloromethane and washed
three times with saturated aqueous sodium bicarbonate solution. The aqueous
phase was extracted once with dichloromethane and the combined organic
phase was washed twice with saturated aqueous sodium chloride solution. The
organic phase was dried with sodium sulfate, filtered and the solvent was
removed in vacuo. The residue was dissolved in 2N aqueous hydrochloric acid.
The hydrochloric acid was removed in vacuo, the residue was dissolved in
acetonitrile and added to water. This mixture was lyophilized. Yield 444 mg.
MS
(ES''): m/e = 600.4 (M+H)'.
Example 30
(2S)-2-{Naphthalene-1-sulfonylamino)-3-(4-{2-(1,4,5,6-tetrahydropyrimidin-2-
ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid ethyl ester
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0
O
~-- N ~
' H N O
H H NH
I
O=S=O
590 mg of (2S)-2-(naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-
tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoyiamino)-propionic acid was
dissolved in 80 ml of ethanol and 12 drops of concentrated sulfuric acid was
added. The reaction solution was boiled for 3 hours. The solvent was removed
in vacuo, the residue was dissolved in dichloromethane and washed three times
with saturated aqueous sodium bicarbonate solution. The aqueous phase was
extracted once with dichloromethane and the combined organic phase was
washed twice with saturated aqueous sodium chloride solution. The organic
phase was dried with sodium sulfate, ~Itered and the solvent was removed in
vacuo. The residue was dissolved in 2N aqueous hydrochloric acid. The
hydrochloric acid was removed in vacuo, the residue was dissolved in
acetonitrile and added to water. This mixture was lyophilized. Yield 381 mg.
MS
(ES+): m/e = 580.3 (M+H)+.
Example 31
(2S)-2-(Naphthalene-1-sulfonylamino)-3-(4-(2-( 1,4, 5,6-tetrahydropyrimidin-2-
ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid isopropyl ester
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WO 99/37621 PCT/EP99/00242
63
O
O
~-- N ~--~ ~
' H ~~N O
NH
I
O=S=O
1.5 g of (2S)-2-(naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-
tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid was
dissolved in 250 ml of isopropanol and 1 ml of concentrated sulfuric acid was
added. The reaction solution was boiled for 3 days. The solvent was removed in
vacuo, the residue was dissolved in dichloromethane and washed three times
with saturated aqueous sodium bicarbonate solution. The aqueous phase was
extracted once with dichloromethane and the combined organic phase was
washed twice with saturated aqueous sodium chloride solution. The organic
phase was dried with sodium sulfate, filtered and the solvent was removed in
vacuo. The residue was dissolved in 2N aqueous hydrochloric acid. The
hydrochloric acid was removed in vacuo, the residue was dissolved in
acetonitrile and added to water. This mixture was lyophilized. Yield 950 mg.
MS
(ES+): m/e = 594.4 (M+H)+.
Example 32
(2S)-2-(Naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-
ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid isobutyl ester
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WO 99/37621 PCT/EP99/00242
64
O
O
j-N
N H N .,r _O
H H NH
I
O=S=O
600 mg of (2S)-2-(naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-
tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid was
dissolved in 12 ml of isobutanol and 0.1 ml of concentrated sulfuric acid was
added. The reaction solution was boiled for 24 hours. The solvent was removed
in vacuo, and the residue was chromatographed on silica gel eluting with
dichioromethane/methanol/acetic acidlwater (9/1/0.110.1 ). The product was
dissolved in acetic acid/water and lyophilized. Yield 250 mg. MS (ES''): m/e =
608.5 (M+H)''.
Pharmacological Testing
The inhibition of bone resorption by the compounds according to the invention
can be determined, for example, with the aid of an osteoclast resorption test
("PIT ASSAY"), for example analogously to WO-A-95132710 which is
incorporated herein by reference.
The inhibitory action of the compounds according to the invention against the
vitronectin receptor a"~i3 can be determined, for example, as described below.
Test for the measurement of the inhibition of binding of 293 cells to human
vitronectin (Vn/293 cell test)
1. Purification of human vitronectin
Human vitronectin is isolated from human plasma and purified by affinity
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WO 99/37621 PCT/EP99/00242
chromatography according to the method of Yatohyo et al., Cell Structure and
Function, 1988, 23, 281-292.
2. Cell test
5 293 cells, a human embryonic kidney cell line, which are cotransfected with
DNA
sequences for the ocr and ~i3 subunits of the vitronectin receptor a"~i3, are
selected for a high rate of expression (> 500,000 a"~i3 receptorslcell)
according
to the FACS method. The selected cells are cultured and sorted again by means
of FACS in order to obtain a stable cell line (15 D) with expression rates
10 > 1,000,000 copies of a~,~i3 per cell.
A Linbro 96-well tissue culture plate with a flat bottom is coated overnight
at 4°C
with human vitronectin (0.01 mg/ml, 0.05 ml/well) in phosphate-buffered saline
solution (PBS) and then blocked with 0.5°~ strength BSA (bovine serum
15 albumin). Solutions of the test substances from 10''° mol/I to 2 x
10-3 moll in
glucose-containing DMEM medium are prepared and 0.05 mllwell of the solution
are added to the plate in each case. The cells which express high levels of
a"~3
(for example 15 D) are suspended in glucose-containing DMEM medium and the
suspension is adjusted to a content of 25,000 cellsl0.05 ml of medium. 0.05 ml
20 of this cell suspension is added to each well and the plate is incubated at
37°C
for 90 minutes. The plate is washed three times with warm PBS in order to
remove unbound cells. The bound cells are lyzed in citrate buffer {25 mM,
pH 5.0) which contains 0.25°~ Triton X-100. The hexoseamidase substrate
p-
nitrophenyl-N-acetyl-a-D-glucosaminide is then added and the plate is
incubated
25 at 37°C for 90 minutes. The reaction is stopped with a glycine (50
mM)/EDTA
(5 mM) buffer (pH 10.4), and the absorption of each well is measured at 405 -
650 nm. The data are analyzed according to standard processes.
The following test results (inhibitory concentrations ICso) were obtained.
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66
Example Number ICso Vn/293 cell
test
1 6 nM
2 52 nM
3 27 nM
18 nM
6 32 nM
7 28 nM
8 20 nM
69 nM
29 nM
11 24 nM
12 27 nM
13 27 nM
14 10 nM
6 nM
16 26 nM
17 9 nM
18 14 nM
19 38 nM
5 nM
21 21 nM
22 10 nM
23 30 nM
24 100 nM
