Note: Descriptions are shown in the official language in which they were submitted.
CA 02539572 2006-03-20
Substituted Pentanols, A Process for their Production and their Use as
Anti-inflammatory Agents
The invention relates to quinoline and isoquinoline derivatives, a process for
their production and their use as anti-inflammatory agents.
From the prior art of DE 100 38 639 and W002/10143, anti-inflammatory agents
of general formula
R' RZ HO R3
A B A~ ~I~
are known, whereby the Ar radical comprises phthalides, thiophthalides,
benzoxazinones
or phthalazinones. In the experiment, these compounds show dissociations of
action
between anti-inflammatory and undesirable metabolic actions and are superior
to the
previously described nonsteroidal glucocorticoids or exhibit at least just as
good an
action.
The selectivity of the compounds of the prior art compared to the other
steroid
receptors still requires improvement, however.
It was therefore the object of this invention to make available compounds
whose
selectivity is improved compared to the other steroid receptors.
This object is achieved by the compounds according to the claims.
CA 02539572 2006-03-20
2
This invention therefore relates to compounds of general formula I
R~ R2 Rs
A'\~B~ ~Q
HO (I)
in which
A stands for an aryl, a benzyl or a phenethyl group, whereby the aryl, benzyl
or phenethyl group optionally can be substituted by one or more radicals
from the group C~-CS-alkyl, C~-CS-alkoxy, C,-CS-alkylthio, C~-CS-
perfluoroalkyl, halogen, hydroxy, cyano, nitro, -O-(CHz)"-O-, -O-(CHz)"-
CHz-, -O-CH=CH-, or -(CHz)"+z-, whereby n = 1 or 2, and the terminal
oxygen atoms and/or carbon atoms are linked to directly adjacent ring-
carbon atoms,
or NR4R5,
whereby R4 and R5, independently of one another, can be hydrogen, C~-
CS-alkyl or (CO)-C,-CS-alkyl,
R' and Rz, independently of one another, mean a hydrogen atom, a methyl or
ethyl group, or together with the carbon atom mean the chain of a C3-C6-
eycloalkyl ring,
R3 means an optionally substituted group that is selected from CQ-Cg-alkyl,
Cz-C6-alkenyl, Cz-C6-alkinyl, C3-C8-cycloalkyl, C3-C~-heterocyclyl, aryl,
heteroaryl, (C,-Cg-alkyl)C3-C8-cycloalkyl, (C~-Cg-alkyl)aryl, or (C,-Cg-
alkyl)heteroaryl,
B means a methylene group or a carbonyl group that is optionally
substituted by a methyl or ethyl group, and
Q means a quinolinyl or isoquinolinyl group that is linked via any position
CA 02539572 2006-03-20
and that optionally can be substituted by one or more radicals from the
group C~-CS-alkyl, C~-CS-alkoxy, C~-CS-alkylthio, C~-CS-perfluoroalkyl,
halogen, hydroxy, cyano, vitro, or NR4R5,
whereby R4 and R5, independently of one another, can be hydrogen, C~-
CS-alkyl or (CO)-C~-CS-alkyl,
as well as their racemates or separately present stereoisomers, and optionally
their
physiologically compatible salts.
An aryl group comprises phenyl and naphthyl. Phenyl is preferred.
The substituted aryl, benzyl or phenethyl groups carry 1-3 substituents,
preferably 2 substituents, on the ring.
The following substitution patterns on ring A are a special subject of the
invention: 2,5-disubstituted phenyl derivatives and 2,4-disubstituted phenyl
derivatives.
The C~-CS-alkyl groups in A, R4, and RS can be straight-chain or branched and
stand for a methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert.-
butyl- or n-pentyl,
2,2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl group. A methyl or ethyl
group is
preferred.
The Ca-C8-alkyl group R3 can be straight-chain or branched and can mean, e.g.,
butyl, isobutyl, tent-butyl, pentyl or isopentyl.
The CZ-C6-alkenyl group is straight-chain or branched; for example, vinyl,
propenyl, isopropenyl, butenyl, or isobutenyl is suitable.
The CZ-C6-alkinyl group is straight-chain or branched; for example, ethinyl,
propinyl, or butinyl is suitable.
For a cycloalkyl group, for example, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, and cyclooctyl are considered.
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The heterocyclyl group is not aromatic and can be, for example, pyrrolidine,
imidazolidine, pyrazolidine, or piperidine.
The C~-C8-alkyl(C3-Cg)cycloalkyl group can be, for example, cyclobutylmethyl,
cyclopentylmethyl, cyclohexylmethyl, or cycloheptylmethyl. The linkage with
the chain
is carned out via the alkyl group.
For an aryl group, phenyl and naphthyl are considered, and for (C~-
C8)alkylaryl,
benzyl and homobenzyl are considered.
Heteroaryl comprises furanyl, thienyl, thiazolyl, oxazolyl, imidazolyl,
triazolyl,
pyridyl and pyrimidyl;
(C,-C8-Alkyl)heteroaryl comprises all combinations of the above-indicated
definition of alkyl with monocyclic aromatic heterocyclic compounds. The
linkage with
the chain is carried out via the alkyl group, which in turn is linked to any
possible
chemical position of the heterocyclic compound.
The substituents of the groups in R3 can be C~-C6-alkyl, CZ-C6-alkenyl, CZ-C6-
alkinyl, C,-C6-alkoxy, halogen, hydroxy, and NR4R5.
Alkyl radicals R' and RZ together with the carbon atom of the chain can form a
3-
to 6-membered ring.
The C~-CS-alkoxy groups in A and Q can be straight-chain or branched and stand
for a methoxy, ethoxy, n-propoxy-, iso-propoxy-, n-butoxy, iso-butoxy, tert.-
butoxy or
n-pentoxy, 2,2-dimethylpropoxy, 2-methylbutoxy or 3-methylbutoxy group. A
methoxy
or ethoxy group is preferred.
The C~-CS-alkylthio groups in A and Q can be straight-chain or branched and
stand for a methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio,
iso-butylthio,
tert.-butylthio or n-pentylthio, 2,2-dimethylpropylthio, 2-methylbutylthio or
3-
methylbutylthio group. A methylthio or ethylthio group is preferred.
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The designation halogen atom or halogen means a fluorine, chlorine, bromine or
iodine atom. A fluorine, chlorine or bromine atom is preferred.
The NRQRS group can mean, for example, NHz, N(H)CH3, N(CH3)z,
N(H)(CO)CH3, N(CH3)(CO)CH3, N[(CO)CH3Jz, N(H)COzCH3, N(CH3)COZCH3, or
N(COzCH3)z.
As alkyl radicals R4 and R5, C~-C3-alkyl is preferred.
As acyl radicals R4 and R5, (CO)-C,-C3-alkyl is preferred.
For radical B, the unsubstituted methylene group and the carbonyl group are
preferred.
Radical Q can be linked via any ring-carbon atom to the (NH)-group of the
chain. 4-, 5- and 8-positions are preferred for the quinoline ring, and l-
position is
preferred for the isoquinoline ring.
The compounds of general formula I according to the invention can be present
as
different stereoisomers because of the presence of asymmetry centers. Both the
racemates and the separately present stereoisomers are part of the subject of
this
invention.
A special subject of this invention are the separately present stereoisomers,
i.e.,
(+)-enantiomers and (-)-enantiomers.
Another subject of the invention relates to compounds in which A stands for an
aryl, a benzyl or a phenethyl group, whereby the aryl, benzyl or phenethyl
group
optionally can be substituted by one or more radicals from the group C~-CS-
alkyl, C,-CS-
alkoxy, C~-CS-alkylthio, C~-CS-perfluoroalkyl, halogen, hydroxy, cyano, vitro
or NR4R5,
whereby RQ and R5, independently of one another, can be hydrogen, C~-CS-alkyl
or
(CO)-C ~-CS-alkyl.
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Another subject of the invention relates to compounds of general formula I, in
which A stands for -0-(CHz)"-O, -O-(CHz)"-CHz-, -O-CH=CH-, or -(CHz)n+z-~
whereby
n = 1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to
directly
adjacent ring-carbon atoms.
Compounds according to claim l, in which R3 means an optionally substituted
group that is selected from C4-C8-alkyl, C3-C8-cycloalkyl, C3-C~-heterocyclyl,
aryl,
heteroaryl, (C~-C8-alkyl)C3-Cg-cycloalkyl, (C,-Cg-alkyl)aryl, or (C,-C8-
alkyl)heteroaryl,
are another subject of the invention.
Compounds according to claim 1, in which R3 means an optionally substituted
group that is selected from C3-C6-cycloalkyl, C3-C~-heterocyclyl, phenyl,
heteroaryl,
(C~-C3-alkyl)C3-C6-cycloalkyl, (C,-C3-alkyl)phenyl, or (C~-C3-
alkyl)heteroaryl, are
another subject of the invention.
Compounds of general formula I, in which A means an unsubstituted phenyl
group, R' and Rz mean methyl, R3 means a cyclopentyl group, a methylcyclohexyl
group
or a phenyl group, B means a methylene group and Q means a quinoline or
isoquinoline
group, are another subject of the invention.
Compounds of general formula I, in which A means an unsubstituted phenyl
group, R' and Rz mean a methyl group, R3 means a cyclopentyl group, a
methylcyclohexyl group or a phenyl group, B means a methylene group and Q
means a
quinoline group, are another subject of the invention.
In addition, subjects of the invention are the use of the compounds according
to
claim 1 for the production of pharmaceutical agents, the use of the compounds
according
to claim 1 for the production of a pharmaceutical agent for treating
inflammatory
diseases and pharmaceutical preparations that contain at least one compound
according
to claim 1 or their mixtures as well as pharmaceutically compatible vehicles.
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Compounds of general formula I in which R3 means C3-C8-cycloalkyl, (C~-
CBalkyl)C3-C8-eycloalkyl, benzyl or phenyl are a preferred subject of the
invention.
Compounds of general formula I in which R3 means C3-C8-cycloalkyl, (C~-
CBalkyl)C3-C8-cycloalkyl or phenyl are an especially preferred subject of the
invention,
and compounds of general formula I in which R3 means cyclopentyl,
methylcyclohexyl
or phenyl, as described in the examples, are quite especially preferred.
The process for the production of the compounds of W098/54159 (51488),
WO00/32584 (51642), and W002/10143 (S 1877) can also be used for the
production of
the compounds according to the invention. For the linkage of the quinoline or
isoquinoline groups that are characteristic of the compounds according to the
invention,
the following process steps can be performed:
CA 02539572 2006-03-20
8
AI)
forB=CO
R' RZ O Q-NH R' RZ O R' R2 R3
A' v 'COZH - Z A NH-Q ~ A NH-O
(II) O O
(III)
(I)
An a-keto acid of general formula (II), in which A, R' and RZ have the
meanings
that are indicated for formula (I), is converted with an aminoquinoline, an
aminoisoquinoline or a (partially-) hydrogenated quinoline or isoquinoline
derivative
(Q-NHz ) into a-ketoamide (III), whereby A, R' and RZ have the above-indicated
meanings, in the way that is known to one skilled in the art. For example, a-
ketoamide
(III) is obtained with use of dehydrating coupling reagents, as they are known
from
peptide chemistry, e.g., dicyclohexylcarbodiimide, or by upstream conversion
of the acid
into an acid chloride, e.g., with thionyl chloride or POCI3 and subsequent
reaction with
Q-NH2.
R~ R2 O
A\~~ NH-Q
'(III) ~O
Compound (III) is reacted either with an alkyl metal compound, for example a
Grignard reagent, or a lithium alkyl, or by reaction with compound (IV),
(R6)3s1_R3
(IV)
CA 02539572 2006-03-20
9
whereby R3 has the above-indicated meaning, and R6 refers to a C~-CS-alkyl
group, in
the presence of a catalyst, e.g., fluoride salts or bases, such as, for
example, alkali
carbonates (J. Am. Chem. ,Soc. 1989, 111, 393), to form title compound (I).
forB=CO
R3
R' Rz O 1, verestern R' Rz R Q-NHz R R
NH-Q
A~COZH ' A~C02H A
2. (R6)3SiR3 OH O
(II)
(VI)
(I)
[Key: verestern = esterificationJ
As an alternative, a-keto acids (II) can also be esterified to compounds (V),
R' Rz O
A\ v _COZR'
(V)
in which A, R' and RZ are defined as described above, and R' is C~-Ca-alkyl,
according
to commonly used methods, e.g., with thionyl chloride in methanol or ethanol
or with
methyl iodide and alkali carbonate, and can be converted from (III) to (I) in
compound
(VI) analogously to reaction sequence Al).
R' Rz R3
A\ Ho 'C02R'
(VI)
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10
The ester is saponified under standard conditions, for example aqueous alkali
hydroxide solution, to acid (VI; R' = H). The latter is reacted for coupling
with an
aminoquinoline or aminoisoquinoline or a (partially-) hydrogenated quinoline
or
isoquinoline derivative (Q-NHz) with use of a conventional activating reagent,
e.g.,
thionyl chloride, optionally in the presence of a catalyst such as dimethyl
aminopyridine,
to form title compound (I).
B)
R' Rz Ra R' R2 Rs
A\~~O a) A\u~NH-Q
'O~rg
Title compound (I) can also be synthesized by reductive amination of a
compound of formula (XII) with Q-NH2, whereby, e.g., sodium cyanoborohydride,
or
sodium triacetoxy borohydride is considered as a reducing agent.
R' R2 Ra
A O
R
(X11)
Rg means methyl or ethyl according to the substituents that are defined for
the
methylene group in B.
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11
In the case that the compounds of general formula I are present as salts, this
can
be, for example, in the form of hydrochloride, sulfate, nitrate, phosphate,
pivalate,
maleate, fumarate, tartrate, benzoate, mesylate, citrate or succinate.
If the compounds according to the invention are present as racemic mixtures,
they can be separated into pure, optically active forms according to the
methods of
racemate separation that are familiar to one skilled in the art. For example,
the racemic
mixtures can be separated by chromatography on an even optically active
carrier
material (CHIRALPAK AD~) into the pure isomers. It is also possible to
esterify the
free hydroxy group in a racemic compound of general formula I with an
optically active
acid and to separate the diastereoisomeric esters that are obtained by
fractionated
crystallization or by chromatography, and to saponify the separated esters in
each case to
the optically pure isomers. As an optically active acid, for example, mandelic
acid,
camphorsulfonic acid or tartaric acid can be used.
Moreover, the methods for the production of the compounds according to the
invention that are used in the experimental part are also part of the
disclosure for the
producibility of the claimed compounds.
The binding of the substances to the glucocorticoid receptor (GR) and other
steroid hormone receptors (mineral corticoid receptor (MR), progesterone
receptor (PR)
and androgen receptor (AR)) is examined with the aid of recombinantly produced
receptors. Cytosol preparations of Sf9 cells, which had been infected with
recombinant
baculoviruses, which code for the GR, are used for the binding studies. In
comparison
to reference substance [3HJ-dexamethasone, the substances show a high to very
high
affinity to GR.
Moreover, the quinolines and isoquinolines of formula (I) that are described
here
show a high selectivity for the glucocorticoid receptor.
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12
As an essential, molecular mechanism for the anti-inflammatory action of
glucocorticoids, the GR-mediated inhibition of the transcription of cytokines,
adhesion
molecules, enzymes and other pro-inflammatory factors is considered. This
inhibition is
produced by an interaction of the GR with other transcription factors, e.g.,
AP-1 and NF-
kappa-B (for a survey, see Cato, A. C. B. and Wade, E., BioEssays 18, 371-378,
1996).
The compounds of general formula I according to the invention inhibit the
secretion of cytokine IL-8 into the human monocyte cell line THP-1 that is
triggered by
lipopolysaccharide (LPS). The concentration of the cytokines was determined in
the
supernatant by means of commercially available ELISA kits.
The anti-inflammatory action of the compounds of general formula I was tested
in the animal experiment by tests in the croton oil-induced inflammation in
rats and mice
(J. Exp. Med. (1995), 182, 99-108). To this end, croton oil in ethanolic
solution was
applied topically to the animals' ears. The test substances were also applied
topically or
systemically at the same time or two hours before the croton oil. After 16-24
hours, the
ear weight was measured as a yardstick for inflammatory edema, the peroxidase
activity
as a yardstick for the invasions of granulocytes, and the elastase activity as
a yardstick
for the invasion of neutrophilic granulocytes. In this test, the compounds of
general
formula I inhibit the three above-mentioned inflammation parameters both after
topical
administration and after systemic administration.
One of the most frequent undesirable actions of a glucocorticoid therapy is
the
so-called "steroid diabetes" [cf., Hatz, H. J., Glucocorticoide:
Immunologische
Grundlagen, Pharmakologie and Therapierichtlinien, [Glucocorticoids:
Immunological
Bases, Pharmacology and Therapy Guidelines], Wissenschaftliche
Verlagsgesellschaft
mbH, Stuttgart, 1998). The reason for this is the stimulation of
gluconeogenesis in the
liver by induction of the enzymes responsible in this respect and by free
amino acids,
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13
which are produced from the degradation of proteins (catabolic action of
glucocorticoids). A key enzyme of the catabolic metabolism in the liver is
tyrosinamino
transferase (TAT). The activity of this enzyme can be determined from liver
homogenates by photometry and represents a good measurement of the undesirable
metabolic actions of glucocorticoids. To measure the TAT induction, the
animals are
sacrificed 8 hours after the test substances are administered, the livers are
removed, and
the TAT activity is measured in the homogenate. In this test, at doses in
which they
have an anti-inflammatory action, the compounds of general formula I induce
little or
no tyrosinamino transferase.
Because of their anti-inflammatory and, in addition, anti-allergic,
immunosuppressive and antiproliferative action, the compounds of general
formula I
according to the invention can be used as medications for treatment or
prophylaxis of the
following pathologic conditions in mammals and humans: In this case, the term
"DISEASE" stands for the following indications:
(i) Lung diseases that are accompanied by inflammatory, allergic and/or
proliferative
processes:
- Chronic, obstructive lung diseases of any origin, primarily bronchial
asthma
- Bronchitis of different origins
- All forms of restrictive lung diseases, primarily allergic alveolitis,
All forms of pulmonary edema, primarily toxic pulmonary edema
- Sarcoidoses and granulomatoses, especially Boeck's disease
(ii) Rheumatic diseases/autoimmune diseases/joint diseases that are
accompanied by inflammatory, allergic andlor proliferative processes:
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14
- All forms of rheumatic diseases, especially rheumatoid arthritis, acute
rheumatic fever, polymyalgia rheumatica
- Reactive arthritis
- Inflammatory soft-tissue diseases of other origins
- Arthritic symptoms in the case of degenerative joint diseases (arthroses)
- Traumatic arthritides
- Collagenoses of any origin, e.g., systemic lupus erythematodes,
sclervdermia, polymyositis, dermatomyositis, Sjogren's syndrome, Still's
syndrome, Felty's syndrome
(iii) Allergies that are accompanied by inflammatory and/or proliferative
processes:
- All forms of allergic reactions, e.g., Quincke's edema, hay fever, insect
bites, allergic reactions to pharmaceutical agents, blood derivatives,
contrast media, etc., anaphylactic shock, urticaria, contact dermatitis
(iv) Vascular inflammations (vasculitides)
- Panarteritis nodosa, temporal arteritis, erythema nodosum
(v) Dermatological diseases that are accompanied by inflammatory, allergic
andlor
proliferative processes:
- Atopic dermatitis (primarily in children)
- Psoriasis
- Pityriasis rubra pilaris
- Erythematous diseases, triggered by different noxae, e.g., radiation,
chemicals, burns, etc.
- Bullous dermatoses
- Diseases of the lichenoid group,
- Pruritis (e.g., of allergic origin)
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15
- Seborrhea) eczema
- Rosacea
- Pemphigus vulgaris
- Erythema exudativum multiforme
- Balanitis
- Vulvitis
- Hair loss such as alopecia areata
- Cutaneous T-cell lymphoma
(vi) Kidney diseases that are accompanied by inflammatory, allergic and/or
proliferative processes:
- Nephrotic syndrome
- All nephritides
(vii) Liver diseases that are accompanied by inflammatory, allergic and/or
proliferative
processes:
- Acute liver cell decomposition
- Acute hepatitis of different origins, e.g., viral, toxic, pharmaceutical
agent-induced
- Chronic aggressive hepatitis and/or chronic intermittent hepatitis
(viii) Gastrointestinal diseases that are accompanied by inflammatory,
allergic andlor
proliferative processes:
- Regional enteritis (Crohn's disease)
- Colitis ulcerosa
- Gastritis
- Reflux esophagitis
- Ulcerative colitis of other origins, e.g., native spree
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16
(ix) Proctologic diseases that are accompanied by inflammatory, allergic
and/or
proliferative processes:
- Anal eczema
- Fissures
- Hemorrhoids
- Idiopathic proctitis
(x) Eye diseases that are accompanied by inflammatory, allergic and/or
proliferative
processes:
- Allergic keratitis, uveitis, iritis
- Conjunctivitis
- Blepharitis
- Optic neuritis
- Chorioiditis
- Sympathetic ophthalmia
(xi) Diseases of the ear-nose-throat area that are accompanied by
inflammatory, allergic
and/or proliferative processes:
- Allergic rhinitis, hay fever
Otitis externa, e.g., caused by contact dermatitis, infection, etc.
- Otitis media
(xii) Neurological diseases that are accompanied by inflammatory, allergic
and/or
proliferative processes:
- Cerebral edema, primarily tumor-induced cerebral edema
- Multiple sclerosis
- Acute encephalomyelitis
- Meningitis
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17
- Various forms of convulsions, e.g., infantile nodding spasms
(xiii) Blood diseases that are accompanied by inflammatory, allergic and/or
proliferative processes:
- Acquired hemolytic anemia
- Idiopathic thrombocytopenia
(xiv) Tumor diseases that are accompanied by inflammatory, allergic and/or
proliferative processes:
- Acute lymphatic leukemia
- Malignant lymphoma
Lymphogranulomatoses
- Lymphosarcoma
- Extensive metastases, mainly in breast, bronchial and prostate cancers
(xv) Endocrine diseases that are accompanied by inflammatory, allergic and/or
proliferative processes:
- Endocrine orbitopathy
Thyreotoxic crisis
- De Quervain's thyroiditis
- Hashimoto's thyroiditis
- Basedow's disease
(xvi) Organ and tissue transplants, graft-versus-host disease
(xvii) Severe shock conditions, e.g., anaphylactic shock, systemic
inflammatory
response syndrome (SIRS)
(xviii) Substitution therapy in:
- Innate primary suprarenal insufficiency, e.g., congenital adrenogenital
syndrome
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18
- Acquired primary suprarenal insufficiency, e.g., Addison's disease,
autoimmune adrenalitis, meta-infective tumors, metastases, etc.
- Innate secondary suprarenal insufficiency, e.g., congenital
hypopituitarism
- Acquired secondary suprarenal insufficiency, e.g., meta-infective tumors,
etc.
(xix) Vomiting that is accompanied by inflammatory, allergic and/or
proliferative
processes:
- e.g., in combination with a 5-HT3 antagonist in cytostatic-agent-induced
vomiting
(xx) Pains of inflammatory origins, e.g., lumbago.
Moreover, the compounds of general formula I according to the invention can be
used for treatment and prophylaxis of additional pathologic conditions that
are not
mentioned above, for which synthetic glucocorticoids are now used (see in this
respect
Hatz, H. J., Glucocorticoide: Immunologische Grundlagen, Pharmakologie and
Therapierichtlinien, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart,
1998).
All previously mentioned indications (i) to (xx) are described in more detail
in
Hatz, H. J., Glucocorticoide: Immunologische Grundlagen, Pharmakologie and
Therapierichtlinien, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart,
1998.
For the therapeutic actions in the above-mentioned pathologic conditions, the
suitable dose varies and depends on, for example, the active strength of the
compound of
general formula I, the host, the type of administration, and the type and
severity of the
conditions that are to be treated, as well as the use as a prophylactic agent
or therapeutic
agent.
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19
In addition, the invention provides:
(i) The use of one of the compounds of general formula I according to the
invention or mixture thereof for the production
