NZ617624B2 - 7-(heteroaryl-amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol acetic acid derivatives and their use as prostaglandin d2 receptor modulators - Google Patents
7-(heteroaryl-amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol acetic acid derivatives and their use as prostaglandin d2 receptor modulators Download PDFInfo
- Publication number
- NZ617624B2 NZ617624B2 NZ617624A NZ61762412A NZ617624B2 NZ 617624 B2 NZ617624 B2 NZ 617624B2 NZ 617624 A NZ617624 A NZ 617624A NZ 61762412 A NZ61762412 A NZ 61762412A NZ 617624 B2 NZ617624 B2 NZ 617624B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- tetrahydropyrido
- methyl
- amino
- acetic acid
- indolyl
- Prior art date
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- 230000002633 protecting Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000027425 release of sequestered calcium ion into cytosol Effects 0.000 description 1
- 230000000717 retained Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran THF Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 238000004450 types of analysis Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/14—Decongestants or antiallergics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The disclosure relates to 7-(heteroaryl-amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol acetic acid derivatives of the formula (I), wherein R1, R2, R3 and R4 are as described in the description and their use as prostaglandin receptor modulators, most particularly as prostaglandin D2 receptor modulators. The disclosure also relates to pharmaceutical compositions containing these compounds and their use in the treatment of chronic and acute allergic/immune diseases/disorders, including asthma, food allergy, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease and rheumatoid arthritis. Example compounds include: 2-(7-((6-fluorobenzo[d]thiazol-2-yl)(methyl)amino)-2-(trifluoromethoxy)-6,7,8,9-tetrahydropyrido[1 ,2-a]indol-10-yl)acetic acid; 2-(7-((5-fluorobenzo[d]oxazol-2-yl)(methyl)amino)-3-(trifluoromethyl)-6, 7,8,9-tetrahydropyrido[1 ,2-a]indol-10-yl)acetic acid; 2-(7-((5-fluorobenzo[d]oxazol-2-yl)(methyl)amino)-2-(trifluoromethoxy)-6, 7,8,9-tetrahydropyrido[1 ,2-a]indol-10-yl)acetic acid; 2-(3-chloro-7-((5-fluoropyrimidin-2-yl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1 ,2-a]indol-10-yl)acetic acid; 2-(2-fluoro-7-((5-fluorobenzo[d]oxazol-2-yl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1 ,2-a]indol-10-yl)acetic acid; 2-(3-fluoro-7-((5-fluoropyrimidin-2-yl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetic acid. The disclosure also relates to pharmaceutical compositions containing these compounds and their use in the treatment of chronic and acute allergic/immune diseases/disorders, including asthma, food allergy, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease and rheumatoid arthritis. Example compounds include: 2-(7-((6-fluorobenzo[d]thiazol-2-yl)(methyl)amino)-2-(trifluoromethoxy)-6,7,8,9-tetrahydropyrido[1 ,2-a]indol-10-yl)acetic acid; 2-(7-((5-fluorobenzo[d]oxazol-2-yl)(methyl)amino)-3-(trifluoromethyl)-6, 7,8,9-tetrahydropyrido[1 ,2-a]indol-10-yl)acetic acid; 2-(7-((5-fluorobenzo[d]oxazol-2-yl)(methyl)amino)-2-(trifluoromethoxy)-6, 7,8,9-tetrahydropyrido[1 ,2-a]indol-10-yl)acetic acid; 2-(3-chloro-7-((5-fluoropyrimidin-2-yl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1 ,2-a]indol-10-yl)acetic acid; 2-(2-fluoro-7-((5-fluorobenzo[d]oxazol-2-yl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1 ,2-a]indol-10-yl)acetic acid; 2-(3-fluoro-7-((5-fluoropyrimidin-2-yl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetic acid.
Description
-(Heteroaryl-amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol acetic acid derivatives
and their use as prostaglandin D2 receptor modulators
Field of the invention:
The present invention relates to 7-(heteroaryl-amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol
acetic acid derivatives of formula (I) and their use as prostaglandin receptor modulators,
most particularly as prostaglandin D receptor (“DP receptor”) modulators, in the treatment
of various prostaglandin-mediated diseases and disorders, to pharmaceutical compositions
containing these compounds and to processes for their preparation. In particular, such
derivatives may be used alone or in pharmaceutical compositions for the treatment of both,
chronic and acute allergic/immune diseases/disorders such as asthma, allergic asthma,
eosinophilic asthma, severe asthma, rhinitis, allergic rhinitis, angioedema, insect venom
allergy, drug allergies, allergic sinusitis, allergic nephritis, allergic conjunctivitis, atopic
dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic
shock, urticaria, eczema, ulcerative colitis, chronic obstructive pulmonary disease (COPD),
inflammatory bowel disease and rheumatoid arthritis; eosinophil-related diseases
comprising small vessel vasculitides like Churg-Strauss syndrome, Wegener's
granulomatosis, microscopic polyangiitis (and organ-specific subsets of the latter),
hypereosinophilic syndromes like eosinophilic pneumonia, eosinophilic esophagitis, reflux
esophagitis, eosinohilic endocarditis (Loeffler’s endocarditis), eosinophilia-myalgia
syndrome, eosinophilic fasciitis, eosinohilic pustular folliculitis (Ofuji's disease), eosinophilic
ulcers, angiolymphoid hyperplasia with eosinophilia (ALHE), eosinophilic cellulitis (Wells
syndrome), chronic eosinophilic leukemia and DRESS syndrome (Drug Rash with
Eosinophilia and Systemic Symptoms); and basophil-related diseases, comprising
basophilic leukemia and basophilic leukocytosis.
Background of the invention:
As a response to allergen exposure in allergic conditions, mast cells are activated and
release mediators like histamine, thromboxane A2 (TxA2), cysteinyl leukotrienes (CysLTs)
and prostaglandin D (PGD ). These mediators interact with their respective receptors and
cause physiological effects such as increased vascular permeability, edema, pruritus, nasal
and pulmonary congestion, bronchoconstriction, and mucus secretion. An increased
vascular permeability for example, allows excessive infiltration of eosinophilic and
basophilic leukocytes into the tissue and thus amplifies the allergic response.
Current treatments of allergic diseases comprise agents that can block or otherwise
interrupt such interactions, e.g. anti-histamines (histamine H1 receptor antagonists),
leukotriene receptor antagonists, beta-adrenergic receptor agonists, and corticosteroids.
Generally, treatments with anti-histamines and leukotriene antagonists are limited in
efficacy, and long-term usage of corticosteroids is often associated with unwanted side
effects.
PGD is an agonist known to act on two G-protein-coupled receptors, the PGD receptor
DP1 and the recently identified CRTH2 (chemoattractant receptor-homologous molecule
expressed on Th2 cells) receptor (also referred to as “DP2 receptor”).
Elevated PGD levels are considered to cause inflammation as observed in allergic
diseases such as allergic rhinitis, allergic asthma, allergic conjunctivitis, atopic dermatitis
and the like. Therefore, blocking the interaction of PGD with its receptors is considered a
useful therapeutic strategy for the treatment of such diseases.
GB 2388540 discloses the use of ramatroban ((3R)(4-fluorobenzene-sulfonamido)-
1,2,3,4-tetrahydrocarbazolepropionic acid), a TxA2 receptor (also referred to as “TP
receptor”) antagonist with additional antagonistic activity on CRTH2, for the prophylaxis
and treatment of allergic diseases, such as asthma, allergic rhinitis or allergic conjunctivitis.
In T. Ishizuka et al., Cardiovascular Drug Rev. 2004, 22(2), 71-90 effects of ramatroban on
late-phase inflammation are described. Furthermore, oral bioavailability of ramatroban and
its ability to inhibit prostaglandin D -induced eosinophil migration in vitro has been reported
(Journal of Pharmacology and Experimental Therapeutics, 305(1), p.347-352 (2003)).
and disclose Ramatroban analogues with CRTH2
antagonistic activity. Ulven et al, J. Med. Chem. 2005, 48(4), 897-900 disclose further
ramatroban analogues.
discloses (3-amino-1,2,3,4-tetrahydro-9H-carbazolyl)-acetic acid
derivatives with CRTH2 antagonistic activity. discloses 3-(heteroaryl-
amino)-1,2,3,4-tetrahydro-9H-carbazole derivatives.
, and disclose different 6,7,8,9-
tetrahydro-pyrido[1,2-a]indol acetic acid derivatives with CRTH2 antagonistic activity.
WO 10/031184 discloses azaindole derivatives with CRTH2 antagonistic activity.
Description of the invention:
1) The present invention relates to 7-(heteroaryl-amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol
acetic acid derivatives of the formula (I),
(I)
wherein
R and R represent independently of each other hydrogen, (C -C )alkyl, (C -C )alkoxy,
1 4 1 4
halogen, trifluoromethoxy or trifluoromethyl;
R represents hydrogen, (C -C )alkyl, (C -C )alkoxy-(C -C )alkyl, (C -C )fluoroalkyl or
1 4 1 2 2 3 1 4
(C -C )cycloalkyl-(C -C )alkyl; and
3 6 1 2
R represents a heteroaryl group which is unsubstituted or mono-, di- or tri-substituted,
wherein the substituents are independently selected from the group consisting of halogen,
(C -C )alkyl, (C -C )cycloalkyl, (C -C )alkoxy, (C -C )fluoroalkyl and phenyl (preferably from
1 4 3 6 1 4 1 4
halogen, (C -C )alkyl and (C -C )fluoroalkyl); wherein the term "heteroaryl" means a 5- to
1 4 1 4
10-membered monocyclic or bicyclic aromatic ring containing 1, 2 or 3 heteroatoms
independently selected from oxygen, nitrogen and sulfur;
and to the pharmaceutically acceptable salts of such compounds.
The invention also provides a pharmaceutical composition comprising a compound of the
invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable
carrier.
The invention also provides a use of a compound of the invention, or a pharmaceutically
acceptable salt thereof, for the preparation of a medicament for the prevention and/or
treatment of a disease selected from the group consisting of chronic and acute
allergic/immune diseases/disorders, comprising asthma, allergic asthma, eosinophilic
asthma, severe asthma, rhinitis, allergic rhinitis, angioedema, insect venom allergy, drug
allergies, allergic sinusitis, allergic nephritis, allergic conjunctivitis, atopic dermatitis,
bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria,
eczema, ulcerative colitis, chronic obstructive pulmonary disease (COPD), inflammatory
bowel disease and rheumatoid arthritis; eosinophil-related diseases comprising small
vessel vasculitides like Churg-Strauss syndrome, Wegener's granulomatosis, microscopic
polyangiitis (and organ-specific subsets of the latter), hypereosinophilic syndromes like
eosinophilic pneumonia, eosinophilic esophagitis, reflux esophagitis, eosinohilic
endocarditis (Loeffler’s endocarditis), eosinophilia-myalgia syndrome, eosinophilic fasciitis,
eosinohilic pustular folliculitis (Ofuji's disease), eosinophilic ulcers, angiolymphoid
hyperplasia with eosinophilia (ALHE), eosinophilic cellulitis (Wells syndrome), chronic
eosinophilic leukemia and DRESS syndrome (Drug Rash with Eosinophilia and Systemic
Symptoms); and basophil-related diseases, comprising basophilic leukemia and basophilic
leukocytosis.
The compounds of formula (I) according to disclosure 1) may contain one or more
stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms.
Substituents at a double bond may be present in the (Z)- or (E)-configuration unless
indicated otherwise. The compounds of formula (I) may thus be present as mixtures of
stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be
separated in a manner known to a person skilled in the art.
The following paragraphs provide definitions of the various chemical moieties for the
compounds according to the invention and are intended to apply uniformly throughout the
specification and claims unless an otherwise expressly set out definition provides a broader
or narrower definition.
The term “alkyl”, used alone or in combination, refers to a straight or branched chain alkyl
group containing one to four carbon atoms. The term “(C -C )alkyl” (x and y each being an
integer), refers to an alkyl group as defined before containing x to y carbon atoms. For
example a (C -C )alkyl group contains from one to four carbon atoms. Representative
examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-
butyl and tert-butyl.
In case “R “ represents “(C -C )alkyl” the term means (C -C )alkyl groups as defined
1 4 1 4
above. Examples of said groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
sec-butyl and tert-butyl. Preferred is methyl.
In case “R “ represents “(C -C )alkyl” the term means (C -C )alkyl groups as defined
1 4 1 4
above. Examples of said groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
sec-butyl and tert-butyl. Preferred is methyl.
In case “R “ represents “(C -C )alkyl” the term means (C -C )alkyl groups as defined
1 4 1 4
above. Examples of said groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
sec-butyl and tert-butyl. Preferred are methyl, ethyl, n-propyl, iso-propyl and iso-butyl; more
preferred are methyl, ethyl and n-propyl; most preferred is methyl.
In case “R “ represents “heteroaryl which is substituted with (C -C )alkyl” the term “(C -
1 4 1
C )alkyl” means (C -C )alkyl groups as defined above. Examples of said groups are methyl,
4 1 4
ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. Preferred is methyl.
The term “alkoxy”, used alone or in combination, refers to an alkyl-O- group wherein the
alkyl group is as defined before. The term “(C -C )alkoxy” (x and y each being an integer)
refers to an alkoxy group as defined before containing x to y carbon atoms. For example a
(C -C )alkoxy group contains from one to four carbon atoms. Representative examples of
alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-
butoxy and tert-butoxy.
In case “R “ represents “(C -C )alkoxy” the term means (C -C )alkoxy groups as defined
1 4 1 4
above. Examples of said groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy,
iso-butoxy, sec-butoxy and tert-butoxy. Preferred is methoxy.
In case “R “ represents “(C -C )alkoxy” the term means (C -C )alkoxy groups as defined
1 4 1 4
above. Examples of said groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy,
iso-butoxy, sec-butoxy and tert-butoxy. Preferred is methoxy.
In case “R “ represents “heteroaryl which is substituted with (C -C )alkoxy” the term “(C -
1 4 1
C )alkoxy” means (C -C )alkoxy groups as defined above. Examples of said groups are
4 1 4
methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy.
Preferred is methoxy.
The term “(C -C )alkoxy-(C -C )alkyl” refers to an (C -C )alkyl group as defined above in
1 2 2 3 2 3
which one hydrogen atom has been replaced with an (C -C )alkoxy group as defined
above. Examples of (C -C )alkoxy-(C -C )alkyl groups are methoxy-ethyl (notably 2-
1 2 2 3
methoxy-ethyl), methoxy-propyl (notably 2-methoxy-propyl and 3-methoxy-propyl), ethoxy-
ethyl (notably 2-ethoxy-ethyl) and ethoxy-propyl (notably 2-ethoxy-propyl and 3-ethoxy-
propyl). Preferred is 2-methoxy-ethyl.
The term “(C -C )cycloalkyl”, used alone or in combination, means a cycloalkyl group with 3
to 6 carbon atoms. Examples of (C -C )cycloalkyl groups are cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl. Preferred is cyclopropyl.
The term “(C -C )cycloalkyl-(C -C )-alkyl” refers to an (C -C )alkyl group as defined above
3 6 1 2 1 2
in which one hydrogen atom has been replaced with an (C -C )cycloalkyl group as defined
above. Examples of (C -C )cycloalkyl-(C -C )alkyl groups are cyclopropyl-methyl,
3 6 1 2
cyclobutyl-methyl, cyclopentyl-methyl, cyclohexyl-methyl, cyclopropyl-ethyl (notably 1-
cyclopropyl-ethyl and 2-cyclopropyl-ethyl), cyclobutyl-ethyl (notably 1-cyclobutyl-ethyl and
2-cyclobutyl-ethyl), cyclopentyl-ethyl (notably 1-cyclopentyl-ethyl and 2-cyclopentyl-ethyl)
and cyclohexyl-ethyl (notably 1-cyclohexyl-ethyl and 2-cyclohexyl-ethyl). Preferred is
cyclopropyl-methyl.
The term “(C -C )fluoroalkyl” (x and y each being an integer) refers to an alkyl group as
defined before containing x to y carbon atoms in which one or more (and possibly all)
hydrogen atoms have been replaced with fluorine. For example a (C -C )fluoroalkyl group
contains from one to four carbon atoms in which one to nine hydrogen atoms have been
replaced with fluorine.
In case “R “ represents “(C -C )fluoroalkyl” the term means a (C -C )fluoroalkyl group as
1 4 1 4
defined above. Examples of said groups are difluoromethyl, trifluoromethyl, 2,2-
difluoroethyl and 2,2,2-trifluoroethyl. Preferred examples are 2,2-difluoroethyl and 2,2,2-
trifluoroethyl. Most preferred is 2,2-difluoroethyl.
In case “R “ represents “heteroaryl which is substituted with (C -C )fluoroalkyl” the term
“(C -C )fluoroalkyl” means a (C -C )fluoroalkyl group as defined above. Examples of said
1 4 1 4
groups are difluoromethyl, trifluoromethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl.
Preferred examples are difluoromethyl and trifluoromethyl. Most preferred is trifluoromethyl.
The term halogen means fluoro, chloro, bromo or iodo.
In case “R “ represents “halogen” the term means preferably fluorine and chlorine and most
preferably fluorine.
In case “R “ represents “halogen” the term means preferably fluorine and chlorine and most
preferably fluorine.
In case “R “ represents “heteroaryl which is substituted with halogen” the term “halogen”
means preferably fluorine, chlorine and bromine, more preferably fluorine and chlorine and
most preferably chlorine.
The term “heteroaryl”, used alone or in combination, means a 5- to 10-membered
monocyclic or bicyclic aromatic ring containing 1, 2 or 3 heteroatoms independently
selected from oxygen, nitrogen and sulfur. Preferably the term “heteroaryl” means a 5- to
-membered monocyclic or bicyclic aromatic ring containing one nitrogen atom and
optionally one additional heteroatom selected from oxygen, nitrogen and sulfur. Most
preferred are 6-membered monocyclic aromatic ring systems containing one or two
nitrogen atoms. Examples of such heteroaryl groups are furanyl, oxazolyl, isoxazolyl,
oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl,
triazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl,
isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,
benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzo[2,1,3]oxadiazolyl,
benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl,
quinazolinyl, quinoxalinyl and phthalazinyl. Preferred examples of such heteroaryl groups
are pyridyl (notably pyridinyl), pyrimidyl (notably pyrimidinyl), benzoxazolyl (notably
benzoxazolyl), benzothiazolyl (notably benzothiazolyl) and quinazolinyl (notably
quinazolinyl and quinazolinyl). Further preferred examples are isoxazolyl (notably
isoxazolyl), thiazolyl (notably thiazolyl), thiadiazolyl (notably thiadiazolyl), pyrazolyl
(notably pyrazolyl) and quinoxalinyl (notably quinoxalinyl). More preferred are
pyrimidyl (notably pyrimidinyl), benzoxazolyl (notably benzoxazolyl) and
benzothiazolyl (notably benzothiazolyl). Most preferred is pyrimidyl (notably pyrimidin
yl). The heteroaryl group may be unsubstituted or mono-, di- or tri-substituted (preferably
unsubstituted or mono-substituted and most preferably mono-substituted), wherein the
substituents are independently selected from the group consisting of halogen, (C -C )alkyl,
(C -C )cycloalkyl, (C -C )alkoxy, (C -C )fluoroalkyl and phenyl. Examples of such
3 6 1 4 1 4
unsubstituted, mono-, di- or tri-substituted heteroaryl groups are 5-fluoro-pyrimidinyl, 5-
chloro-pyrimidinyl, 5-trifluoromethyl-pyrimidinyl, 5-fluoro-benzoxazolyl, 6-fluoro-
benzoxazolyl, 5-fluoro-benzothiazolyl, and 6-fluoro-benzothiazolyl. Further
examples are 5-methyl-pyrimidinyl, quinazolinyl, 6-fluoro-quinazolinyl, 7-fluoro-
quinazolinyl, 2-methyl-quinazolinyl and 6-fluoro-quinoxalinyl. Preferred examples
are 5-fluoro-pyrimidinyl, 5-chloro-pyrimidinyl, 5-methyl-pyrimidinyl, 5-fluoro-
benzoxazolyl, 6-fluoro-benzoxazolyl, quinazolinyl, 7-fluoro-quinazolinyl and 6-
fluoro-quinoxalinyl. More preferred examples are 5-fluoro-pyrimidinyl, 5-chloro-
pyrimidinyl, 5-fluoro-benzoxazolyl, and 6-fluoro-benzoxazolyl. Most preferred are 5-
fluoro-pyrimidinyl and 5-chloro-pyrimidinyl.
The term 'comprising' as used in this specification and claims means 'consisting at least in
part of'. When interpreting statements in this specification and claims which include the
term 'comprising', other features besides the features prefaced by this term in each
statement can also be present. Related terms such as 'comprise' and 'comprised' are to be
interpreted in similar manner.
In this specification where reference has been made to patent specifications, other external
documents, or other sources of information, this is generally for the purpose of providing a
context for discussing the features of the invention. Unless specifically stated otherwise,
reference to such external documents is not to be construed as an admission that such
documents, or such sources of information, in any jurisdiction, are prior art, or form part of
the common general knowledge in the art.
In the description in this specification reference may be made to subject matter that is not
within the scope of the claims of the current application. That subject matter should be
readily identifiable by a person skilled in the art and may assist in putting into practice the
invention as defined in the claims of this application.
2) Also described are compounds according to disclosure 1), wherein
R represents hydrogen, (C -C )alkyl, (C -C )alkoxy, halogen or trifluoromethoxy;
1 4 1 4
R represents hydrogen, halogen or trifluoromethyl;
R represents hydrogen, (C -C )alkyl, (C -C )alkoxy-(C -C )alkyl, (C -C )fluoroalkyl or
1 4 1 2 2 3 1 4
(C -C )cycloalkyl-(C -C )alkyl; and
3 6 1 2
R represents a heteroaryl group which is unsubstituted or mono- or di-substituted, wherein
the substituents are independently selected from the group consisting of halogen, (C -
C )alkyl, (C -C )cycloalkyl, (C -C )alkoxy, (C -C )fluoroalkyl and phenyl (preferably from
4 3 6 1 4 1 4
halogen, (C -C )alkyl and (C -C )fluoroalkyl);
1 4 1 4
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
3) Also described are compounds according to disclosure 1), wherein
R represents hydrogen, (C -C )alkyl, (C -C )alkoxy, halogen or trifluoromethoxy;
1 4 1 4
R represents hydrogen, halogen or trifluoromethyl;
R represents hydrogen or (C -C )alkyl; and
R represents a heteroaryl group which is unsubstituted or mono- or di-substituted (notably
mono-substituted), wherein the substituents are independently selected from the group
consisting of halogen, (C -C )alkyl and (C -C )fluoroalkyl (preferably from halogen and (C -
1 4 1 4 1
C )fluoroalkyl);
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
4) Also described are compounds according to disclosure 1), wherein
R represents hydrogen, methyl, methoxy, fluoro, chloro or trifluoromethoxy (notably
hydrogen);
R represents hydrogen, fluoro, chloro or trifluoromethyl (notably fluoro, chloro or
trifluoromethyl);
R represents hydrogen or methyl; and
R represents a heteroaryl group which is unsubstituted or mono-substituted with fluoro,
chloro or trifluoromethyl (notably fluoro or chloro);
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
) Also described are compounds according to disclosure 1), wherein
R represents hydrogen;
R represents hydrogen, fluoro, chloro or trifluoromethyl (notably fluoro or chloro);
R represents methyl; and
R represents a heteroaryl group which is mono-substituted with fluoro or chloro, wherein
the heteroaryl group is selected from pyrimidinyl, benzoxazolyl and benzothiazolyl;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
6) Also described are compounds according to any one of disclosures 1) to 4), wherein
R represents hydrogen, (C -C )alkyl or halogen (notably hydrogen, methyl, fluoro or
chloro);
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
7) Also described are compounds according to any one of disclosures 1) to 4), wherein
R represents hydrogen or halogen (notably hydrogen, fluoro or chloro);
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
8) A further embodiment of the invention relates to compounds according to any one of
disclosures 1) to 5), wherein
R represents hydrogen;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
9) Also described are compounds according to any one of disclosures 1) to 3) or 6) to 8),
wherein
R represents hydrogen, halogen or trifluoromethyl;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
) Also described are compounds according to any one of disclosures 1) to 4) or 6) to 8),
wherein
R represents hydrogen, fluoro, chloro or trifluoromethyl;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
11) Also described are compounds according to any one of disclosures 1) to 8), wherein
R represents fluoro or chloro;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
12) Also described are compounds according to any one of disclosures 1), 2) or 6) to 11),
wherein
R represents hydrogen, (C -C )alkyl, (C -C )alkoxy-(C -C )alkyl or (C -C )cycloalkyl-(C -
1 4 1 2 2 3 3 6 1
C )alkyl;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
13) Also described are compounds according to any one of disclosures 1), 2) or 6) to 11),
wherein
R represents hydrogen, methyl, ethyl, n-propyl, 2-methoxy-ethyl, 2,2-difluoroethyl or
cyclopropyl-methyl;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
14) Also described are compounds according to any one of disclosures 1) to 4) or 6) to 11),
wherein
R represents hydrogen or methyl;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
) Also described are compounds according to any one of disclosures 1) to 11), wherein
R represents (C -C )alkyl (notably methyl);
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
16) Also described are compounds according to any one of disclosures 1) to 4) or 6) to 11),
wherein
R represents hydrogen;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
17) Also described are compounds according to any one of disclosures 1), 2) or 6) to 16),
wherein
R represents a heteroaryl group which is unsubstituted or mono- or di-substituted (notably
mono-substituted), wherein the substituents are independently selected from the group
consisting of halogen, (C -C )alkyl, (C -C )cycloalkyl, (C -C )alkoxy and (C -C )fluoroalkyl;
1 4 3 6 1 4 1 4
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
18) Also described are compounds according to any one of disclosures 1), 2) or 6) to 16),
wherein
R represents a heteroaryl group which is unsubstituted or mono-substituted (notably
mono-substituted) with halogen, (C -C )cycloalkyl or (C -C )fluoroalkyl (notably fluorine,
3 6 1 4
chlorine, cyclopropyl or trifluoromethyl);
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
19) Also described are compounds according to any one of disclosures 1) to 3) or 6) to 16),
wherein
R represents a heteroaryl group which is mono-substituted with halogen or (C -
C )fluoroalkyl (notably fluoro, chloro or trifluoromethyl);
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
) Also described are compounds according to any one of disclosures 1) to 16), wherein
R represents a heteroaryl group which is mono-substituted with fluoro or chloro;
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
21) Also described are compounds according to any one of disclosures 17) to 20), wherein
the heteroaryl group is selected from pyrimidyl (notably pyrimidinyl), benzoxazolyl
(notably benzoxazolyl) and benzothiazolyl (notably benzothiazolyl);
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
22) Also described are compounds according to any one of disclosures 17) to 20), wherein
the heteroaryl group is pyrimidyl (notably pyrimidinyl);
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
23) Also described are compounds according to any one of disclosures 17) to 20), wherein
the heteroaryl group is benzoxazolyl (notably benzoxazolyl);
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
24) Also described are compounds according to any one of disclosures 17) to 20), wherein
the heteroaryl group is benzothiazolyl (notably benzothiazolyl);
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
) Also described are compounds according to any one of disclosures 1) to 24), wherein
the absolute configuration of the stereogenic center is as depicted in formula I
CO H
(I )
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
26) Also described are compounds according to any one of disclosures 1) to 24), wherein
the absolute configuration of the stereogenic center is as depicted in formula I
CO H
(I )
and to the salts (in particular pharmaceutically acceptable salts) of such compounds.
27) Described compounds of formula (I) as defined in disclosure 1) are selected from the
group consisting of:
2-(7-((5-chloropyrimidinyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol
yl)acetic acid;
2-(7-((5-fluoropyrimidinyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic
acid;
2-(7-(methyl(5-(trifluoromethyl)pyrimidinyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-
-yl)acetic acid;
2-(7-((6-fluorobenzo[d]thiazolyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol
yl)acetic acid;
2-(7-((5-fluorobenzo[d]oxazolyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol
yl)acetic acid;
2-(7-((5-fluorobenzo[d]thiazolyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol
yl)acetic acid;
2-(2-fluoro((5-fluoropyrimidinyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-
-yl)acetic acid,
2-(2-fluoro((5-fluorobenzo[d]oxazolyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-
a]indolyl)acetic acid;
2-(3-fluoro((5-fluoropyrimidinyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-
-yl)acetic acid;
2-(3-fluoro((5-fluorobenzo[d]oxazolyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-
a]indolyl)acetic acid;
2-(7-((5-fluoropyrimidinyl)(methyl)amino)methoxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-
-yl)acetic acid;
2-(7-((5-fluorobenzo[d]oxazolyl)(methyl)amino)methoxy-6,7,8,9-tetrahydropyrido[1,2-
a]indolyl)acetic acid;
2-(7-((5-fluoropyrimidinyl)(methyl)amino)methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-
-yl)acetic acid;
2-(7-((5-fluorobenzo[d]oxazolyl)(methyl)amino)methyl-6,7,8,9-tetrahydropyrido[1,2-
a]indolyl)acetic acid;
2-(2-chloro((5-fluoropyrimidinyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-
-yl)acetic acid;
2-(2-chloro((5-fluorobenzo[d]oxazolyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-
a]indolyl)acetic acid;
2-(7-((5-chloropyrimidinyl)(methyl)amino)fluoro-6,7,8,9-tetrahydropyrido[1,2-a]indol-
10-yl)acetic acid;
2-(3-fluoro(methyl(5-(trifluoromethyl)pyrimidinyl)amino)-6,7,8,9-tetrahydropyrido[1,2-
a]indolyl)acetic acid;
2-(3-fluoro((5-fluorobenzo[d]thiazolyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-
a]indolyl)acetic acid;
2-(3-fluoro((6-fluorobenzo[d]oxazolyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-
a]indolyl)acetic acid;
2-(3-chloro((5-chloropyrimidinyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-
-yl)acetic acid;
2-(7-((5-chloropyrimidinyl)(methyl)amino)(trifluoromethyl)-6,7,8,9-tetrahydropyrido[1,2-
a]indolyl)acetic acid;
2-(7-((5-chloropyrimidinyl)(methyl)amino)(trifluoromethoxy)-6,7,8,9-
tetrahydropyrido[1,2-a]indolyl)acetic acid;
2-(7-((5-fluoropyrimidinyl)(methyl)amino)(trifluoromethyl)-6,7,8,9-tetrahydropyrido[1,2-
a]indolyl)acetic acid;
2-(7-((5-fluoropyrimidinyl)(methyl)amino)(trifluoromethoxy)-6,7,8,9-
tetrahydropyrido[1,2-a]indolyl)acetic acid;
2-(7-((6-fluorobenzo[d]thiazolyl)(methyl)amino)(trifluoromethyl)-6,7,8,9-
tetrahydropyrido[1,2-a]indolyl)acetic acid;
2-(7-((6-fluorobenzo[d]thiazolyl)(methyl)amino)(trifluoromethoxy)-6,7,8,9-
tetrahydropyrido[1,2-a]indolyl)acetic acid;
2-(7-((5-fluorobenzo[d]oxazolyl)(methyl)amino)(trifluoromethyl)-6,7,8,9-
tetrahydropyrido[1,2-a]indolyl)acetic acid;
2-(7-((5-fluorobenzo[d]oxazolyl)(methyl)amino)(trifluoromethoxy)-6,7,8,9-
tetrahydropyrido[1,2-a]indolyl)acetic acid;
2-(3-chloro((5-fluoropyrimidinyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-
10-yl)acetic acid;
2-(3-chloro((5-fluorobenzo[d]oxazolyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-
a]indolyl)acetic acid;
(S)(3-chloro((5-fluoropyrimidinyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-
a]indolyl)acetic acid;
(R)(3-chloro((5-fluoropyrimidinyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-
a]indolyl)acetic acid;
2-(3-fluoro((5-fluoropyrimidinyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol
yl)acetic acid;
2-(3-fluoro((5-fluorobenzo[d]oxazolyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol
yl)acetic acid;
2-(3-chloro((5-fluoropyrimidinyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol
yl)acetic acid; and
2-(3-chloro((5-chloropyrimidinyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol
yl)acetic acid;
or salts (in particular pharmaceutically acceptable salts) of such compounds;
it is to be understood for any of the above listed compounds, that a stereogenic center,
which is not specifically assigned, may be in absolute (R)- or absolute (S)-configuration.
28) Further described compounds of formula (I) as defined in disclosure 1) are selected
from the group consisting of:
2-(3-chloro(methyl(5-methylpyrimidinyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-
-yl)acetic acid;
2-(3-chloro(methyl(quinazolinyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol
yl)acetic acid;
2-(3-chloro((6-fluoroquinazolinyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-
-yl)acetic acid;
2-(3-chloro((7-fluoroquinazolinyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-
-yl)acetic acid;
2-(3-chloro(methyl(2-methylquinazolinyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-
-yl)acetic acid;
2-(3-chloro((6-fluoroquinoxalinyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-
-yl)acetic acid;
2-(3-chloro((2,2-difluoroethyl)(5-fluorobenzo[d]oxazolyl)amino)-6,7,8,9-
tetrahydropyrido[1,2-a]indolyl)acetic acid;
2-(3-chloro(ethyl(5-fluoropyrimidinyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol
yl)acetic acid;
2-(3-chloro((5-fluorobenzo[d]oxazolyl)(isopropyl)amino)-6,7,8,9-tetrahydropyrido[1,2-
a]indolyl)acetic acid;
2-(3-chloro((5-fluoropyrimidinyl)(2-methoxyethyl)amino)-6,7,8,9-tetrahydropyrido[1,2-
a]indolyl)acetic acid;
2-(3-chloro((5-fluorobenzo[d]oxazolyl)(isobutyl)amino)-6,7,8,9-tetrahydropyrido[1,2-
a]indolyl)acetic acid;
2-(3-chloro((5-fluoropyrimidinyl)(propyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-
-yl)acetic acid;
2-(3-chloro(ethyl(5-fluorobenzo[d]oxazolyl)amino)-6,7,8,9-tetrahydropyrido[1,2-
a]indolyl)acetic acid; and
2-(3-chloro((cyclopropylmethyl)(5-fluoropyrimidinyl)amino)-6,7,8,9-
tetrahydropyrido[1,2-a]indolyl)acetic acid;
or salts (in particular pharmaceutically acceptable salts) of such compounds;
it is to be understood for any of the above listed compounds, that a stereogenic center,
which is not specifically assigned, may be in absolute (R)- or absolute (S)-configuration.
Unless explicitly stated otherwise, the general terms and names used hereinbefore and
hereinafter preferably have within the context of this disclosure the following meanings:
Where the plural form is used for compounds, salts, pharmaceutical compositions,
diseases and the like, this is intended to mean also a single compound, salt, or the like.
The term "pharmaceutically acceptable salts" refers to non-toxic, inorganic or organic acid
and/or base addition salts. Reference can be made to "Salt selection for basic drugs", Int.
J. Pharm. (1986), 33, 201-217.
The compounds of formula (I) according to any one of disclosures 1) to 28), or
pharmaceutically acceptable salts thereof, may be used for the preparation of a
medicament, and are suitable for the prevention and/or treatment of diseases selected from
the group consisting of chronic and acute allergic/immune diseases/disorders, comprising
asthma, allergic asthma, eosinophilic asthma, severe asthma, rhinitis, allergic rhinitis,
angioedema, insect venom allergy, drug allergies, allergic sinusitis, allergic nephritis,
allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell
disorders, anaphylactic shock, urticaria, eczema, ulcerative colitis, chronic obstructive
pulmonary disease (COPD), inflammatory bowel disease and rheumatoid arthritis;
eosinophil-related diseases comprising small vessel vasculitides like Churg-Strauss
syndrome, Wegener's granulomatosis, microscopic polyangiitis (and organ-specific subsets
of the latter), hypereosinophilic syndromes like eosinophilic pneumonia, eosinophilic
esophagitis, reflux esophagitis, eosinophilic endocarditis (Loeffler’s endocarditis),
eosinophilia-myalgia syndrome, eosinophilic fasciitis, eosinophilic pustular folliculitis (Ofuji's
disease), eosinophilic ulcers, angiolymphoid hyperplasia with eosinophilia (ALHE),
eosinophilic cellulitis (Wells syndrome), chronic eosinophilic leukemia and DRESS
syndrome (Drug Rash with Eosinophilia and Systemic Symptoms); and basophil-related
diseases, comprising basophilic leukemia and basophilic leukocytosis.
The compounds of formula (I) according to any one of disclosures 1) to 28), or
pharmaceutically acceptable salts thereof, may be used for the preparation of a
medicament, and are suitable for the prevention and/or treatment of diseases selected from
the group consisting of asthma, allergic asthma, eosinophilic asthma, severe asthma,
allergic rhinitis, angioedema, insect venom allergy, drug allergies, allergic sinusitis, allergic
nephritis, allergic conjunctivitis, atopic dermatitis, food allergy, systemic mast cell disorders,
anaphylactic shock, urticaria and eczema.
The compounds of formula (I) according to any one of disclosures 1) to 28), or
pharmaceutically acceptable salts thereof, may be used for the preparation of a
medicament, and are suitable for the prevention and/or treatment of diseases selected from
the group consisting of eosinophil-related diseases comprising small vessel vasculitides
like Churg-Strauss syndrome, Wegener's granulomatosis, microscopic polyangiitis (and
organ-specific subsets of the latter), hypereosinophilic syndromes like eosinophilic
pneumonia, eosinophilic esophagitis, reflux esophagitis, eosinophilic endocarditis
(Loeffler’s endocarditis), eosinophilia-myalgia syndrome, eosinophilic fasciitis, eosinophilic
pustular folliculitis (Ofuji's disease), eosinophilic ulcers, angiolymphoid hyperplasia with
eosinophilia (ALHE), eosinophilic cellulitis (Wells syndrome), chronic eosinophilic leukemia
and DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms).
The compounds of formula (I) according to any one of disclosures 1) to 28), or
pharmaceutically acceptable salts thereof, may be used for the preparation of a
medicament, and are suitable for the prevention and/or treatment of diseases selected from
the group consisting of basophil-related diseases, comprising basophilic leukemia and
basophilic leukocytosis.
Also described is the use of a compound of formula (I) according to any one of disclosures
1) to 28) for the preparation of pharmaceutical compositions for the treatment and/or
prophylaxis of the above-mentioned diseases.
Also described are pharmaceutically acceptable salts and to pharmaceutical compositions
and formulations of compounds of formula (I) according to any one of disclosures 1) to 28).
A pharmaceutical composition as described herein contains at least one compound of
formula (I) according to any one of disclosures 1) to 28) (or a pharmaceutically acceptable
salt thereof) as the active agent and optionally carriers and/or diluents and/or adjuvants.
The compounds of formula (I) according to any one of disclosures 1) to 28) and their
pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of
pharmaceutical compositions for enteral (such as especially oral) or parenteral (including
topical application or inhalation) administration.
The production of the pharmaceutical compositions can be effected in a manner which will
be familiar to any person skilled in the art (see for example Remington, The Science and
Practice of Pharmacy, 21st Edition (2005), Part 5, “Pharmaceutical Manufacturing”
[published by Lippincott Williams & Wilkins]) by bringing the described compounds of
formula (I) or their pharmaceutically acceptable salts, optionally in combination with other
therapeutically valuable substances, into a galenical administration form together with
suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if
desired, usual pharmaceutical adjuvants.
The present invention also relates to a method for the prevention or treatment of a disease
or disorder mentioned herein comprising administering to a subject a pharmaceutically
active amount of a compound of formula (I) according to any one of embodiments 1) to 28),
or a pharmaceutically acceptable salt thereof.
The present invention also includes isotopically labelled, especially H (deuterium) labelled
compounds of formula (I), which compounds are identical to the compounds of formula (I)
except that one or more atoms have each been replaced by an atom having the same
atomic number but an atomic mass different from the atomic mass usually found in nature.
Isotopically labelled, especially H (deuterium) labelled compounds of formula (I) and salts
thereof are within the scope of the present invention. Substitution of hydrogen with the
heavier isotope H (deuterium) may lead to greater metabolic stability, resulting e.g. in
increased in-vivo half-life or reduced dosage requirements, or may lead to reduced
inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile. In one
embodiment of the invention, the compounds of formula (I) are not isotopically labelled, or
they are labelled only with one or more deuterium atoms. In a sub-embodiment, the
compounds of formula (I) are not isotopically labelled at all. Isotopically labelled
compounds of formula (I) may be prepared in analogy to the methods described
hereinafter, but using the appropriate isotopic variation of suitable reagents or starting
materials.
Any reference to a compound of formula (I), (I ) or (I ) in this text is to be understood as
ST1 ST2
referring also to the salts (and especially the pharmaceutically acceptable salts) of such
compounds, as appropriate and expedient. The preferences indicated for the compounds
of formula (I) of course apply mutatis mutandis to the compounds of formula (I ) and the
compounds of formula (I ) as well as to the salts and pharmaceutically acceptable salts of
the compounds of formula (I), of formula (I ) or of formula (I ). The same applies to
ST1 ST2
these compounds as medicaments, to pharmaceutical compositions containing these
compounds as active principles or to the uses of these compounds for the manufacture of a
medicament for the treatment of the diseases according to this invention.
Unless used regarding temperatures, the term “about” (or alternatively “around”) placed
before a numerical value “X” refers in the current application to an interval extending from X
minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus
5% of X to X plus 5% of X. In the particular case of temperatures, the term “about” (or
alternatively “around”) placed before a temperature “Y” refers in the current application to
an interval extending from the temperature Y minus 10 ºC to Y plus 10 ºC, and preferably
to an interval extending from Y minus 5 ºC to Y plus 5 ºC. Besides, the term “room
temperature” (rt) as used herein refers to a temperature of about 25°C.
Whenever the word “between” is used to describe a numerical range, it is to be understood
that the end points of the indicated range are explicitly included in the range. For example:
if a temperature range is described to be between 40 ºC and 80 ºC, this means that the end
points 40 ºC and 80 ºC are included in the range or if a variable is defined as being an
integer between 1 and 4, this means that the variable is the integer 1, 2, 3, or 4.
As mentioned earlier, compounds of formula (I) modulate the PGD activation of the
CRTH2 receptor. The biological effect of such compounds may be tested in a variety of in
vitro, ex vivo and in vivo assays. The ability of the compounds of formula (I) to bind to the
CRTH2 receptor may be measured by methods similar to those described in the literature
(Arimura A. et al., J. Pharmacol. Exp. Ther. 2001, 298(2), 411-419; and Sawyer N. et al.,
Br. J. Pharmacol, 2002, 137, 1163-1172, respectively) and by the assays described below
in the experimental part.
Also described is a process for the preparation of compounds of formula (I). Compounds
according to formula (I) of the present invention can be prepared according to the
1 2 3 4
sequence of reactions outlined in the schemes below wherein R , R , R and R are as
defined for formula (I). Other abbreviations used are defined in the experimental section. In
1 2 3 4
some instances the generic groups R , R , R and R might be incompatible with the
assembly illustrated in the schemes below and, therefore, will require the use of protecting
groups (PG). For example it may be necessary to protect reactive functional groups such
as hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final
product, to avoid their unwanted participation in the reactions. The use of protecting groups
is well known in the art. It will be assumed that such protecting groups are as necessary in
place.
In general, all chemical transformations can be performed according to well-known
standard methodologies as described in the literature, or as described in the procedures
below. The compounds obtained may also be converted into pharmaceutically acceptable
salts thereof in a manner known per se.
The compounds of formula (I) may be prepared from the respective (E)-ethyl 3-(1-(2-(tert-
butoxy)oxoethyl)-1H-indolyl)acrylate derivatives (4). Compounds (4) are obtained by
reaction of the corresponding (E)-ethyl 3-(1H-indolyl)acrylate derivatives (3) with tert-
butyl bromoacetate in the presence of a base such as Cs CO in an aprotic solvent such as
DMF. The (E)-ethyl 3-(1H-indolyl)acrylate derivatives (3) may be prepared either via
Wittig reaction from commercially available or well-known 1H-indolecarbaldehyde
derivatives (1) by reaction with carbethoxymethylene triphenylphosphorane in an aprotic
solvent such as DCM or via Heck reaction from commercially available or well known indole
derivatives (2) by reaction with ethyl acrylate in the presence of a catalyst such as
Pd(OAc) and an oxidant such as tert-butyl perbenzoate in a mixture of AcOH and dioxane
(Gaunt M.J. et al, Angewandte Chemie, 2005, 44, 3125-3129).
Hydrogenation of the obtained (E)-ethyl 3-(1-(2-(tert-butoxy)oxoethyl)-1H-indol
yl)acrylate derivatives (4) over a catalyst such as Pd-C 10% or PtO in an aprotic solvent
such as EA followed by reaction with KOtBu in an aprotic solvent such as THF gives the
corresponding tert-butyl 7-oxo-6,7,8,9-tetrahydropyrido[1,2-a]indolecarboxylate
derivatives (5). Decarboxylation by reaction with silica gel in an aprotic solvent such as
toluene and subsequent reductive aminations with, first, benzylamine in the presence of a
reducing agent such NaBH(OAc) in an aprotic solvent such as DCM, and with, second, an
appropriate aldehyde (as precursor of R ) in the presence of a reducing agent such NaBH
in a protic solvent such as MeOH gives the corresponding N-benzyl-6,7,8,9-
tetrahydropyrido[1,2-a]indolamine derivatives (6). Friedel-Craft acylation with oxalyl
chloride in an aprotic solvent such as DCM, followed by esterification with MeOH and
subsequent reduction with triethylsilane in the presence of TFA gives the corresponding
methyl 2-(7-(benzylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetate derivatives (7).
Debenzylation by hydrogenation over a catalyst such as Pd-C 10% in a protic solvent such
as EtOH or by reaction with 1-chloroethyl chloroformate and MeOH in an aprotic solvent
such as DCM gives the respective N-substituted methyl 2-(7-amino-6,7,8,9-
tetrahydropyrido[1,2-a]indolyl)acetate derivatives (8). Reaction with an appropriate
heteroaryl halide like R -Cl in the presence of a base such as K CO in an aprotic solvent
such as DMA followed by saponification with a base such as NaOH furnished the
compounds of formula (I) (Method A).
CO Et Wittig reaction
2 Heckreaction
CO Et/ Pd(OAc) /
(Ph) P
dioxane/AcOH
CO Et
OtBu
Cs CO /DMF
CO Et
tBuO C
1)H /Pd-C10%orPtO
2)KOtBu/THF
tBuO C
silica gel/ toluene
NaBH(OAc) /DCM
3) aldehyde/ NaBH /MeOH
1) (COCl) / DCM
2) MeOH
3) Et SiH/TFA
H / Pd-C10% 4
1)R -Cl/ K CO /DMA
2 2 3 R
N or
2) 1N NaOH
Cl O
CO H
CO Me
CO Me
O Cl/DCM
2) MeOH
Scheme 1: General synthetic route for the preparation of compounds of formula (I)
(Method A)
Compounds of formula (I) wherein R represents hydrogen may be prepared from the
respective tert-butyl 7-oxo-6,7,8,9-tetrahydropyrido[1,2-a]indolecarboxylate derivatives
(5). Decarboxylation by reaction with silica gel in an aprotic solvent such as toluene gives
the corresponding 8,9-dihydropyrido[1,2-a]indol-7(6H)-one derivatives (9). Reductive
amination with ammonium acetate in the presence of a reducing agent such as NaBH CN
in a mixture of AcOH and EtOH and subsequent Boc protection yields the corresponding
tert-butyl (6,7,8,9-tetrahydropyrido[1,2-a]indolyl)carbamate derivatives (10). Friedel-Craft
acylation by reaction with oxalyl chloride in an aprotic solvent such as DCM, followed by
esterification with MeOH and subsequent reduction with triethylsilane in the presence of
TFA gives the corresponding methyl 2-(7-amino-6,7,8,9-tetrahydropyrido[1,2-a]indol
yl)acetate (11). Reaction with an appropriate heteroaryl halide like R -Cl in the presence of
a base such as K CO in an aprotic solvent such as DMA and subsequent saponification
with a base such as NaOH furnished the compounds of formula (I).
Scheme 2: General synthetic route for the preparation of compounds of formula (I)
(R represents H)
1H-indolecarbaldehyde derivatives (1) may be prepared by reduction of commercially
available or well known ethyl 1H-indolecarboxylate derivatives (12) with a reducing
agent such as LAH in an aprotic solvent such as THF to give the corresponding (1H-indol-
2-yl)methanol derivative (13). Oxidation with an oxidizing agent such as active manganese
dioxide in an aprotic solvent such as DCM gives the desired 1H-indolecarbaldehyde
derivatives (1).
Scheme 3: General synthetic route for the preparation of
1H-indolecarbaldehyde derivatives (1)
Compounds of formula (I) might also be prepared from the respective 8,9-
dihydropyrido[1,2-a]indol-7(6H)-one derivatives (9). Reductive amination with ammonium
acetate in the presence of a reducing agent such as NaBH CN in a mixture of AcOH and
EtOH yields the corresponding 6,7,8,9-tetrahydropyrido[1,2-a]indolamine derivatives
(14). Reaction with an appropriate heteroaryl halide like R -Cl in the presence of a base
such as K CO in an aprotic solvent such as DMA and subsequent alkylation with the
respective R -X (with X = I, Br, OTf) in the presence of a strong base such as NaH in an
aprotic solvent like DMA gives the desired 7-(Heteroaryl(alkyl)amino)-6,7,8,9-
tetrahydropyrido[1,2-a]indole derivative (15). Friedel-Craft acylation by reaction with oxalyl
chloride in an aprotic solvent such as DCM, followed by esterification with MeOH, reduction
with triethylsilane in the presence of TFA and finally saponification with a base such as
NaOH furnished the compounds of formula (I) (Method B).
Scheme 4: General synthetic route for the preparation of compounds of formula (I)
(Method B)
Whenever the compounds of formula (I) or an intermediate of structures 6 to 8, 10 or 15
are obtained in the form of mixtures of enantiomers, the enantiomers may be separated
using methods known to the one skilled in the art: e.g. by formation and separation of
diastereomeric salts or by HPLC over a chiral stationary phase such as a Regis Whelk-
O1(R,R) (10 μm) column, a Daicel ChiralCel OD-H (5-10 μm) column, or a Daicel ChiralPak
IA (10 μm) or AD-H (5 μm) column. Typical conditions of chiral HPLC are an isocratic
mixture of eluent A (EtOH, in presence or absence of an amine such as TEA and/or
diethylamine) and eluent B (hexane), at a flow rate of 0.8 to 150 mL/min.
Experimental section:
Abbreviations (as used herein):
Ac Acetyl
AcOH Acetic acid
aq. Aqueous
APC Allophycocyanin
Bdg Binding
Boc tert-butoxycarbonyl
BSA Bovine Serum Albumin
DCM Dichloromethane
DEA Diethylamine
DIEA N,N-Diisopropylethylamine
DMF Dimethylformamide
DMA Dimethylacetamide
DMSO Dimethylsulfoxide
dpm decays per minute
EA Ethyl acetate
EDTA Ethylene Diamine Tetraacetic Acid
Eq equivalent
ESI-MS Electrospray Ionization Mass Spectroscopy
Et Ethyl
EtOH Ethanol
FC Flash Chromatography
h Hour(s)
HEPES 4-(2-hydroxyethyl)piperazineethanesulfonic acid
HPLC High Performance Liquid Chromatography
HSA Human Serum Albumin
iPr Isopropyl
l Liter(s)
LAH Lithium aluminum hydride
LC-MS Liquid Chromatography – Mass Spectroscopy
Me Methyl
MeCN Acetonitrile
MeOH Methanol
min Minute(s)
MS Mass Spectroscopy
MW Microwave
N Normality of solution
PBS Phosphate Buffered Saline
PEI Polyethyleneimine
PG Protecting group
PGD Prostaglandin D
2 2
Ph Phenyl
Pr Propyl
rt Room temperature
s Second(s)
sat Saturated
tBu tert-butyl
TEA Triethylamine
Tf Trifluoromethanesulfonyl
TFA Trifluoroacetic acid
THF Tetrahydrofuran
t Retention time
Tris Tris-(hydroxymethyl)aminomethane buffer
Vol Volume
Chemistry
General remarks
All solvents and reagents are used as obtained from commercial sources unless otherwise
indicated.
Temperatures are indicated in degrees Celsius (°C). Unless otherwise indicated, the
reactions take place at room temperature (rt).
In mixtures, relations of parts of solvent or eluent or reagent mixtures in liquid form are
given as volume relations (v/v), unless indicated otherwise.
Analytical HPLC conditions as used in the Examples below:
HPLC/MS analyses are performed on a Agilent 1100 system, equipped with a Dionex P580
binary pump, a Dionex PDA-100 Photodiode Array Detector and a Finnigan AQA mass
spectrometer (LC-1 and LC-2).
The LC retention times are obtained using the following elution conditions:
- LC-1: Analytical HPLC on a Waters Atlantis T3 column (4.6x30 mm, 5 μm); Linear
gradient of water/ 0.04% TFA (A) and MeCN (B) from 5% to 95% B over 1.5 min; flow rate
4.5 ml/min, detection at 210 nm.
- LC-2: Analytical HPLC on a Zorbax SB-AQ column (4.6x50 mm, 3.5 μm, Agilent); Linear
gradient of water/ 0.04% TFA (A) and MeCN (B) from 5% to 95% B over 1.5 min; flow rate
4.5 ml/min, detection at 210 nm.
Preparative HPLC/MS purifications are performed on a Gilson 333/334 binary high
pressure gradient pump system with a Gilson 215 autosampler and fraction collector, a
Dionex UVD340U DAD detector, a polymerlabs PL-ELS 1000 ELS detector and a Finnigan
AQA MS detector or a Thermo MSQ Plus MS detector, using a Waters Atlantis T3 column
(10 μm, 30 × 75 mm), with a linear gradient of MeCN (A) and water/ 0.5% formic acid (B)
over 5 min.; flow rate 75 ml/min.
Analytical HPLC over a chiral stationary phase are performed on a Daicel ChiralPak AD-H
(4.6 X 250 mm, 5 μm) column. Typical conditions of chiral HPLC are an isocratic mixture of
50% heptane + 0.05% DEA and 50% EtOH + 0.05% DEA, at a flow rate of 0.8 mL/min.,
detection at 210 nm (chiral HPLC-1) or an isocratic mixture of 50% heptane and 50% EtOH
+ 0.1% TFA, at a flow rate of 0.8 mL/min., detection at 210 nm (chiral HPLC-2).
Preparative HPLC over a chiral stationary phase are performed on a Daicel ChiralPak AD-
H (20 X 250 mm, 5 μm) column. Typical conditions of chiral HPLC are an isocratic mixture
of 50% EtOH and 50% hexane, at a flow rate of 16 mL/min., detection at 210 nm (chiral
HPLC-3).
A. Synthesis of 7-(Heteroaryl-amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol acetic acid
derivatives (Method A)
A.1.Synthesis of ethyl 3-(1H-indolyl)acrylate derivatives
General procedure A (via Wittig reaction):
CO Et
(Ph) P
CO Et
DCM H
To a solution of the respective 1H-indolecarbaldehyde derivative (12 mmol) in DCM (135
ml) was added carbethoxymethylene triphenylphosphorane (12 mmol).The reaction mixture
was stirred at rt for 16h, concentrated in vacuo and the residue was purified by FC (EA/ n-
heptane: 0/10 to 3/7) to give the title compound as a solid.
The following (E)-ethyl 3-(1H-indolyl)acrylate derivatives were synthetized according to
the above general procedure
Table 1
t [min]
[M+H]
R Name LC-MS
method
0.91
H (E)-ethyl 3-(1H-indolyl)acrylate 216.02
LC-1
0.96
Cl (E)-ethyl 3-(5-chloro-1H-indolyl)acrylate 250.01
LC-1
F (E)-ethyl 3-(5-fluoro-1H-indolyl)acrylate 234.08
LC-1
0.94
Me (E)-ethyl 3-(5-methyl-1H-indolyl)acrylate 230.17
LC-1
0.87
OMe (E)-ethyl 3-(5-methoxy-1H-indolyl)acrylate 246.07
LC-1
(E)-ethyl 3-(5-(trifluoromethoxy)-1H-indol 1.00
OCF 300.12
yl)acrylate LC-1
General procedure B (via Heck reaction):
CO Et/Pd(OAc) /
2 CO Et
dioxane/ AcOH
To a mixture of the respective indole derivative (14 mmol), ethyl acrylate (28 mmol), tert-
butyl perbenzoate (12.6 mmol) in a mixture of dioxane (27 ml) and AcOH (9 ml) was added
Pd(OAc) . The reaction mixture was stirred at 70°C for 18h. After cooling to rt, the reaction
mixture was neutralized with sat. NaHCO solution, diluted with EA and filtered over Celite.
The organic extract was washed again with sat. NaHCO solution, brine, dried over MgSO ,
filtered and concentrated in vacuo. The resulting residue was purified by FC (EA/ n-
heptane: 0/10 to 3/7) to give the title compound as a solid.
The following (E)-ethyl 3-(1H-indolyl)acrylate derivatives were synthetized according to
the above general procedure
Table 2
t [min]
[M+H]
R Name LC-MS
method
0.97
Cl (E)-ethyl 3-(6-chloro-1H-indolyl)acrylate 250.09
LC-1
0.90
F (E)-ethyl 3-(6-fluoro-1H-indolyl)acrylate 234.16
LC-1
(E)-ethyl 3-(6-(trifluoromethyl)-1H-indol 0.99
CF 284.10
yl)acrylate LC-1
A.2 Synthesis of (E)-ethyl 3-(1-(2-(tert-butoxy)oxoethyl)-1H-indolyl)acrylate
derivatives
General procedure:
To a solution of the respective (E)-ethyl 3-(1H-indolyl)acrylate derivative (26 mmol) in dry
DMF (85 ml) were added tert-butyl bromoacetate (43 mmol) and Cs CO (56 mmol). The
reaction mixture was stirred at 60°C for 20h. After cooling to rt, the reaction mixture was
diluted with acetone (85 ml) and filtered. The filtrate was concentrated in vacuo and the
residue was purified by FC (EA/ n-heptane: 0/10 to 2/8) to give the title compound as an oil.
The following (E)-ethyl 3-(1-(2-(tert-butoxy)oxoethyl)-1H-indolyl)acrylate derivatives
were synthetized according to the above general procedure
Table 3
t [min]
[M+H]
R R Name LC-MS
method
(E)-ethyl 3-(1-(2-(tert-butoxy)oxoethyl)-1H- 1.03
330.16
indolyl)acrylate LC-1
(E)-ethyl 3-(1-(2-(tert-butoxy)oxoethyl) 1.08
Cl H 363.95
chloro-1H-indolyl)acrylate LC-1
(E)-ethyl 3-(1-(2-(tert-butoxy)oxoethyl)fluoro- 1.03
F H 348.07
1H-indolyl)acrylate LC-1
(E)-ethyl 3-(1-(2-(tert-butoxy)oxoethyl) 1.08
Me H 344.01
methyl-1H-indolyl)acrylate LC-1
(E)-ethyl 3-(1-(2-(tert-butoxy)oxoethyl) 1.01
OMe H 360.11
methoxy-1H-indolyl)acrylate LC-1
(E)-ethyl 3-(1-(2-(tert-butoxy)oxoethyl) 1.1
OCF H
413.94
(trifluoromethoxy)-1H-indolyl)acrylate LC-1
(E)-ethyl 3-(1-(2-(tert-butoxy)oxoethyl) 1.09
H Cl 363.88
chloro-1H-indolyl)acrylate LC-1
(E)-ethyl 3-(1-(2-(tert-butoxy)oxoethyl)fluoro- 1.04
H F 348.10
1H-indolyl)acrylate LC-1
(E)-ethyl 3-(1-(2-(tert-butoxy)oxoethyl) 1.1
H CF 397.99
(trifluoromethyl)-1H-indolyl)acrylate LC-1
A.3 Synthesis of tert-butyl 7-oxo-6,7,8,9-tetrahydropyrido[1,2-a]indolecarboxylate
derivatives
General procedure:
A suspension of the respective (E)-ethyl 3-(1-(2-(tert-butoxy)oxoethyl)-1H-indol
yl)acrylate derivative (8.5 mmol), Pd-C 10% (300 mg) in EA (28 ml) was stirred under
hydrogen atmosphere for 2h at rt. The reaction was then filtered over celite to give the
crude diester which was used for the next step without further purification. To a cold (-10
°C) solution of the crude diester (8.5 mmol) in dry THF (22.5 ml) was added dropwise a
solution of potassium tert-butoxide (8.5 mmol) in dry THF (112.5 ml). The reaction mixture
was allowed to stir at rt for 10 min., quenched with HCl 1N (12 ml) and extracted with n-
hexane. The combined organic extracts were dried over MgSO , filtered and concentrated
in vacuo. The resulting residue was purified by FC (EA/ n-heptane: 0/10 to 1/9) to give the
title compound as an oil.
The following tert-butyl 7-oxo-6,7,8,9-tetrahydropyrido[1,2-a]indolecarboxylate
derivatives were synthetized according to the above general procedure, except for tert-
butyl 3-chlorooxo-6,7,8,9-tetrahydropyrido[1,2-a]indolecarboxylate where Pd-C 10%
was replaced by PtO hydrate.
Table 4
t [min]
[M+H]
R R Name LC-MS
method
tert-butyl 7-oxo-6,7,8,9-tetrahydropyrido[1,2- 0.96
H H 286.16
a]indolecarboxylate LC-1
tert-butyl 2-chlorooxo-6,7,8,9- 1.02
Cl H 320.08
tetrahydropyrido[1,2-a]indolecarboxylate LC-1
tert-butyl 2-fluorooxo-6,7,8,9- 0.97
F H 304.05
tetrahydropyrido[1,2-a]indolecarboxylate LC-1
tert-butyl 2-methyloxo-6,7,8,9- 1.01
Me H 300.12
tetrahydropyrido[1,2-a]indolecarboxylate LC-1
tert-butyl 2-methoxyoxo-6,7,8,9- 0.94
OMe H 316.11
tetrahydropyrido[1,2-a]indolecarboxylate LC-1
tert-butyl 7-oxo(trifluoromethoxy)-6,7,8,9- 1.05
OCF H 369.83
tetrahydropyrido[1,2-a]indolecarboxylate LC-1
tert-butyl 3-chlorooxo-6,7,8,9- 1.02
H Cl 320.05
tetrahydropyrido[1,2-a]indolecarboxylate LC-1
tert-butyl 3-fluorooxo-6,7,8,9- 0.97
H F 304.07
tetrahydropyrido[1,2-a]indolecarboxylate LC-1
tert-butyl 7-oxo(trifluoromethyl)-6,7,8,9- 1.03
H CF 353.78
tetrahydropyrido[1,2-a]indolecarboxylate LC-1
A.4 Synthesis of 8,9-dihydropyrido[1,2-a]indol-7(6H)-one derivatives
General procedure:
A mixture of the respective tert-butyl 7-oxo-6,7,8,9-tetrahydropyrido[1,2-a]indole
carboxylate derivative (5.3 mmol) and silica gel (7 g) in toluene (70 ml) was stirred at reflux
for 6h and allowed to stir at rt overnight.The reaction mixture was then filtered, the solid
was washed with EA and the filtrate was concentrated in vacuo to give the title compound
which was used for the next step without further purification.
The following 8,9-dihydropyrido[1,2-a]indol-7(6H)-one derivatives were synthetized
according to the above general procedure.
Table 5
t [min]
[M+H]
R R Name LC-MS
method
0.79
H H 8,9-dihydropyrido[1,2-a]indol-7(6H)-one 186.23
LC-1
2-chloro-8,9-dihydropyrido[1,2-a]indol-7(6H)- 0.87
Cl H 220.01
one LC-1
0.82
F H 2-fluoro-8,9-dihydropyrido[1,2-a]indol-7(6H)-one 204.15
LC-1
2-methyl-8,9-dihydropyrido[1,2-a]indol-7(6H)- 0.86
Me H 200.19
one LC-1
2-methoxy-8,9-dihydropyrido[1,2-a]indol-7(6H)- 0.77
OMe H 216.14
one LC-1
2-(trifluoromethoxy)-8,9-dihydropyrido[1,2- 0.93
OCF H 270.08
a]indol-7(6H)-one LC-1
3-chloro-8,9-dihydropyrido[1,2-a]indol-7(6H)- 0.88
H Cl
220.08
one LC-1
0.82
H F 3-fluoro-8,9-dihydropyrido[1,2-a]indol-7(6H)-one 204.18
LC-1
3-(trifluoromethyl)-8,9-dihydropyrido[1,2-a]indol- 0.91
H CF 254.03
7(6H)-one LC-1
A.5 Synthesis of N-benzyl-6,7,8,9-tetrahydropyrido[1,2-a]indolamine derivatives
General procedure:
To a solution of the respective 8,9-dihydropyrido[1,2-a]indol-7(6H)-one derivative (2.7
mmol) in dry DCM (20 ml) were added successively benzylamine (3 mmol) and
NaBH(OAc) (2.7 mmol). The resulting reaction mixture was stirred at rt for 1h and then
quenched with sat. NaHCO solution.The aqueous phase was extracted with DCM, the
combined organic extracts were washed with water, brine, dried over MgSO , filtered and
concentrated in vacuo. The resulting residue was purified by FC (EA/ n-heptane: 0/10 to
3/7) to give the title compound as an oil.
The following N-benzyl-6,7,8,9-tetrahydropyrido[1,2-a]indolamine derivatives were
synthetized according to the above general procedure.
Table 6
t [min]
[M+H]
R R Name LC-MS
method
N-benzyl-6,7,8,9-tetrahydropyrido[1,2-a]indol 0.62
H H 277.15
amine LC-1
N-benzylchloro-6,7,8,9-tetrahydropyrido[1,2- 0.68
Cl H 311.06
a]indolamine LC-1
N-benzylfluoro-6,7,8,9-tetrahydropyrido[1,2- 0.63
295.11
a]indolamine LC-1
N-benzylmethyl-6,7,8,9-tetrahydropyrido[1,2- 0.66
Me H 291.21
a]indolamine LC-1
N-benzylmethoxy-6,7,8,9- 0.60
OMe H 307.16
tetrahydropyrido[1,2-a]indolamine LC-1
N-benzyl(trifluoromethoxy)-6,7,8,9- 0.72
OCF H 360.99
tetrahydropyrido[1,2-a]indolamine LC-1
N-benzylchloro-6,7,8,9-tetrahydropyrido[1,2- 0.68
H Cl 311.10
a]indolamine LC-1
N-benzylfluoro-6,7,8,9-tetrahydropyrido[1,2- 0.64
295.11
a]indolamine LC-1
N-benzyl(trifluoromethyl)-6,7,8,9- 0.72
H CF 344.96
tetrahydropyrido[1,2-a]indolamine LC-1
A.6 Synthesis of N-benzyl-N-alkyl-6,7,8,9-tetrahydropyrido[1,2-a]indolamine
derivatives
General procedure:
To a cold (0°C) solution of the respective N-benzyl-6,7,8,9-tetrahydropyrido[1,2-a]indol
amine derivative (2 mmol) and formaldehyde (36.5% in water, 10 mmol) in dry MeOH (20
ml) was added portionwise over 20 min. NaBH (6 mmol). The resulting reaction was
allowed to warm-up to rt and stirred overnight. The reaction mixture was then poured into
water and extracted with EA. The combined organic extracts were washed with brine, dried
over MgSO , filtered and concentrated in vacuo to give the title compound as an oil which
was used for the next step without further purification.
The following N-benzyl-N-alkyl-6,7,8,9-tetrahydropyrido[1,2-a]indolamine derivatives
were synthetized according to the above general procedure.
Table 7
t [min]
[M+H]
1 2 3
R R R Name LC-MS
method
N-benzyl-N-methyl-6,7,8,9- 0.73
H H Me
291.35
tetrahydropyrido[1,2-a]indolamine LC-2
N-benzylchloro-N-methyl-6,7,8,9- 0.65
Cl H Me
325.17
tetrahydropyrido[1,2-a]indolamine LC-1
N-benzylfluoro-N-methyl-6,7,8,9- 0.68
F H Me 309.11
tetrahydropyrido[1,2-a]indolamine LC-1
N-benzyl-N,2-dimethyl-6,7,8,9- 0.68
Me H Me 305.22
tetrahydropyrido[1,2-a]indolamine LC-1
N-benzylmethoxy-N-methyl-6,7,8,9- 0.62
OMe H Me 321.17
tetrahydropyrido[1,2-a]indolamine LC-1
N-benzyl-N-methyl(trifluoromethoxy)- 0.75
OCF H Me 375.14
6,7,8,9-tetrahydropyrido[1,2-a]indolamine LC-1
N-benzylchloro-N-methyl-6,7,8,9- 0.71
H Cl Me 325.06
tetrahydropyrido[1,2-a]indolamine LC-1
N-benzylfluoro-N-methyl-6,7,8,9- 0.66
H F Me 309.12
tetrahydropyrido[1,2-a]indolamine LC-1
N-benzyl-N-methyl(trifluoromethyl)- 0.74
H CF Me
358.85
6,7,8,9-tetrahydropyrido[1,2-a]indolamine LC-1
A.7 Synthesis of methyl 2-(7-(benzyl(alkyl)amino)-6,7,8,9-tetrahydropyrido[1,2-
a]indolyl)oxoacetate derivatives
General procedure:
To a cold (0°C) solution of the respective N-benzyl-N-alkyl-6,7,8,9-tetrahydropyrido[1,2-
a]indolamine derivative (2 mmol) in dry DCM (40 ml) was added oxalyl chloride (4
mmol). After stirring at 0°C for 1h, MeOH (3 ml) was added and the reaction mixture was
stirred at 0°C for 1h, quenched with sat.NaHCO solution. The aqueous phase was
extracted with DCM, the combined extracts were dried over MgSO , filtered and
concentrated in vacuo to give the title compound as an oil which was used for the next step
without further purification.
The following methyl 2-(7-(benzyl(alkyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indolyl)
oxoacetate derivatives were synthetized according to the above general procedure.
Table 8
t [min]
[M+H]
1 2 3
R R R Name LC-MS
method
methyl 2-(7-(benzyl(methyl)amino)-6,7,8,9-
0.70
H H Me tetrahydropyrido[1,2-a]indolyl) 377.34
LC-2
oxoacetate
methyl 2-(7-(benzyl(methyl)amino)chloro-
0.66
Cl H Me 6,7,8,9-tetrahydropyrido[1,2-a]indolyl) 411.08
LC-1
oxoacetate
methyl 2-(7-(benzyl(methyl)amino)fluoro-
0.63
F H Me 6,7,8,9-tetrahydropyrido[1,2-a]indolyl) 394.88
LC-1
oxoacetate
methyl 2-(7-(benzyl(methyl)amino)
0.63
Me H Me methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol- 391.14
LC-1
-yl)oxoacetate
methyl 2-(7-(benzyl(methyl)amino)
0.61
OMe H Me methoxy-6,7,8,9-tetrahydropyrido[1,2- 407.04
LC-1
a]indolyl)oxoacetate
methyl 2-(7-(benzyl(methyl)amino)
(trifuoromethoxy)-6,7,8,9- 0.72
OCF H Me 460.96
tetrahydropyrido[1,2-a]indolyl) LC-1
oxoacetate
methyl 2-(7-(benzyl(methyl)amino)chloro-
0.69
H Cl Me 6,7,8,9-tetrahydropyrido[1,2-a]indolyl) 411.07
LC-1
oxoacetate
methyl 2-(7-(benzyl(methyl)amino)fluoro-
0.64
H F Me 6,7,8,9-tetrahydropyrido[1,2-a]indolyl) 395.02
LC-1
oxoacetate
methyl 2-(7-(benzyl(methyl)amino)
(trifluoromethyl)-6,7,8,9- 0.72
H CF Me 445.13
tetrahydropyrido[1,2-a]indolyl) LC-1
oxoacetate
A.8 Synthesis of methyl 2-(7-(benzyl(alkyl)amino)-6,7,8,9-tetrahydropyrido[1,2-
a]indolyl)acetate derivatives
General procedure:
To a solution of the respective methyl 2-(7-(benzyl(alkyl)amino)-6,7,8,9-
tetrahydropyrido[1,2-a]indolyl)oxoacetate (1 mmol) in TFA (11 ml) was added
triethylsilane (2 mmol). The reaction mixture was stirred at rt for 2h and concentrated in
vacuo. The resulting residue was dissolved in EA, washed with sat.NaHCO solution,
water, brine, dried over MgSO , filtered and concentrated in vacuo. The resulting residue
was purified by FC (EA/ n-heptane: 0/10 to 3/7) to give the title compound as a solid.
The following methyl 2-(7-(benzyl(alkyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol
yl)acetate derivatives were synthetized according to the above general procedure.
Table 9
t [min]
[M+H]
1 2 3
R R R Name LC-MS
method
methyl 2-(7-(benzyl(methyl)amino)-6,7,8,9- 0.73
H H Me 363.35
tetrahydropyrido[1,2-a]indolyl)acetate LC-2
methyl 2-(7-(benzyl(methyl)amino)chloro-
0.69
Cl H Me 6,7,8,9-tetrahydropyrido[1,2-a]indol 396.96
LC-1
yl)acetate
methyl 2-(7-(benzyl(methyl)amino)fluoro-
0.65
F H Me 6,7,8,9-tetrahydropyrido[1,2-a]indol 381.08
LC-1
yl)acetate
methyl 2-(7-(benzyl(methyl)amino)
0.67
Me H Me methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol- 376.97
LC-1
-yl)acetate
methyl 2-(7-(benzyl(methyl)amino)
0.63
OMe H Me methoxy-6,7,8,9-tetrahydropyrido[1,2- 393.11
LC-1
a]indolyl)acetate
methyl 2-(7-(benzyl(methyl)amino)
0.73
OCF H Me
(trifuoromethoxy)-6,7,8,9- 446.96
LC-1
tetrahydropyrido[1,2-a]indolyl)acetate
methyl 2-(7-(benzyl(methyl)amino)chloro-
0.70
H Cl Me 6,7,8,9-tetrahydropyrido[1,2-a]indol 396.72
LC-1
yl)acetate
methyl 2-(7-(benzyl(methyl)amino)fluoro-
0.66
H F Me 6,7,8,9-tetrahydropyrido[1,2-a]indol 381.04
LC-1
yl)acetate
N-benzyl-N-methyl(trifluoromethyl)- 0.73
H CF Me 430.96
6,7,8,9-tetrahydropyrido[1,2-a]indolamine LC-1
A.9 Synthesis of methyl 2-(7-(alkylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol
yl)acetate derivatives
General procedure A (via hydrogenation over Pd-C 10%):
A mixture of the respective methyl 2-(7-(benzyl(alkyl)amino)-6,7,8,9-tetrahydropyrido[1,2-
a]indolyl)acetate derivative (1 mmol) and Pd-C 10% (60 mg) in MeOH (30 ml) was
stirred under hydrogen atmosphere for 12h. The reaction mixture was filtered over celite,
and the filtrate was concentrated in vacuo to give the title compound as an oil which was
used for the next step without further purification.
The following methyl 2-(7-(alkylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetate
derivatives were synthetized according to the above general procedure.
Table 10
t [min]
[M+H]
1 2 3
R R R Name LC-MS
method
methyl 2-(7-(methylamino)-6,7,8,9- 0.6
H H Me 273.15
tetrahydropyrido[1,2-a]indolyl)acetate LC-2
methyl 2-(2-fluoro(methylamino)-6,7,8,9- 0.55
F H Me 291.03
tetrahydropyrido[1,2-a]indolyl)acetate LC-1
methyl 2-(2-methyl(methylamino)-6,7,8,9- 0.57
Me H Me 287.16
tetrahydropyrido[1,2-a]indolyl)acetate LC-1
methyl 2-(2-methoxy(methylamino)-
0.51
OMe H Me 6,7,8,9-tetrahydropyrido[1,2-a]indol 303.07
LC-1
yl)acetate
methyl 2-(7-(methylamino)
0.64
OCF H Me (trifluoromethoxy)-6,7,8,9- 357
LC-1
tetrahydropyrido[1,2-a]indolyl)acetate
methyl 2-(3-fluoro(methylamino)-6,7,8,9- 0.55
H F Me 290.89
tetrahydropyrido[1,2-a]indolyl)acetate LC-1
methyl 2-(7-(methylamino)
0.63
H CF Me (trifluoromethyl)-6,7,8,9- 341.09
LC-1
tetrahydropyrido[1,2-a]indolyl)acetate
General procedure B (via reaction with 1-chloroethyl chloroformate):
To a solution of the respective methyl 2-(7-(benzyl(alkyl)amino)-6,7,8,9-
tetrahydropyrido[1,2-a]indolyl)acetate derivative (1 mmol) in dry DCM (15 ml) in a
sealed tube, was added 1-chloroethyl chloroformate (2 mmol). The reaction mixture was
stirred at 80°C for 12h. After cooling to rt, the reaction mixture was concentrated in vacuo.
To the residue was added MeOH (15 ml), the reaction mixture was stirred at reflux for 1h
and concentrated in vacuo. The residue was dissolved in EA and washed with with sat.
NaHCO solution. The aqueous phase was extracted with EA, the combined extracts were
dried over MgSO , filtered and concentrated in vacuo. The resulting residue was purified by
FC (DCM/ MeOH: 10/0 to 9/1) to give the title compound as an oil.
The following methyl 2-(7-(alkylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetate
derivatives were synthetized according to the above general procedure.
Table 11
t [min]
[M+H]
1 2 3
R R R Name LC-MS
method
methyl 2-(2-chloro(methylamino)-6,7,8,9- 0.58
Cl H Me 307.12
tetrahydropyrido[1,2-a]indolyl)acetate LC-1
methyl 2-(3-chloro(methylamino)-6,7,8,9- 0.59
H Cl Me 306.96
tetrahydropyrido[1,2-a]indolyl)acetate LC-1
A.10 Synthesis of 7-(Heteroaryl(alkyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol
acetic acid derivatives
General procedure :
A mixture of the respective methyl 2-(7-(alkylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-
-yl)acetate derivative (1 mmol), the appropriate R -Cl (1 mmol) and K CO (1.5 mmol) in
DMA (20 ml) was stirred at 130°C for 12h. After cooling to rt, 1N NaOH (20 ml) was added
to the reaction mixture. The reaction mixture was stirred at rt for 2h and then 37% HCl was
added until pH 1-2.The products were directly purified by prep. HPLC to provide the final
compound.
Preparation of examples
The following 7-(Heteroaryl(alkyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol acetic acid
derivatives were synthetized according to the above general procedure.
Table 12
R [min.]
Example [M+H]
Name LC-MS
method
2-(7-((5-chloropyrimidinyl)(methyl)amino)-
1 0.93
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic 370.97
LC-1
acid
2-(7-((5-fluoropyrimidinyl)(methyl)amino)-
2 0.86
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic 355.05
LC-1
acid
2-(7-(methyl(5-(trifluoromethyl)pyrimidin
3 0.95
yl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol 405.02
LC-1
yl)acetic acid
2-(7-((6-fluorobenzo[d]thiazolyl)(methyl)amino)-
4 0.89
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic 410
LC-1
acid
2-(7-((5-fluorobenzo[d]oxazolyl)(methyl)amino)-
0.86
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic 394.06
LC-1
acid
2-(7-((5-fluorobenzo[d]thiazolyl)(methyl)amino)-
6 0.91
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic 410
LC-1
acid
2-(2-fluoro((5-fluoropyrimidin
0.88
yl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2- 372.95
LC-1
a]indolyl)acetic acid
2-(2-fluoro((5-fluorobenzo[d]oxazol
8 0.88
yl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2- 412.07
LC-1
a]indolyl)acetic acid
2-(3-fluoro((5-fluoropyrimidin
0.88
yl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2- 373.05
LC-1
a]indolyl)acetic acid
2-(3-fluoro((5-fluorobenzo[d]oxazol
0.88
yl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2- 412.07
LC-1
a]indolyl)acetic acid
2-(7-((5-fluoropyrimidinyl)(methyl)amino)
0.85
methoxy-6,7,8,9-tetrahydropyrido[1,2-a]indol 384.99
LC-1
yl)acetic acid
2-(7-((5-fluorobenzo[d]oxazolyl)(methyl)amino)-
0.85
2-methoxy-6,7,8,9-tetrahydropyrido[1,2-a]indol 424.08
LC-1
yl)acetic acid
2-(7-((5-fluoropyrimidinyl)(methyl)amino)
0.91
methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol 368.94
LC-1
yl)acetic acid
2-(7-((5-fluorobenzo[d]oxazolyl)(methyl)amino)-
0.91
2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol 408.09
LC-1
yl)acetic acid
2-(2-chloro((5-fluoropyrimidin
0.93
yl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2- 388.79
LC-1
a]indolyl)acetic acid
2-(2-chloro((5-fluorobenzo[d]oxazol
0.92
yl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2- 428.06
LC-1
a]indolyl)acetic acid
2-(7-((5-chloropyrimidinyl)(methyl)amino)
0.94
fluoro-6,7,8,9-tetrahydropyrido[1,2-a]indol 388.9
LC-1
yl)acetic acid
2-(3-fluoro(methyl(5-(trifluoromethyl)pyrimidin
0.96
yl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol 422.89
LC-1
yl)acetic acid
2-(3-fluoro((5-fluorobenzo[d]thiazol
0.93
yl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2- 427.75
LC-1
a]indolyl)acetic acid
2-(3-fluoro((6-fluorobenzo[d]oxazol
0.87
yl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2- 411.93
LC-1
a]indolyl)acetic acid
2-(3-chloro((5-chloropyrimidin
0.95
yl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2- 404.93
LC-2
a]indolyl)acetic acid
2-(7-((5-chloropyrimidinyl)(methyl)amino)
0.96
(trifluoromethyl)-6,7,8,9-tetrahydropyrido[1,2- 438.79
LC-2
a]indolyl)acetic acid
2-(7-((5-chloropyrimidinyl)(methyl)amino)
0.98
(trifluoromethoxy)-6,7,8,9-tetrahydropyrido[1,2- 454.87
LC-2
a]indolyl)acetic acid
2-(7-((5-fluoropyrimidinyl)(methyl)amino)
0.94
(trifluoromethyl)-6,7,8,9-tetrahydropyrido[1,2- 423
LC-2
a]indolyl)acetic acid
2-(7-((5-fluoropyrimidinyl)(methyl)amino)
0.95
(trifluoromethoxy)-6,7,8,9-tetrahydropyrido[1,2- 438.86
LC-2
a]indolyl)acetic acid
2-(7-((6-fluorobenzo[d]thiazolyl)(methyl)amino)-
0.95
3-(trifluoromethyl)-6,7,8,9-tetrahydropyrido[1,2- 477.84
LC-2
a]indolyl)acetic acid
2-(7-((6-fluorobenzo[d]thiazolyl)(methyl)amino)-
0.96
2-(trifluoromethoxy)-6,7,8,9-tetrahydropyrido[1,2- 493.83
LC-2
a]indolyl)acetic acid
2-(7-((5-fluorobenzo[d]oxazolyl)(methyl)amino)-
0.94
3-(trifluoromethyl)-6,7,8,9-tetrahydropyrido[1,2- 461.69
LC-2
a]indolyl)acetic acid
2-(7-((5-fluorobenzo[d]oxazolyl)(methyl)amino)-
0.95
2-(trifluoromethoxy)-6,7,8,9-tetrahydropyrido[1,2- 477.89
LC-2
a]indolyl)acetic acid
2-(3-chloro((5-fluoropyrimidin
0.91
yl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2- 388.98
LC-2
a]indolyl)acetic acid
2-(3-chloro((5-fluorobenzo[d]oxazol
0.92
yl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2- 427.9
LC-2
a]indolyl)acetic acid
2-(3-chloro(methyl(5-methylpyrimidin
0.82
yl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol 385.16
LC-2
yl)acetic acid
2-(3-chloro(methyl(quinazolinyl)amino)-
0.79
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic 421.25
LC-2
acid
2-(3-chloro((6-fluoroquinazolin
0.90
yl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2- 439.38
LC-2
a]indolyl)acetic acid
2-(3-chloro((7-fluoroquinazolin
0.91
yl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2- 439.12
LC-2
a]indolyl)acetic acid
2-(3-chloro(methyl(2-methylquinazolin
0.72
yl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol 435.19
LC-2
yl)acetic acid
2-(3-chloro((6-fluoroquinoxalin
0.95
yl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2- 439.39
LC-2
a]indolyl)acetic acid
B.1 Synthesis of (S)(3-chloro((5-fluoropyrimidinyl)(methyl)amino)-6,7,8,9-
tetrahydropyrido[1,2-a]indolyl)acetic acid and (R)(3-chloro((5-
fluoropyrimidinyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic
acid
B.1.1 Synthesis of (S)-methyl 2-(3-chloro(methylamino)-6,7,8,9-
tetrahydropyrido[1,2-a]indolyl)acetate and (R)-methyl 2-(3-chloro
(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetate
To a solution of methyl 2-(7-(benzyl(methyl)amino)chloro-6,7,8,9-tetrahydropyrido[1,2-
a]indolyl)acetate (365 mg, 0.92 mmol) in dry DCM (13.4 ml) in a sealed tube, was
added 1-chloroethyl chloroformate (0.2 ml, 1.84 mmol). The reaction mixture was stirred at
80°C for 12h. After cooling to rt, the reaction mixture was concentrated in vacuo. To the
residue was added MeOH (13.4 ml), the reaction mixture was stirred at reflux for 1h and
concentrated in vacuo. The residue was dissolved in EA and washed with with sat.NaHCO
solution. The aqueous phase was extracted with EA, the combined extracts were dried
over MgSO , filtered and concentrated in vacuo. The resulting residue was purified by FC
(DCM/ MeOH: 10/0 to 9/1) to give the racemate as an oil.
LC-MS (LC-1): t : 0.59 min./ [M+H] : 306.96.
The two enantiomers of the obtained product were separated by preparative chiral HPLC
(chiral HPLC-3):
(S)-methyl 2-(3-chloro(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetate
(60 mg, 21%): HPLC (chiral HPLC-1): t : 8.45 min;
(R)-methyl 2-(3-chloro(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetate
(60 mg, 21%): HPLC (chiral HPLC-1): t : 10.23 min.
B.1.2 Synthesis of (S)(3-chloro((5-fluoropyrimidinyl)(methyl)amino)-
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid (example 32)
A mixture of (S)-methyl 2-(3-chloro(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-
-yl)acetate (60mg, 0.19 mmol), 2-chlorofluoropyrimidine (0.0175 ml, 0.19 mmol) and
K CO (65.5 mg, 0.47 mmol) in DMA (2 ml) was stirred at 130°C for 2 days. After cooling to
rt, 1N NaOH (2.5 ml) was added to the reaction mixture. The reaction mixture was stirred at
rt for 2h and then 37% HCl was added until pH 1-2.The product was directly purified by
prep. HPLC to provide the title compound as an oil.
LC-MS (LC-2): t : 0.91 min./ [M+H] : 389.18.
HPLC (chiral HPLC-2): t : 8.6 min.
B.1.3 Synthesis of (R)(3-chloro((5-fluoropyrimidinyl)(methyl)amino)-
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid (example 33)
A mixture of (R)-methyl 2-(3-chloro(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-
-yl)acetate (60mg, 0.19 mmol), 2-chlorofluoropyrimidine (0.0175 ml, 0.19 mmol) and
K CO (65.5 mg, 0.47 mmol) in DMA (2 ml) was stirred at 130°C for 2 days. After cooling to
rt, 1N NaOH (2.5 ml) was added to the reaction mixture. The reaction mixture was stirred at
rt for 2h and then 37% HCl was added until pH 1-2.The product was directly purified by
prep. HPLC to provide the title compound as an oil.
LC-MS (LC-2): t : 0.91 min./ [M+H] : 389.16.
HPLC (chiral HPLC-2): t : 11.25 min.
C.1 Synthesis of 2-(7-(heteroarylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol
yl)acetic acid derivatives (R represents H)
C.1.1 Synthesis of tert-butyl (6,7,8,9-tetrahydropyrido[1,2-a]indol
yl)carbamate derivatives
General Procedure:
To a solution of the respective 8,9-dihydropyrido[1,2-a]indol-7(6H)-one derivative (0.23
mmol) in EtOH (5 ml) were added portionwise successively ammonium acetate (4.6 mmol,
eq) and NaBH CN (0.11 mmol, 0.5 eq). Then AcOH was added (0.3 ml) and the
reaction mixture was stirred at rt for 1h30. The reaction mixture was then quenched with
water, basified until pH 9 with 1N NaOH and filtered. The filtrate was extracted twice with
DCM, the combined extracts were dried over MgSO , filtered and concentrated in vacuo to
give the amine which was used for the next step without further purification.
To a solution of this crude amine (0.23 mmol) in dry DCM (2 ml), were added successively
Boc O (0.23 mmol) and DIEA (0.46 mmol). The reaction mixture was stirred at rt for 3h,
diluted with DCM and washed with sat. NaHCO solution. The aqueous phase was
extracted twice with DCM, the combined extracts were dried over MgSO , filtered and
concentrated in vacuo. The resulting residue was purified by FC (EA/ n-heptane: 0/10 to
2/8) to give the title compound as an oil.
The following tert-butyl (6,7,8,9-tetrahydropyrido[1,2-a]indolyl)carbamate derivatives
were synthetized according to the above general procedure.
Table 13
t [min]
[M+H]
R R Name LC-MS
method
tert-butyl (3-chloro-6,7,8,9-tetrahydropyrido[1,2- 0.98
H Cl 321.19
a]indolyl)carbamate LC-2
tert-butyl (3-fluoro-6,7,8,9-tetrahydropyrido[1,2- 1.02
H F 305.08
a]indolyl)carbamate LC-2
C.1.2 Synthesis of methyl 2-(7-amino-6,7,8,9-tetrahydropyrido[1,2-a]indol
yl)acetate derivatives
General Procedure:
To a cold (0°C) solution of the respective tert-butyl (6,7,8,9-tetrahydropyrido[1,2-a]indol
yl)carbamate derivative (1.4 mmol) in dry DCM (28.5 ml) was added oxalyl chloride (2.8
mmol). After stirring at 0°C for 1h, MeOH (2.3 ml) was added and the reaction mixture was
stirred at 0°C for 1h, quenched with sat. NaHCO solution. The aqueous phase was
extracted with DCM, the combined extracts were dried over MgSO , filtered and
concentrated in vacuo to give the keto-ester as an oil which was used for the next step
without further purification.
To the crude keto-ester (1.28 mmol) in TFA (12.3 ml) was added triethylsilane (2.56 mmol).
The reaction mixture was stirred at rt for 2h and concentrated in vacuo. The resulting
residue was dissolved in EA, washed with sat. NaHCO solution, water, brine, dried over
MgSO , filtered and concentrated in vacuo. The resulting residue was purified by FC (EA/
n-heptane: 0/10 to 3/7) to give the title compound as a solid.
The following methyl 2-(7-amino-6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetate
derivatives were synthetized according to the above general procedure.
Table 14
t [min]
[M+H]
R R Name LC-MS
method
methyl 2-(7-aminochloro-6,7,8,9- 0.64
H Cl 293.26
tetrahydropyrido[1,2-a]indolyl)acetate LC-2
methyl 2-(7-aminofluoro-6,7,8,9- 0.66
H F 277.08
tetrahydropyrido[1,2-a]indolyl)acetate LC-2
C.1.3 Synthesis of 2-(7-(heteroarylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-
-yl)acetic acid derivatives
General Procedure:
A mixture of the respective methyl 2-(7-amino-6,7,8,9-tetrahydropyrido[1,2-a]indol
yl)acetate derivative (1 mmol), the appropriate R -Cl (1 mmol) and K CO (1.5 mmol) in
DMA (20 ml) was stirred at 130°C for 12h. After cooling to rt, 1N NaOH (20 ml) was added
to the reaction mixture. The reaction mixture was stirred at rt for 2h and then 37% HCl was
added until pH 1-2.The products were directly purified by prep. HPLC to provide the final
compound.
Preparation of examples
The following 2-(7-(heteroarylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol
yl)acetic acid derivatives were synthetized according to the above general procedure.
Table 15
t [min]
[M+H]
Name LC-MS
Example m/z
method
2-(3-fluoro((5-fluoropyrimidinyl)amino)-6,7,8,9- 0.78
359.14
tetrahydropyrido[1,2-a]indolyl)acetic acid LC-1
2-(3-fluoro((5-fluorobenzo[d]oxazolyl)amino)- 0.82
398.03
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid LC-1
2-(3-chloro((5-fluoropyrimidinyl)amino)-6,7,8,9- 0.85
375.13
tetrahydropyrido[1,2-a]indolyl)acetic acid LC-2
2-(3-chloro((5-chloropyrimidinyl)amino)-6,7,8,9- 0.88
391.09
37 tetrahydropyrido[1,2-a]indolyl)acetic acid LC-2
D.1 Synthesis of 7-(Heteroaryl-amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol acetic acid
derivatives (Method B)
D.1.1 Synthesis of 7-(Heteroaryl(alkyl)amino)-6,7,8,9-tetrahydropyrido[1,2-
a]indole derivatives
General Procedure:
To a solution of the respective 8,9-dihydropyrido[1,2-a]indol-7(6H)-one derivative (9.1
mmol) in EtOH (208 ml) were added portionwise successively ammonium acetate (182
mmol, 20 eq) and NaBH CN (4.55 mmol, 0.5 eq). Then AcOH was added (12 ml) and the
reaction mixture was stirred at rt for 1h30. The reaction mixture was then quenched with
water, basified until pH 9 with 1N NaOH and filtered. The filtrate was extracted twice with
DCM, the combined extracts were dried over MgSO , filtered and concentrated in vacuo to
give the amine which was used for the next step without further purification.
To a solution of the crude amine (0.77 mmol) in DMA (2 ml) were added successively the
appropriate R -Cl (0.77 mmol, 1 eq) and K CO (1.15 mmol, 1.5 eq). The reaction mixture
was stirred at 100°C for 3h. After cooling to rt, the mixture was diluted with EA, washed
with sat. NaHCO solution, water, brine, dried over MgSO , filtered and concentrated in
vacuo. The resulting residue was purified by FC (n-heptane to n-heptane/ EA: 8/2) to give
the desired 7-(Heteroaryl-amino)-6,7,8,9-tetrahydropyrido[1,2-a]indole derivatives as a
solid.
To a solution of the respective 7-(Heteroaryl-amino)-6,7,8,9-tetrahydropyrido[1,2-a]indole
derivative (0.045 mmol) in DMA (1 ml), was added NaH (50% in mineral oil) (0.09 mmol, 2
eq). The reaction mixture was stirred at rt for 5 min., then the appropriate R -X (with X = I,
Br or OTf) (0.45 mmol, 10 eq) was added and the reaction mixture was stirred at 50°C for
16 h. More NaH (4 eq) and R -X (10 eq) were added and the stirring at 50°C was continued
for 1 day. The product was directly purified by prep. HPLC to provide the title compound as
an oil.
The following 7-(Heteroaryl(alkyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indole derivatives
were synthetized according to the above general procedure.
Table 16
1 2 3 4 +
R R R R Name [M+H] t [min]
LC-MS
m m m m////z z z z
m me etth ho od d
m me etth ho od d
H Cl N-(3-chloro-6,7,8,9- 419.97 0.93
tetrahydropyrido[1,2-a]indol-
LC-2
7-yl)-N-(2,2-difluoroethyl)
(X= OTf)
fluorobenzo[d]oxazolamine
H Cl Et 3-chloro-N-ethyl-N-(5- 345.25 1.06
fluoropyrimidinyl)-6,7,8,9-
(X = I) LC-2
tetrahydropyrido[1,2-a]indol-
7-amine
H Cl iPr N-(3-chloro-6,7,8,9- 398.05 1.07
tetrahydropyrido[1,2-a]indol-
(X = I) LC-2
7-yl)fluoro-N-
isopropylbenzo[d]oxazol
amine
H Cl 3-chloro-N-(5-fluoropyrimidin- 375.22 1.04
(X = Br)
2-yl)-N-(2-methoxyethyl)-
LC-2
6,7,8,9-tetrahydropyrido[1,2-
a]indolamine
H Cl N-(3-chloro-6,7,8,9- 412.05 1.09
tetrahydropyrido[1,2-a]indol-
LC-2
7-yl)fluoro-N-
(X = I)
isobutylbenzo[d]oxazol
amine
H Cl n-Pr 3-chloro-N-(5-fluoropyrimidin- 359.23 1.09
2-yl)-N-propyl-6,7,8,9-
(X = I) LC-2
tetrahydropyrido[1,2-a]indol-
7-amine
H Cl Et N-(3-chloro-6,7,8,9- 384.03 1.04
tetrahydropyrido[1,2-a]indol-
(X = I) LC-2
7-yl)-N-ethyl
fluorobenzo[d]oxazolamine
1.09
H Cl 3-chloro-N- 371.22
(cyclopropylmethyl)-N-(5-
LC-2
fluoropyrimidinyl)-6,7,8,9-
(X = I)
tetrahydropyrido[1,2-a]indol-
7-amine
D.1.2 Synthesis of 7-(Heteroaryl(alkyl)amino)-6,7,8,9-tetrahydropyrido[1,2-
a]indol acetic acid derivatives
General Procedure:
To a cold (0°C) solution of the respective 7-(Heteroaryl(alkyl)amino)-6,7,8,9-
tetrahydropyrido[1,2-a]indole derivative (0.05 mmol) in DCM (1 ml), was added oxalyl
chloride (0.1 mmol, 2 eq). After stirring at 0°C for 1h, MeOH (0.08 ml) was added and the
reaction mixture was stirred at 0°C for 1h, quenched with sat. NaHCO solution. The
aqueous phase was extracted with DCM, the combined extracts were dried over MgSO ,
filtered and concentrated in vacuo to give the keto-ester as an oil which was used for the
next step without further purification.
To the crude keto-ester (0.01mmol) in TFA (0.1 ml) was added triethylsilane (0.025 mmol,
2.5 eq). The reaction mixture was stirred at rt for 16h and concentrated in vacuo. The
resulting residue was dissolved in EA, washed with sat. NaHCO solution, water, brine,
dried over MgSO , filtered and concentrated in vacuo to provide the methyl 7-
(Heteroaryl(alkyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol acetate derivative as an oil
which was used for the next step without further purification.
To a solution of the crude methyl 7-(Heteroaryl(alkyl)amino)-6,7,8,9-tetrahydropyrido[1,2-
a]indol acetate derivative (0.01 mmol) in a mixture MeCN (0.5 ml)/ DMF (0.1 ml) was added
1N NaOH (1ml). The reaction mixture was stirred at rt for 3h, acidified with 37% HCl (0.02
ml) and purified by prep-HPLC to provide the final compound as a solid.
The following 7-(Heteroaryl(alkyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol acetic acid
derivatives were synthetized according to the above general procedure.
Table 17
R [min.]
Example [M+H]
Name LC-MS
method
2-(3-chloro((2,2-difluoroethyl)(5-
44 0.95
fluorobenzo[d]oxazolyl)amino)-6,7,8,9- 478
LC-2
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro(ethyl(5-fluoropyrimidinyl)amino)-
45 0.94
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic 403.13
LC-2
acid
2-(3-chloro((5-fluorobenzo[d]oxazol
46 0.97
yl)(isopropyl)amino)-6,7,8,9-tetrahydropyrido[1,2- 456.19
LC-2
a]indolyl)acetic acid
2-(3-chloro((5-fluoropyrimidinyl)(2-
0.93
methoxyethyl)amino)-6,7,8,9-tetrahydropyrido[1,2- 433.05
LC-2
a]indolyl)acetic acid
2-(3-chloro((5-fluorobenzo[d]oxazol
1.00
yl)(isobutyl)amino)-6,7,8,9-tetrahydropyrido[1,2- 470.2
LC-2
a]indolyl)acetic acid
2-(3-chloro((5-fluoropyrimidin
49 0.98
yl)(propyl)amino)-6,7,8,9-tetrahydropyrido[1,2- 417
LC-2
a]indolyl)acetic acid
2-(3-chloro(ethyl(5-fluorobenzo[d]oxazol
0.94
yl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol 442.16
LC-2
yl)acetic acid
2-(3-chloro((cyclopropylmethyl)(5-
51 0.99
fluoropyrimidinyl)amino)-6,7,8,9- 429.26
LC-2
tetrahydropyrido[1,2-a]indolyl)acetic acid
Biological assays:
Preparation of hCRTH2 receptor membranes and radioligand displacement assay:
First, recombinant HEK293-hCRTH cells were detached from culture plates into 5 ml buffer
A/plate (Buffer A: 5 mM Tris, 1 mM MgCl -6H O pH=7.4) using a rubber policeman. Cells
were then transferred into centrifugation tubes and centrifuged for 5min at 400 g. The cell
pellet was resuspended in the same buffer and tubes were frozen at –80°C. Cells were
thawed and membrane fragments were generated by homogenization using a polytron
homogenizer (30 seconds). The membrane fragments were then centrifuged at 3000 g for
minutes and resuspended in buffer C (Buffer C: 75 mM Tris , 25 mM MgCl , 250 mM
Saccharose pH 7.4). Aliquots of membrane fragements were stored at –20°C.
Binding assay was performed in a final assay volume of 250 μl. First, 25 μl of test
compound, previously diluted in Binding-Buffer (Binding-Buffer: 50 mM Tris-Base, 100 mM
NaCl, 1 mM EDTA, 0.1% BSA (protease free), 0.01 % NaN , 10mM MnCl pH 7.0) was
placed into each well. After addition of 75 μl Binding-Buffer, 50 μl of the radioligand H-
PGD (at 2.5 nM (220.000 dpm/well) from ANAWA ART0662) was added to each well.
Binding assay was started by addition of 100 μl CRTH membrane fragments, reaching a
final concentration of 20µg/well. For non-specific binding, PGD was added to the reaction
mixture to 10 mM final concentration. This assay mix was incubated for 90 minutes at room
temperature and then filtered through a GF/C filter 96-well plate which was pre-soaked for
3 hours in 0.5% polyethyleneimine (PEI). The filter-wells were washed three times with ice
cold Binding-Buffer. Then, 40 μl of Microscint-40 (Packard) was added to each well and the
retained radioactivity quantified in a Topcount (Packard).
Antagonistic activities of exemplified compounds are displayed in Table 16.
Example Name
[nM]
2-(7-((5-chloropyrimidinyl)(methyl)amino)-6,7,8,9-
1 21
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(7-((5-fluoropyrimidinyl)(methyl)amino)-6,7,8,9-
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(7-(methyl(5-(trifluoromethyl)pyrimidinyl)amino)-6,7,8,9-
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(7-((6-fluorobenzo[d]thiazolyl)(methyl)amino)-6,7,8,9-
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(7-((5-fluorobenzo[d]oxazolyl)(methyl)amino)-6,7,8,9-
16
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(7-((5-fluorobenzo[d]thiazolyl)(methyl)amino)-6,7,8,9-
6 92
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(2-fluoro((5-fluoropyrimidinyl)(methyl)amino)-6,7,8,9-
7 17
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(2-fluoro((5-fluorobenzo[d]oxazolyl)(methyl)amino)-
8 12
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-fluoro((5-fluoropyrimidinyl)(methyl)amino)-6,7,8,9-
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-fluoro((5-fluorobenzo[d]oxazolyl)(methyl)amino)-
0.7
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(7-((5-fluoropyrimidinyl)(methyl)amino)methoxy-6,7,8,9-
11 420
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(7-((5-fluorobenzo[d]oxazolyl)(methyl)amino)methoxy-
12 231
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(7-((5-fluoropyrimidinyl)(methyl)amino)methyl-6,7,8,9-
13 417
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(7-((5-fluorobenzo[d]oxazolyl)(methyl)amino)methyl-
14 42
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(2-chloro((5-fluoropyrimidinyl)(methyl)amino)-6,7,8,9-
136
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(2-chloro((5-fluorobenzo[d]oxazolyl)(methyl)amino)-
16 21
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(7-((5-chloropyrimidinyl)(methyl)amino)fluoro-6,7,8,9-
17 4
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-fluoro(methyl(5-(trifluoromethyl)pyrimidinyl)amino)-
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-fluoro((5-fluorobenzo[d]thiazolyl)(methyl)amino)-
19 51
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-fluoro((6-fluorobenzo[d]oxazolyl)(methyl)amino)-
1
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro((5-chloropyrimidinyl)(methyl)amino)-6,7,8,9-
21 7
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(7-((5-chloropyrimidinyl)(methyl)amino)(trifluoromethyl)-
22 9
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(7-((5-chloropyrimidinyl)(methyl)amino)(trifluoromethoxy)-
23 354
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(7-((5-fluoropyrimidinyl)(methyl)amino)(trifluoromethyl)-
24 5
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(7-((5-fluoropyrimidinyl)(methyl)amino)(trifluoromethoxy)-
141
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(7-((6-fluorobenzo[d]thiazolyl)(methyl)amino)
(trifluoromethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic 16
acid
2-(7-((6-fluorobenzo[d]thiazolyl)(methyl)amino)
27 (trifluoromethoxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol 812
yl)acetic acid
2-(7-((5-fluorobenzo[d]oxazolyl)(methyl)amino)
28 (trifluoromethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic 8
acid
2-(7-((5-fluorobenzo[d]oxazolyl)(methyl)amino)
29 (trifluoromethoxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol 964
yl)acetic acid
2-(3-chloro((5-fluoropyrimidinyl)(methyl)amino)-6,7,8,9-
10
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro((5-fluorobenzo[d]oxazolyl)(methyl)amino)-
31 5
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
(S)(3-chloro((5-fluoropyrimidinyl)(methyl)amino)-6,7,8,9-
32 0.8
tetrahydropyrido[1,2-a]indolyl)acetic acid
(R)(3-chloro((5-fluoropyrimidinyl)(methyl)amino)-6,7,8,9-
33 2
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-fluoro((5-fluoropyrimidinyl)amino)-6,7,8,9-
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-fluoro((5-fluorobenzo[d]oxazolyl)amino)-6,7,8,9-
11
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro((5-fluoropyrimidinyl)amino)-6,7,8,9-
36 65
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro((5-chloropyrimidinyl)amino)-6,7,8,9-
37 27
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro(methyl(5-methylpyrimidinyl)amino)-6,7,8,9-
38 2
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro(methyl(quinazolinyl)amino)-6,7,8,9-
39 3
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro((6-fluoroquinazolinyl)(methyl)amino)-6,7,8,9-
40 5
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro((7-fluoroquinazolinyl)(methyl)amino)-6,7,8,9-
41 1
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro(methyl(2-methylquinazolinyl)amino)-6,7,8,9-
42 71
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro((6-fluoroquinoxalinyl)(methyl)amino)-6,7,8,9-
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro((2,2-difluoroethyl)(5-fluorobenzo[d]oxazol
44 3
yl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro(ethyl(5-fluoropyrimidinyl)amino)-6,7,8,9-
45 1
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro((5-fluorobenzo[d]oxazolyl)(isopropyl)amino)-
46 3
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro((5-fluoropyrimidinyl)(2-methoxyethyl)amino)-
47 0.8
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro((5-fluorobenzo[d]oxazolyl)(isobutyl)amino)-
48 2
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro((5-fluoropyrimidinyl)(propyl)amino)-6,7,8,9-
49 1
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro(ethyl(5-fluorobenzo[d]oxazolyl)amino)-6,7,8,9-
50 1
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro((cyclopropylmethyl)(5-fluoropyrimidinyl)amino)-
51 0.6
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
Radioligand Displacement Assay-Human Serum Albumin (HSA):
Radioligand displacement assay in presence of human serum albumin (HSA) was
performed as described above, with following modifications. Binding-Buffer-HSA: Binding-
buffer + 0.5% Sigma Albumin from Human serum A1887 (instead of 0.1% BSA). A volume
of 25 μl test compound, previously diluted in Binding-Buffer–HSA was placed into each
well. After addition of 75 μl Binding-Buffer-HSA, 50 μl of H-PGD (at 2.5 nM (220.000
dpm/well) from ANAWA ART0662) was added to each well. Remaining protocol was
identical as described above.
Antagonistic activities of exemplified compounds are displayed in Table 17.
Example Name
[nM]
2-(7-((5-chloropyrimidinyl)(methyl)amino)-6,7,8,9-
1 66
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(7-((5-fluoropyrimidinyl)(methyl)amino)-6,7,8,9-
2 29
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(7-(methyl(5-(trifluoromethyl)pyrimidinyl)amino)-6,7,8,9-
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(7-((6-fluorobenzo[d]thiazolyl)(methyl)amino)-6,7,8,9-
4 43
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(7-((5-fluorobenzo[d]oxazolyl)(methyl)amino)-6,7,8,9-
24
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(7-((5-fluorobenzo[d]thiazolyl)(methyl)amino)-6,7,8,9-
6 59
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(2-fluoro((5-fluoropyrimidinyl)(methyl)amino)-6,7,8,9-
7 119
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(2-fluoro((5-fluorobenzo[d]oxazolyl)(methyl)amino)-
8 123
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-fluoro((5-fluoropyrimidinyl)(methyl)amino)-6,7,8,9-
9 10
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-fluoro((5-fluorobenzo[d]oxazolyl)(methyl)amino)-
7
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(7-((5-fluorobenzo[d]oxazolyl)(methyl)amino)methyl-
14 >1000
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(2-chloro((5-fluorobenzo[d]oxazolyl)(methyl)amino)-
16 >1000
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(7-((5-chloropyrimidinyl)(methyl)amino)fluoro-6,7,8,9-
17 46
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-fluoro(methyl(5-(trifluoromethyl)pyrimidinyl)amino)-
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-fluoro((6-fluorobenzo[d]oxazolyl)(methyl)amino)-
20
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro((5-chloropyrimidinyl)(methyl)amino)-6,7,8,9-
21 31
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(7-((5-chloropyrimidinyl)(methyl)amino)(trifluoromethyl)-
22 38
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(7-((5-fluoropyrimidinyl)(methyl)amino)(trifluoromethyl)-
24 11
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(7-((6-fluorobenzo[d]thiazolyl)(methyl)amino)
(trifluoromethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic 15
acid
2-(7-((5-fluorobenzo[d]oxazolyl)(methyl)amino)
28 (trifluoromethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic 20
acid
2-(3-chloro((5-fluoropyrimidinyl)(methyl)amino)-6,7,8,9-
9
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro((5-fluorobenzo[d]oxazolyl)(methyl)amino)-
31 13
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
(S)(3-chloro((5-fluoropyrimidinyl)(methyl)amino)-6,7,8,9-
32 2
tetrahydropyrido[1,2-a]indolyl)acetic acid
(R)(3-chloro((5-fluoropyrimidinyl)(methyl)amino)-6,7,8,9-
33 57
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-fluoro((5-fluoropyrimidinyl)amino)-6,7,8,9-
34 304
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-fluoro((5-fluorobenzo[d]oxazolyl)amino)-6,7,8,9-
20
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro((5-fluoropyrimidinyl)amino)-6,7,8,9-
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro((5-chloropyrimidinyl)amino)-6,7,8,9-
37 385
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro(methyl(5-methylpyrimidinyl)amino)-6,7,8,9-
38 246
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro(methyl(quinazolinyl)amino)-6,7,8,9-
39 5
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro((6-fluoroquinazolinyl)(methyl)amino)-6,7,8,9-
40 4
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro((7-fluoroquinazolinyl)(methyl)amino)-6,7,8,9-
41 37
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro((6-fluoroquinoxalinyl)(methyl)amino)-6,7,8,9-
43 12
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro((2,2-difluoroethyl)(5-fluorobenzo[d]oxazol
44 6
yl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro(ethyl(5-fluoropyrimidinyl)amino)-6,7,8,9-
45 3
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro((5-fluorobenzo[d]oxazolyl)(isopropyl)amino)-
46 5
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro((5-fluoropyrimidinyl)(2-methoxyethyl)amino)-
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro((5-fluorobenzo[d]oxazolyl)(isobutyl)amino)-
48 6
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro((5-fluoropyrimidinyl)(propyl)amino)-6,7,8,9-
49 21
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro(ethyl(5-fluorobenzo[d]oxazolyl)amino)-6,7,8,9-
50 9
tetrahydropyrido[1,2-a]indolyl)acetic acid
2-(3-chloro((cyclopropylmethyl)(5-fluoropyrimidinyl)amino)-
51 9
6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid
Intracellular calcium mobilization assay (FLIPR):
Cells (HEK-293), stably expressing the hCRTH2 receptor under the control of the
cytomegalovirus promotor from a single insertion of the expression vector pcDNA5
(Invitrogen), are grown to confluency in DMEM (low glucose, Gibco) medium supplemented
with 10% fetal calf serum (Bioconcept, Switzerland) under standard mammalian cell culture
conditions (37°C in a humidified atmosphere of 5% CO ). Cells are detached from culture
dishes using a dissociation buffer (0.02% EDTA in PBS, Gibco) for 1 min, and collected by
centrifugation at 200 g at rt for 5 min in assay buffer (equal parts of Hank's BSS (HBSS,
Bioconcept) and DMEM (low glucose, without phenol red, Gibco)). After incubation for 45
min (37°C and 5% CO ) in the presence of 1 μM Fluo-4 and 0.04% Pluronic F-127 (both
Molecular Probes), and 20 mM HEPES (Gibco) in assay buffer, the cells are washed with
and resuspended in assay buffer, then seeded onto 384-well FLIPR assay plates (Greiner)
at 50,000 cells in 66 μl per well, and sedimented by centrifugation.
Stock solutions of test compounds are made up at a concentration of 10 mM in DMSO, and
serially diluted in assay buffer to concentrations required for inhibition dose response
curves. Prostaglandin D (Biomol, Plymouth Meeting, PA) is used as an agonist.
A FLIPR Tetra instrument (Molecular Devices) is operated according to the manufacturer's
standard instructions, adding 4 μl of test compound dissolved at 10 mM in DMSO and
diluted prior to the experiment in assay buffer to obtain the desired final concentration. 10
μl of 80 nM prostaglandin D (Biomol, Plymouth Meeting, PA) in assay buffer,
supplemented with 0.8% bovine serum albumin (fatty acid content <0.02%, Sigma), is then
added to obtain a final concentration of 10 nM and 0.1%, respectively. Changes in
fluorescence are monitored before and after the addition of test compounds at λ =488 nm
and λ =540 nm. Emission peak values above base level after prostaglandin D addition
em 2
are exported after base line subtraction. Values are normalized to high-level control (no test
compound added) after subtraction of base line value (no prostaglandin D added). The
program XLlfit 3.0 (IDBS) is used to fit the data to a single site dose response curve of the
equation (A+((B-A)/(1+((C/x)^D)))) and to calculate the IC values.
Claims (17)
1. A compound of formula (I): 5 wherein R and R represent independently of each other hydrogen, (C -C )alkyl, (C -C )alkoxy, 1 4 1 4 halogen, trifluoromethoxy or trifluoromethyl; R represents hydrogen, (C -C )alkyl, (C -C )alkoxy-(C -C )alkyl, (C -C )fluoroalkyl or 1 4 1 2 2 3 1 4 (C -C )cycloalkyl-(C -C )alkyl; and 3 6 1 2 10 R represents a heteroaryl group which is unsubstituted or mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C -C )alkyl, (C -C )cycloalkyl, (C -C )alkoxy, (C -C )fluoroalkyl and phenyl; wherein the 1 4 3 6 1 4 1 4 term “heteroaryl” means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur; 15 or a pharmaceutically acceptable salt of such a compound.
2. A compound according to claim 1, wherein R represents hydrogen, (C -C )alkyl, (C -C )alkoxy, halogen or trifluoromethoxy; 1 4 1 4 R represents hydrogen, halogen or trifluoromethyl; R represents hydrogen or (C -C )alkyl; and 20 R represents a heteroaryl group which is unsubstituted or mono- or di-substituted, wherein the substituents are independently selected from the group consisting of halogen and (C - C )fluoroalkyl; or a pharmaceutically acceptable salt of such a compound.
3. A compound according to claim 1, wherein 25 R represents hydrogen; R represents hydrogen, fluoro, chloro or trifluoromethyl; R represents methyl; and R represents a heteroaryl group which is mono-substituted with fluoro or chloro, wherein the heteroaryl group is selected from pyrimidinyl, benzoxazolyl and benzothiazolyl; or a pharmaceutically acceptable salt of such a compound. 5
4. A compound according to any one of claims 1 to 3, wherein R represents hydrogen; or a pharmaceutically acceptable salt of such a compound.
5. A compound according to any one of claims 1, 2 or 4, wherein 10 R represents hydrogen, halogen or trifluoromethyl; or a pharmaceutically acceptable salt of such a compound.
6. A compound according to any one of claims 1 to 5, wherein R represents fluoro or chloro; 15 or a pharmaceutically acceptable salt of such a compound.
7. A compound according to any one of claims 1, 2 or 4 to 6, wherein R represents hydrogen or methyl; or a pharmaceutically acceptable salt of such a compound.
8. A compound according to any one of claims 1, 2 or 4 to 7, wherein R represents a heteroaryl group which is mono-substituted with halogen or (C - C )fluoroalkyl; or a pharmaceutically acceptable salt of such a compound.
9. A compound according to claim 8, wherein the heteroaryl group is selected from pyrimidyl, benzoxazolyl and benzothiazolyl; or a pharmaceutically acceptable salt of such a compound. 30 10. A compound according to claim 1 selected from the group consisting of: 2-(7-((5-chloropyrimidinyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol yl)acetic acid; 2-(7-((5-fluoropyrimidinyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indolyl)acetic acid; 35 2-(7-(methyl(5-(trifluoromethyl)pyrimidinyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol- 10-yl)acetic acid; 2-(7-((6-fluorobenzo[d]thiazolyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol yl)acetic acid; 2-(7-((5-fluorobenzo[d]oxazolyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol yl)acetic acid; 5 2-(7-((5-fluorobenzo[d]thiazolyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol yl)acetic acid; 2-(2-fluoro((5-fluoropyrimidinyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol- 10-yl)acetic acid, 2-(2-fluoro((5-fluorobenzo[d]oxazolyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2- 10 a]indolyl)acetic acid; 2-(3-fluoro((5-fluoropyrimidinyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol- 10-yl)acetic acid; 2-(3-fluoro((5-fluorobenzo[d]oxazolyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2- a]indolyl)acetic acid; 15 2-(7-((5-fluoropyrimidinyl)(methyl)amino)methoxy-6,7,8,9-tetrahydropyrido[1,2-a]indol- 10-yl)acetic acid; 2-(7-((5-fluorobenzo[d]oxazolyl)(methyl)amino)methoxy-6,7,8,9-tetrahydropyrido[1,2- a]indolyl)acetic acid; 2-(7-((5-fluoropyrimidinyl)(methyl)amino)methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol- 20 10-yl)acetic acid; 2-(7-((5-fluorobenzo[d]oxazolyl)(methyl)amino)methyl-6,7,8,9-tetrahydropyrido[1,2- a]indolyl)acetic acid; 2-(2-chloro((5-fluoropyrimidinyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol- 10-yl)acetic acid; 25 2-(2-chloro((5-fluorobenzo[d]oxazolyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2- a]indolyl)acetic acid; 2-(7-((5-chloropyrimidinyl)(methyl)amino)fluoro-6,7,8,9-tetrahydropyrido[1,2-a]indol- 10-yl)acetic acid; 2-(3-fluoro(methyl(5-(trifluoromethyl)pyrimidinyl)amino)-6,7,8,9-tetrahydropyrido[1,2- 30 a]indolyl)acetic acid; 2-(3-fluoro((5-fluorobenzo[d]thiazolyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2- a]indolyl)acetic acid; 2-(3-fluoro((6-fluorobenzo[d]oxazolyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2- a]indolyl)acetic acid; 35 2-(3-chloro((5-chloropyrimidinyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol- 10-yl)acetic acid; 2-(7-((5-chloropyrimidinyl)(methyl)amino)(trifluoromethyl)-6,7,8,9-tetrahydropyrido[1,2- a]indolyl)acetic acid; 2-(7-((5-chloropyrimidinyl)(methyl)amino)(trifluoromethoxy)-6,7,8,9- tetrahydropyrido[1,2-a]indolyl)acetic acid; 5 2-(7-((5-fluoropyrimidinyl)(methyl)amino)(trifluoromethyl)-6,7,8,9-tetrahydropyrido[1,2- a]indolyl)acetic acid; 2-(7-((5-fluoropyrimidinyl)(methyl)amino)(trifluoromethoxy)-6,7,8,9- tetrahydropyrido[1,2-a]indolyl)acetic acid; 2-(7-((6-fluorobenzo[d]thiazolyl)(methyl)amino)(trifluoromethyl)-6,7,8,9- 10 tetrahydropyrido[1,2-a]indolyl)acetic acid; 2-(7-((6-fluorobenzo[d]thiazolyl)(methyl)amino)(trifluoromethoxy)-6,7,8,9- tetrahydropyrido[1,2-a]indolyl)acetic acid; 2-(7-((5-fluorobenzo[d]oxazolyl)(methyl)amino)(trifluoromethyl)-6,7,8,9- tetrahydropyrido[1,2-a]indolyl)acetic acid; 15 2-(7-((5-fluorobenzo[d]oxazolyl)(methyl)amino)(trifluoromethoxy)-6,7,8,9- tetrahydropyrido[1,2-a]indolyl)acetic acid; 2-(3-chloro((5-fluoropyrimidinyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-
10-yl)acetic acid; 2-(3-chloro((5-fluorobenzo[d]oxazolyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2- 20 a]indolyl)acetic acid; (S)(3-chloro((5-fluoropyrimidinyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2- a]indolyl)acetic acid; (R)(3-chloro((5-fluoropyrimidinyl)(methyl)amino)-6,7,8,9-tetrahydropyrido[1,2- a]indolyl)acetic acid; 25 2-(3-fluoro((5-fluoropyrimidinyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol yl)acetic acid; 2-(3-fluoro((5-fluorobenzo[d]oxazolyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol yl)acetic acid; 2-(3-chloro((5-fluoropyrimidinyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol 30 yl)acetic acid; and 2-(3-chloro((5-chloropyrimidinyl)amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol yl)acetic acid; 35 or a pharmaceutically acceptable salt of such a compound.
11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 5
12. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use as a medicament.
13. Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention and/or 10 treatment of a disease selected from the group consisting of chronic and acute allergic/immune diseases/disorders, comprising asthma, allergic asthma, eosinophilic asthma, severe asthma, rhinitis, allergic rhinitis, angioedema, insect venom allergy, drug allergies, allergic sinusitis, allergic nephritis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, 15 eczema, ulcerative colitis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease and rheumatoid arthritis; eosinophil-related diseases comprising small vessel vasculitides like Churg-Strauss syndrome, Wegener's granulomatosis, microscopic polyangiitis (and organ-specific subsets of the latter), hypereosinophilic syndromes like eosinophilic pneumonia, eosinophilic esophagitis, reflux esophagitis, eosinohilic 20 endocarditis (Loeffler’s endocarditis), eosinophilia-myalgia syndrome, eosinophilic fasciitis, eosinohilic pustular folliculitis (Ofuji's disease), eosinophilic ulcers, angiolymphoid hyperplasia with eosinophilia (ALHE), eosinophilic cellulitis (Wells syndrome), chronic eosinophilic leukemia and DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms); and basophil-related diseases, comprising basophilic leukemia and basophilic 25 leukocytosis.
14. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for the prevention and/or treatment of a disease selected from the group consisting of chronic and acute allergic/immune diseases/disorders, comprising asthma, 30 allergic asthma, eosinophilic asthma, severe asthma, rhinitis, allergic rhinitis, angioedema, insect venom allergy, drug allergies, allergic sinusitis, allergic nephritis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, ulcerative colitis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease and rheumatoid arthritis; 35 eosinophil-related diseases comprising small vessel vasculitides like Churg-Strauss syndrome, Wegener's granulomatosis, microscopic polyangiitis (and organ-specific subsets of the latter), hypereosinophilic syndromes like eosinophilic pneumonia, eosinophilic esophagitis, reflux esophagitis, eosinohilic endocarditis (Loeffler’s endocarditis), eosinophilia-myalgia syndrome, eosinophilic fasciitis, eosinohilic pustular folliculitis (Ofuji's disease), eosinophilic ulcers, angiolymphoid hyperplasia with eosinophilia (ALHE), 5 eosinophilic cellulitis (Wells syndrome), chronic eosinophilic leukemia and DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms); and basophil-related diseases, comprising basophilic leukemia and basophilic leukocytosis.
15. A compound according to claim 1, substantially as herein described with reference to 10 any example thereof.
16. A pharmaceutical composition according to claim 11, substantially as herein described with reference to any example thereof. 15
17. A use according to claim 13, substantially as herein described with reference to any example thereof.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IB2011051615 | 2011-04-14 | ||
PCT/IB2012/051831 WO2012140612A1 (en) | 2011-04-14 | 2012-04-13 | 7-(heteroaryl-amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol acetic acid derivatives and their use as prostaglandin d2 receptor modulators |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ617624A NZ617624A (en) | 2015-05-29 |
NZ617624B2 true NZ617624B2 (en) | 2015-09-01 |
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