Patent Application
20060183909
The present invention concerns compounds derived from quinoline and quinoxaline, their preparation and their uses, particularly in the field of therapeutics and vaccines or for developing active compounds.
The present invention concerns in particular the use of compounds represented by general formula (I):
and their pharmaceutically acceptable salts for treating nervous system pathologies, the novel derivatives of formula (I), their methods of preparation and the pharmaceutical compositions containing them.
The compound of formula (I) wherein E is COOH, Z is C—OH, R5, R4, R6 and R7 are hydrogen atoms and X is OH (xanthurenic acid) is a known metabolite of tryptophan (Bioorg. Med. Chem. Letters, 1999, 17, 2607). This same compound interacts with bovine serum albumin (Chem. Pharm. Bull., 1980, 28, 10, 2960-2966) and is useful in the treatment of dermatoses (Farmaco Ed., 1981, 36, 7, 557-564).
Other compounds represented by formula (I) wherein Z is C—OH, R3 is hydrogen and E is COOH, COOC2H5 or COOCH3 are mentioned in DE 2130408 for the treatment of asthma, urticaria and autoimmune diseases.
Compounds represented by formula (I) wherein E is COOH, Z is CR4, R4 is hydrogen, methoxy or p-chlorophenyl, R3, R5 and R7 are hydrogen atoms, R6 and X are chlorine atoms or wherein E is CHO, Z is CR4, R4 is hydrogen, R8 is chloro, R3, R5, R6 and R7 are hydrogen are described in J. Med. Chem., 1972, 15, 490-493 for the treatment of malaria.
Compounds represented by formula (I) wherein E is COOH or COOC2H5, Z is CR4, R4 is OH, R7 is chloro, R8 is methyl, R3, R5 and R6 are hydrogen are described in WO94/17042 as anticonvulsants and inhibitors of the glycine site of the NMDA receptor.
Compounds represented by formula (I) wherein E is CHO, CH2OH or COOH, Z is CR4, R4 is hydrogen, R3 and R6 are hydrogen, R5 and R7 are chloro and R8 is benzyloxy are described in U.S. Pat. No. 3,682,927 as antiseptics and antifungals.
The present invention follows from the demonstration that compounds represented by formula (I) have particularly advantageous biological and therapeutic properties. The invention results in particular from the demonstration that compounds modulating the activity of xanthurenic acid may be used for treating disorders of the nervous system, particularly central. The invention more specifically results from the synthesis, development and characterization of compounds modulating the activity of xanthurenic acid, which may be used to modulate neurotransmission, particularly dopaminergic. Such compounds may be used in particular for treating central nervous system pathologies such as mental, neurological or traumatic disorders. The compounds are more particularly aimed at treating anxiety, depression, the depressive component of bipolar disorder, ADH syndrome, fibromyalgia, impairment of memory or social interactions, as sedative or hypnotic, disorders of sleep or concentration, for treating neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease or ALS, schizophrenia, epilepsy, some drug dependencies, particularly opioid, or pain. The compounds may also be used for treating obesity.
Within the scope of the invention, the term “treatment” denotes preventive, curative, palliative treatment as well as management of patients (alleviating suffering, prolonging survival, improving quality of life, slowing disease progression, etc.). Furthermore, the treatment may be carried out in combination with other agents or treatments, particularly addressing the late events of the disease, or with other active substances.
The invention is therefore based on using compounds represented by general formula (I) such as described hereinabove for preparing a pharmaceutical composition for treating nervous system pathologies.
In general formula (I)
E is a COOH, COOR1, CH2OH, CHO, CH2COOH, CH2COOR1 group or a group chosen from among the following:
R1 represents (i) a (C1-C12) alkyl group or (ii) a (C6-C18)aryl(C1-C12)alkyl group;
R2 represents (i) a hydrogen atom, (ii) a (C1-C12) alkyl group, (iii) a (C6-C18) aryl group, (iv) a (C6-C18)aryl(C1-C12)alkyl group, (v) a hydroxyl group;
R3 is (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, (iv) a (C1-C12) alkyl group, (v) a (C6-C18) aryl group, (vi) a (C6-C18)aryl(C1-C12)alkyl group or (vii) a (C3-C17) heteroaryl group;
Z is (i) a nitrogen atom or (ii) a CR4 group;
R4 represents (a) a hydrogen atom, (b) a (C1-C12) alkyl group, (c) a (C2-C12) alcyn-1-yl group, (d) a (C6-C18) aryl group, (e) a (C6-C18)aryl(C1-C12) alkyl group, (f) a OR8 group, (g) a NR9R9′ group, (h) a (C1-C17) heteroaryl group or (i) a (C2-C12) alcen-1-yl group;
R5, R6 and R7 represent, independently of each other, (i) a hydrogen atom, (ii) a halogen atom, (iii) a (C1-C12) alkyl group, (iv) a (C6-C18) aryl group, (v) a (C6-C18)aryl(C1-C12)alkyl group, (vi) a NR9R9′ group (vii) a COR10 group, (viii) a (C2-C12) alcen-1-yl group, (ix) a (C2-C12) alcyn-1-yl group, (x) a (C1-C17) heteroaryl group, (xi) a (C3-C17)heteroaryl(C1-C12)alkyl group, (xii) a cyano group or (xiii) a nitro group;
R8 represents (i) a hydrogen atom, (ii) a (C1-C12) alkyl group, (iii) a (C6-C18)aryl(C1-C12)alkyl group;
R9 represents (i) a hydrogen atom, (ii) a (C1-C12) alkyl group, (iii) a (C6-C18) aryl group, (iv) a (C6-C18)aryl(C1-C12)alkyl group, (v) an acyl group, (vi) a tert-butyloxycarbonyl group, (vii) a (C1-C17) heteroaryl group or (viii) a (C6-C18) arylsulfonyl or (C1-C12) alkylsulfonyl group;
R9 which can be the same as or different from R9, represents (i) a hydrogen atom, (ii) a (C1-C12) alkyl group, (iii) a (C6-C18) aryl group, (iv) a (C6-C18)aryl(C1-C12)alkyl group, (v) an acyl group, (vi) a tert-butyloxycarbonyl group, (vii) a (C1-C17) heteroaryl group or (viii) a (C6-C18) arylsulfonyl or (C1-C12) alkylsulfonyl group;
NR9R9′ can also represent a cycloheteroalkyl group of the type:
with n=2 or 3,
m=2 or 3 and
Y represents a CH2, SO2, or NR11 group or else an oxygen or sulfur atom,
R10 represents (i) a hydrogen atom, (ii) a (C1-C12) alkyl group or (iii) a (C6-C18) aryl group or (iv) a NHR2 group;
R11 represents (i) a hydrogen atom, (ii) a (C1-C12) alkyl group, (iii) a (C6-C18) aryl group, (iv) a (C6-C18)aryl(C1-C12)alkyl group, (v) a (C1-C17) heteroaryl group, (vi) a (C1-C17)heteroaryl(C1-C12)alkyl group or (vii) a COR10 group;
X is (i) a halogen atom, (ii) a OR8 group, (iii) a NR9R9′ group, (iv) a (C6-C18) aryl group, (v) a (C6-C18)aryl(C1-C12)alkyl group, (vi) a (C3-C12) alkyl group, (vii) a (C2-C12)alcen-1-yl group, (viii) a (C2-C12)alcyn-1-yl group, (ix) a (C1-C17) heteroaryl group, (x) a COR10 group, (xi) a cyano group or (xii) a nitro group.
The compounds represented by formula (I) which contain one or more asymmetrical carbon atoms may be in the form of racemates, enantiomers and diastereomers. Such forms are also encompassed by the invention.
The compounds represented by formula (I) wherein Z is CR4, R4 is OR8 and R8 is hydrogen may also be present as tautomers. Such tautomers are encompassed by the invention.
The invention is also based on using compounds represented by general formula (I) such as described hereinabove for preparing a pharmaceutical composition for modulating the activity of xanthurenic acid.
The invention is further based on using compounds represented by general formula (I) such as described hereinabove for preparing a pharmaceutical composition for modulating dopaminergic neurotransmission.
As will be demonstrated in the examples, the inventive compounds are able to antagonize the binding of XA to its receptor, or, in contrast, to mimic this binding (agonist). Furthermore, some compounds of the invention are allosteric modulators of XA, that is to say, they are capable of enhancing the binding of XA to its receptors.
The invention also concerns pharmaceutical compositions, compounds represented by formula (I) and treatment methods using them.
Xanthurenic acid (XA) is preferably excluded from the present invention. Derivatives of xanthurenic acid are preferred and in particular compounds represented by formula (I) wherein at least one of the groups R3, R5, R6 and R7 is different from the hydrogen atom and advantageously wherein X represents a hydroxyl group and Z represents COH.
Within the scope of the invention, the described groups are preferably defined as follows:
“Alcen-1-yl” groups are preferably linear or branched hydrocarbons having 2 to 12 carbon atoms and containing a double bond in position −1. They preferably contain from 2 to 6 carbon atoms. Such groups are not substituted or may be substituted by one or more substituents, which are the same or different, preferably chosen from among OR8, aryl, NR9R9′ groups, R8, R9 and R9′ being defined hereinabove.
“Alcyn-1-yl” groups are preferably linear or branched hydrocarbons having 2 to 12 carbon atoms and containing a triple bond in position 1. They preferably contain from 2 to 6 carbon atoms. Such groups are not substituted or may be substituted by one or more substituents, which are the same or different, preferably chosen from among OR8, aryl, NR9R9′ groups, R8, R9 and R9′ being defined hereinabove.
“Alkyl” denotes linear or branched hydrocarbons having from 1 to 12 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, n-hexyl, n-decyl, n-dodecyl, etc. C1-C4 groups are preferred. The alkyl groups are not substituted or may be substituted by one or more substituents, which are the same or different, preferably chosen from among aryl, OR8, —NR9R9′, CONHR2, R8, R9 and R9′ being defined as hereinabove. In the case where R4 represents a substituted alkyl group, the substituents are preferably chosen from among the groups aryl, OR8, —NR9R9′, CONHR2, R9 and R9′ being defined as hereinabove and R8 represents (ii) a (C1-C12) alkyl group or (iii) a (C6-C18)aryl(C1-C12)alkyl group.
“Alkoxy” corresponds to the alkyl groups defined hereinabove, linked to the rest of the molecule by means of an —O— (ether) bond. Methoxy or benzyloxy groups are especially preferred.
“Aryl” groups are mono-, bi- or tri-cyclic aromatic hydrocarbon systems, preferably mono- or bi-cyclic aromatic hydrocarbon systems having from 6 to 18 carbon atoms, even more preferably 6 carbon atoms. Examples include phenyl, naphthyl and biphenyl groups. The aryl groups may possibly be substituted by one or more substituents, which are the same or different, preferably chosen from among the halogen atoms and (C1-C12) alkyl and (C1-C12) alkoxy groups, a cyano group, a CONHR2 or NR9R9′ group.
“Acyl” groups correspond to the alkyl or aryl groups defined hereinabove, linked to the rest of the molecule by means of a —CO— (carbonyl) bond. In other words the acyl groups are —CO—(C1-C12) alkyl or —CO—(C6-C18)aryl groups. The acetyl and benzoyl groups are examples.
“Arylsulfonyl” and “alkylsulfonyl” groups are aryl or alkyl groups linked to the rest of the molecule by means of a SO2 bond. Such groups are exemplified by the p-tolylsulfonyl group.
“Heteroaryl” groups denote aryl groups in which 1 to 4 carbon atoms are replaced by heteroatoms chosen from among N, O, S and containing from 1 to 17 atoms and particularly from 1 to 10 carbon atoms. Examples include pyridyl, thienyl, benzothienyl, benzofuryl, pyrimidinyl, pyridazinyl, isoquinolinyl, thiazolyl, furyl, pyranyl, pyrrolyl, 2H-pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, indolyl and tetrazolyl groups. These may possibly be substituted by halogen atoms or (C1-C12) alkyl or (C1-C12) alkoxy groups.
The term “arylalkyl” refers to an alkyl group substituted by an aryl group. Examples of arylalkyl groups include the benzyl, phenethyl and phenethylpropyl groups.
The term “heteroarylalkyl” denotes an alkyl group substituted by a heteroaryl group. Examples of heteroarylalkyl groups include 2-pyridinylethyl, 3-pyridinylethyl groups.
“Cycloheteroalkyl” denotes nitrogenated cycles with 4 to 7 carbon atoms containing a nitrogen atom and in which one carbon atom may be replaced by a heteroatom chosen from among O, S, SO2 or NR11. In the case where the heteroatom is NR11, it may be substituted or not. Examples of cycloheteroalkyl groups include morpholino, thiomorpholino, piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, 4-(2-pyrimidine)-piperazin-1-yl and 4-phenyl-piperazin-1-yl groups.
“Halogen” signifies a fluorine, chlorine, bromine or iodine atom. In the case where X represents a halogen atom, the bromine atom is preferred.
In general formula (I) hereinabove, preferred compounds are those wherein:
E is a COOH, COOR1, CHO, CH2COOH, CH2COOR1 group or a group chosen from among the following:
and/or
R1 represents a (C1-C12) alkyl or (C6-C18)aryl(C1-C12)alkyl group; and/or
R2 represents (i) a hydrogen atom, (ii) a (C1-C12) alkyl group, (iii) a (C6-C18) aryl group, (iv) a (C6-C18)aryl(C1-C12)alkyl group or (v) a hydroxyl group; and/or
R3 is (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, (iv) a (C1-C12) alkyl group, (vi) a (C6-C18) aryl(C1-C12) alkyl group; and/or
Z is (i) a nitrogen atom or (ii) a CR4 group; and/or
R4 represents (a) a hydrogen atom, (b) a (C1-C12) alkyl group, (c) a (C2-C12) alcyn-1-yl group, (d) a (C6-C18) aryl group, (e) a OR8 group in which R8 represents hydrogen, (f) a (C1-C17) heteroaryl group or (g) a NR9R9′ group in which R9 represents hydrogen, acyl or (C6-C18) arylsulfonyl and R9′ represents hydrogen, acyl or NR9R9′ represents a cycloheteroalkyl group of the type:
with n=2 or 3,
m=2 or 3 and
Y represents a CH2, SO2, or NR11 group or else an oxygen or sulfur atom,
and/or
R5, R6, R7 represent, independently of each other, (i) a hydrogen atom, (ii) a halogen atom, (iii) a (C1-C12) alkyl group, (iv) a (C6-C18) aryl group, (v) a NR9R9′ group in which R9 represents hydrogen, and R9′ represents hydrogen, acyl or (C6-C18) arylsulfonyl or NR9R9′ represents a cycloheteroalkyl group of the type:
with n=2 or 3,
m=2 or 3 and
Y represents a CH2, SO2, or NR11 group or else an oxygen or sulfur atom,
(vi) a COR10 group in which R10 represents hydrogen, (vii) a (C2-C12) alcen-1-yl group, (viii) a (C2-C12) alcyn-1-yl group, (ix) a (C1-C17) heteroaryl group, (x) a (C6-C18)aryl(C1-C12)alkyl group, (xi) a cyano group; and/or
X is (i) a halogen atom, (ii) a OR8 group in which R8 is a hydrogen atom, a (C1-C12) alkyl or (C6-C18)aryl(C1-C12)alkyl group, (iii) a (C6-C18)aryl(C1-C12)alkyl group, (iv) a (C6-C18) aryl group, (v) a (C1-C17) heteroaryl group, (vi) a NR9R9′ group in which R9 is hydrogen, (C6-C18)aryl(C1-C12)alkyl or acyl or (C1-C12) alkylsulfonyl and (C6-C18) arylsulfonyl and R9′ represents hydrogen, acyl or (C6-C18) arylsulfonyl or NR9R9′ which represents a cycloheteroalkyl group of the type:
with n=2 or 3,
m=2 or 3 and
Y represents a CH2, SO2, or NR11 group or else an oxygen or sulfur atom,
R11 represents (i) a hydrogen atom, (ii) a (C1-C12) alkyl group, (iii) a (C6-C18) aryl group, (iv) a (C6-C18)aryl(C1-C12)alkyl group, (v) a (C1-C17) heteroaryl group, (vi) a (C1-C17)heteroaryl(C1-C12)alkyl group or (vii) a COR10 group;
and their pharmaceutically acceptable salts.
A preferred family of compounds is that wherein R1 is an unsubstituted alkyl or benzyl group, preferably when E represents a COOR1 group.
Another preferred family is that wherein E represents a CONHR2 group in which R2 is a hydroxyl group.
Another preferred family is that wherein R3 is (i) a hydrogen atom, (ii) a (C1-C12) alkyl group not substituted or substituted by amino or alkylamino, or (iii) a (C6-C18) aryl group.
A further preferred family is that wherein Z is (i) a nitrogen atom or (ii) a CR4 group in which R4 represents (a) a hydrogen atom, (b) a (C1-C12) alkyl group not substituted or substituted by phenyl or NR9R9′ in which R9 is hydrogen or tert-butyloxycarbonyl and R9′ is hydrogen, or else by NR9R9′ which represents a cycloheteroalkyl group of the type:
with n=2 or 3,
m=2 or 3 and
Y represents a CH2, SO2, or NR11 group or else an oxygen or sulfur atom,
(c) a (C2-C12) alcyn-1-yl group not substituted or substituted by phenyl, hydroxyl, benzyloxy or NR9R9′ with R9 representing tert-butyloxycarbonyl and R9′ hydrogen, or NR9R9′ represents a cycloheteroalkyl group of the type:
with n=2 or 3,
m=2 or 3 and
Y represents a CH2, SO2, or NR11 group or else an oxygen or sulfur atom,
(d) a (C6-C18) aryl group not substituted or substituted by halogen, (e) an OR8 group in which R8 represents hydrogen, (f) a NR9R9′ group in which R9 represents hydrogen or tosyl and R9′ represents hydrogen or else a NR9R9′ group which represents a cycloheteroalkyl group of the type:
with n=2 or 3,
m=2 or 3 and
Y represents a CH2, SO2, or NR11 group or else an oxygen or sulfur atom.
Even more preferred is the use, for treating nervous system pathologies, of compounds represented by formula (I) wherein;
E is a COOH, COOR1, CHO, CH2COOH, CH2COOR1 group or a group chosen from among the following:
R2 represents a hydroxyl group; and/or
Z is (i) a nitrogen atom or (ii) a CR4 group in which R4 represents (a) a hydrogen atom, (b) a (C1-C12) alkyl group not substituted or substituted by phenyl, hydroxyl or by NR9R9′ with R9 being hydrogen or tert-butyloxycarbonyl and R9′ hydrogen or else by NR9R9′ which represents a cycloheteroalkyl group of the type:
with n=2 or 3,
m=2 or 3 and
Y represents a CH2, SO2, or NR11 group or else an oxygen or sulfur atom,
(c) a (C2-C12) alcyn-1-yl group not substituted or substituted by phenyl, hydroxyl, benzyloxy or by NR9R9′ with R9 representing tert-butyloxycarbonyl and R9′ hydrogen, or else by NR9R9′ which represents a cycloheteroalkyl group of the type:
with n=2 or 3,
m=2 or 3 and
Y represents a CH2, SO2, or NR11 group or else an oxygen or sulfur atom,
(d) a (C6-C18) aryl group not substituted or substituted by halogen, (e) a OR8 group in which R8 represents hydrogen, (f) a NR9R9′ in which R9 represents hydrogen or tosyl and R9′ is hydrogen; or a NR9R9′ group which represents a cycloheteroalkyl group of the type:
with n=2 oru 3,
m=2 or 3 and
Y represents a CH2, SO2, or NR11 group or else an oxygen or sulfur atom,
R3 is (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, (iv) a (C1-C12) alkyl group not substituted or substituted by amino, alkylamino, (v) a (C6-C18) aryl group;
R5, R6, R7 represent, independently of each other, (i) a hydrogen atom, (ii) a halogen atom, (iii) a (C1-C12) alkyl group not substituted or substituted by hydroxyl, phenyl or NR9R9′ in which R9 is hydrogen or tert-butyloxycarbonyl and R9′ is hydrogen, (iv) a phenyl group not substituted or substituted by halogen, alkoxy, alkyl, (v) a (C6-C18)aryl(C1-C12)alkyl group, (vi) a NR9R9′ group in which R9 represents hydrogen and R9′ is hydrogen, (vii) a COR10 group in which R10 represents hydrogen, (viii) an unsubstituted (C2-C12) alcen-1-yl group, (ix) a (C2-C12) alcyn-1-yl group not substituted or substituted by phenyl, NR9R9′ in which R9 is hydrogen or tert-butyloxycarbonyl and R9′ is hydrogen, OR8 in which R8 is hydrogen or tert-butoxycarbonyl, (x) a pyridyl group;
X is (i) a halogen atom, (ii) a OR8 group in which R8 is hydrogen, (C1-C6) alkyl or benzyl, (iii) a NR9R9′ group in which R9 is hydrogen, acetyl or benzoyl and R9′ is hydrogen, acetyl or benzoyl, or (iv) phenyl.
and their pharmaceutically acceptable salts.
Even more preferably, in the compounds represented by formula (I) and the subfamilies defined hereinabove, Z is a CR4 group.
According to another variant of the invention, in the compounds represented by formula (I) and the subfamilies defined hereinabove, Z represents CR4 where R4 is a hydroxyl group, X represents a halogen atom, preferably bromine, and in particular at least one of the groups R3, R5, R6 and R7 is different from the hydrogen atom, avantageously with R5 and R7 not representing a halogen atom.
According to yet another variant of the invention, in the compounds represented by formula (I) and the subfamilies defined hereinabove, Z represents CR4 in which R4 is a hydroxyl group, X represents a hydroxyl group and advantageously at least one of the groups R3, R5, R6 and R7 is different from the hydrogen atom.
Among the compounds represented by formula (I), the following compounds are preferably used:
The following compounds are more particularly preferred:
The compounds of the invention may be used in the form of pharmaceutically acceptable salts, particularly acid or base salts, preferably compatible with pharmaceutical use. Non-limiting examples of pharmaceutically acceptable acids include hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, methane or ethanesulfonic, camphoric acids, etc. Non-limiting examples of pharmaceutically acceptable bases include sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
The invention also concerns the use of compounds represented by formula (I) for preparing a pharmaceutical composition for treating nervous system pathologies, especially mental or neurological disorders, particularly anxiety, depression, impairment of memory or social interactions, as sedative or hypnotic, for treating neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease or ALS, schizophrenia, some drug dependencies, particularly opioid, pain or obesity.
In particular, the invention concerns the use of compounds represented by formula (I) for preparing a pharmaceutical composition for treating mental or neurological disorders, particularly anxiety, depression, impairment of memory or social interactions, as sedative or hypnotic, or for treating neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease or ALS, some drug dependencies, particularly opioid.
The invention further concerns pharmaceutical compositions, particularly a medicament for treating central nervous system pathologies, containing as active principle at least one compound represented by formula (I) such as defined hereinabove or their pharmaceutically acceptable salts and a pharmaceutically acceptable vehicle or excipient.
The invention equally concerns novel compounds represented by formula (I) as such. More particularly these are compounds wherein R1 is an unsubstituted alkyl or benzyl group or R2 is a hydroxyl group, and preferably R3 is (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, (iv) a (C1-C12) alkyl group not substituted or substituted by amino or alkylamino, or (v) a (C6-C18) aryl group and/or Z is (i) a nitrogen atom or (ii) a CR4 group in which R4 represents (a) a hydrogen atom, (b) a (C1-C12) alkyl group not substituted or substituted by phenyl, hydroxyl or NR9R9′ where R9 is hydrogen or tert-butyloxycarbonyl and R9′ is hydrogen, (c) a (C2-C12) alcyn-1-yl group not substituted or substituted by phenyl, hydroxyl, benzyloxy or NR9R9′ where R9 represents tert-butyloxycarbonyl and R9′ is hydrogen, (d) a (C6-C18) aryl group not substituted or substituted by a halogen, (e) a OR8 group in which R8 represents hydrogen, (f) a NR9R9′ group in which R9 represents hydrogen or tosyl and R9′ is hydrogen, preferably a CR4 group such as defined hereinabove.
The compounds or compositions of the invention may be administered in different ways and in different forms. For instance, they may be administered systemically, by the oral route, by inhalation or by injection, such as for example by the intravenous, intramuscular, subcutaneous, transdermal, intra-arterial route, etc., the intravenous, intramuscular, subcutaneous, oral and inhalation routes being preferred. For injections, the compounds are generally prepared in the form of liquid suspensions, which may be injected through syringes or by infusion, for instance. In this respect, the compounds are generally dissolved in pharmaceutically compatible saline, physiologic, isotonic, buffered solutions and the like, known to those skilled in the art. For instance, the compositions may contain one or more agents or vehicles chosen from among dispersives, solubilizers, stabilizers, preservatives, and the like. Agents or vehicles that may be used in the liquid and/or injectable formulations comprise in particular methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oils, acacia, and the like.
The compounds may also be administered in the form of gels, oils, tablets, suppositories, powders, capsules, gelules, aerosols, and the like, possibly by means of pharmaceutical forms or devices allowing sustained and/or delayed release. For this type of formulation, an agent such as cellulose, carbonates or starches is advantageously used.
It is understood that the injection rate and/or injected dose may be adapted by those skilled in the art according to the patient, the pathology, the mode of administration, etc. Typically, the compounds are administered at doses ranging from 0.1 to 500 mg/kg of body weight, more generally from 0.3 to 100 mg/kg, typically between 3 and 50 mg/kg. Furthermore, repeated injections may be given, as the case may be. In addition, in the case of chronic treatments, delayed or sustained release systems may be advantageous.
The inventive compounds are especially useful for modulating the activity of XA on the nervous system. As a matter of fact, the invention results from the demonstrated role of XA as a neurotransmitter. The compounds of the invention may also be used to selectively modulate neurotransmission, particularly dopaminergic neurotransmission. As illustrated in the examples, the compounds of the invention may be used either to inhibit XA activity, or to mimic or increase such activity. Thus, the results presented show that the inventive compounds are XA antagonists, XA agonists, or allosteric modulators of XA. For instance, compound 19f displays an activity which is ten-fold more potent than that of XA.
Furthermore, compounds 3x and 22c for example are capable of increasing XA binding to its receptor by more than 100-fold. The compounds particularly capable of increasing XA binding to its receptor preferably correspond to formula (I) wherein Z represents CR4 in which R4 is a hydroxyl group, X represents a halogen atom, preferably bromine, or a cyano group, and in particular at least one of the groups R3, R5, R6 and R7 is different from the hydrogen atom, advantageously with R5 and R7 not representing a halogen atom. Such compounds are also able to selectively increase dopamine levels in the prefrontal cortex (experiments carried out in rats in particular with measurements obtained by microdialysis). In particular they may be used to enhance memory and therefore to treat disorders of memory. They may thus be used to treat pathologies linked to senescence or neurodegeneration or even psychoses, such as schizophrenia. Lastly, other compounds such as compound 3u are potent inhibitors of XA binding to its site.
Compounds represented by formula (I) may be obtained from intermediates available commercially or possibly modified by carrying out a combination of chemical reactions known to those skilled in the art such as those described hereinbelow for functionalization of the products.
Compounds represented by formula (I) wherein Z is a nitrogen atom and E is a COOR1 group or a CH2COOR1 group may be prepared according to the following reaction route:
in such formulas, R1, R3, R5, R6, R7 and X are defined as in formula (I) and E is COOR1 or CH2COOR1.
This reaction is generally carried out according to the conditions described in J. Org. Chem., 1990, 55, 2820-2822. Preferably, the reaction is carried out in an inert solvent such as benzene or toluene in the presence of para-toluene sulfonic acid under reflex of the solvent.
Compounds represented by formula (I) wherein Z is a C—R4 group, R4 represents hydrogen and E is COOH, may be prepared according to the following reaction route:
in these formulas, R3, R5, R6, R7 and X are defined as in formula (I).
This reaction is generally carried out in basic medium according to the conditions described in Tetrahedron Lett., 1984, 25, 923-926 or J. Am. Chem. Soc., 1998, 6, 1218-1222. Preferably it is carried out in the presence of sodium methylate, in an inert solvent such as an aliphatic alcohol like methanol, at a temperature of 60° C.
Compounds represented by formula (I) wherein Z is a C—R4 group, R4 is OR8, R8 is hydrogen, E is COOR1 and R1 is methyl, may be prepared according to the following reaction route:
in these formulas, R5, R6 and R7 are defined as in formula (I), X′ has the same definition as X and may also represent a nitro group, Me represents a methyl group and Bn represents a benzyl group.
The reaction is carried out according to the conditions described in J. Med. Chem., 1985, 28, 298-302 or J. Org. Chem. 1966, 31, 3369-3374. Preferably, an aliphatic alcohol such as methanol or ethanol is used, at the boiling temperature of the reaction medium.
Reactions b and c are generally carried out in diphenyl ether, at a temperature of 250° C. or in polyphosphoric acid at 100° C.
Deprotection of the hydroxyl group (reaction d) is carried out either when X′ is benzyloxy by catalytic hydrogenation in the presence of Pd/charcoal, in an inert solvent such as ethyl acetate, an aliphatic alcohol (methanol, ethanol for example) or acetic acid, at room temperature or with AlCl3 in an inert solvent such as a chlorinated solvent (dichloroethane for example), in the presence of dimethylaniline, at room temperature or under reflux in a mixture of acetic acid/37% hydrochloric acid and, in this case, the ester is hydrolyzed simultaneously, or, when X′ is methoxy, in H3PO4 medium in the presence of KI and, in this case, hydrolysis of the ester occurs simultaneously.
Reduction of the nitro group (reaction e) is a catalytic reduction with hydrogen, in the presence of Pd/charcoal, in an inert solvent such as an aliphatic alcohol (methanol for example), at room temperature. However in the case where there is also a halogen present on the quinoline nucleus, the reduction of the nitro group to an amino group is carried out as described in J.O.C., 1985, 50, 26, 5782-5789 and, preferably, in THF with Na2S2O4 at room temperature (approximately 18° C. to 25° C.) or at 60° C.
Compounds represented by formula (I) wherein Z is a C—R4 group, R4 is a halogen atom and E is a COOR1 group may be prepared by reacting a corresponding compound represented by formula (I) in which Z is a C—R4 group and R4 is a hydroxyl group, with a halogenating agent.
It is preferable to use a phosphorus oxyhalogenide as halogenating agent (phosphorus oxychloride, phosphorus oxybromide, phosphorus oxyfluoride) according to the conditions described in Chem. Pharm. Bull., 1990, 2919-2925. Preferably the reaction is carried out at the boiling temperature of the reaction medium.
Compounds represented by formula (I) wherein Z is a CR4 group, R4 is a hydrogen atom, R3 is a hydrogen atom and E is a COOR1 group and the other substitutents are not halogen may be prepared by catalytic hydrogenation of compounds having formula (I) in which Z is a C—R4 group, R4 is a halogen atom.
Such hydrogenation is carried out with hydrogen, preferably, in the presence of Pd/charcoal, in an inert solvent such as an aliphatic alcohol (methanol for example) at room temperature and at variable pressure.
Compounds represented by formula (I) wherein Z is a C—R4 group, R4 is an aryl, heteroaryl or arylalkyl group and E is COOR1 and/or one of the substituents R5, R6, R7 or X is an aryl, heteroaryl or arylalkyl group may be prepared by reacting a corresponding compound represented by formula (I) in which Z is a C—R4 group, R4 is a halogen atom and/or one of the substituents R5, R6, R7 or X is a halogen atom, with a derivative of formula R4′B(OH)2 for which R4′ is an aryl, heteroaryl or arylalkyl group. The halogen atoms are preferably chlorine or bromine atoms.
This reaction is preferably carried out in the presence of Pd(PPh3)4 and K3PO4, in an inert solvent such as dimethylformamide or toluene, at a temperature of 90° C. to 115° C.
Compounds represented by formula (I) wherein Z is a CR4 group, R4 is an alcyn-1-yl or (C2-C12)alkyl group and E is COOR1 may be prepared by the following reaction route:
in these formulas R5, R6, R7, X are defined as in formula (I), E is COOR1, OTf represents a triflate group, R″ represents a hydrogen atom, an alkyl group, an aryl group or a heteroaryl group.
Reaction a is carried out with triflic anhydride in a chlorinated solvent such as dichloromethane, in the presence of pyridine, at a temperature ranging from 0° C. to 25° C.
Reaction b is generally carried out in the presence of a palladium halogenide such as PdCl2, copper iodide, triphenylphosphine and triethylamine, in an inert solvent such as acetonitrile, at a temperature comprised between 30° C. and 60° C.
The reduction in reaction c is generally carried out by means of hydrogen, in the presence of Pd/charcoal, in an inert solvent such as a chlorinated solvent (dichloromethane for example), an aliphatic alcohol (methanol for example), or acetic acid, at room temperature.
Compounds represented by formula (I) wherein Z is a CR4 group, R4 is a NR9R9′ group in which R9 represents (i) a hydrogen atom, (ii) a (C1-C12) alkyl group, (iii) a (C6-C18) aryl group, (iv) a (C6-C18)aryl(C1-C12)alkyl group or (v) a (C1-C17) heteroaryl group and R9′ which may be the same as or different from R9 represents (i) a hydrogen atom, (ii) a (C1-C12) alkyl group, (iii) a (C6-C18) aryl group, (iv) a (C6-C18)aryl(C1-C12)alkyl group or (v) a (C1-C17) heteroaryl group;
or NR9R9′ represents a cycloheteroalkyl group of the type:
with n=2 or 3,
m=2 or 3
and Y represents CH2, O, S, SO2, or NR11
R11 represents (i) a hydrogen atom, (ii) a (C1-C12) alkyl group, (iii) a (C6-C18) aryl group, (iv) a (C6-C18)aryl(C1-C12)alkyl group, (v) a (C1-C17) heteroaryl group, (vi) a (C1-C17)heteroaryl(C1-C12)alkyl group or (vii) a COR10 group;
and E is COOR1 may be prepared according to the following reaction route:
Reaction a is carried out by means of triflic anhydride, in a chlorinated solvent such as dichloromethane, in the presence of pyridine, at a temperature ranging from 0° C. to 25° C.
Reaction b is generally carried out in the presence of a palladium (0) (Pd2(dba)3) or palladium (II) complex such as Pd(OAc)2 in the presence of the amine HNR9R9′, cesium carbonate and racemic BINAP in an inert solvent such as toluene, at a temperature comprised between 30° C. and 60° C.
Compounds represented by formula (I) wherein Z is a CR4 group, R4 is a OR8 group and R5, R6, R7 and/or X represents a NR9R9′ group in which R9 represents (i) a hydrogen atom, (ii) a (C1-C12) alkyl group, (iii) a (C6-C18) aryl group, (iv) a (C6-C18)aryl(C1-C12)alkyl group or (v) a (C1-C17) heteroaryl group and R9′ which may be the same as or different from R9 represents (i) a hydrogen atom, (ii) a (C1-C12) alkyl group, (iii) a (C6-C18) aryl group, (iv) a (C6-C18)aryl(C1-C12)alkyl group or (v) a (C1-C17) heteroaryl group;
or NR9R9′ represents a cycloheteroalkyl group of the type:
with n=2 or 3,
m=2 or 3,
and Y represents CH2, O, S, SO2, or NR11
R11 represents (i) a hydrogen atom, (ii) a (C1-C12) alkyl group, (iii) a (C6-C18) aryl group, (iv) a (C6-C18)aryl(C1-C12)alkyl group, (v) a (C1-C17) heteroaryl group, (vi) a (C1-C17)heteroaryl(C1-C12)alkyl group or (vii) a COR10 group;
and E is COOR1 may be prepared according to the following reaction route:
Reaction a is carried out with triflic anhydride, in a chlorinated solvent such as dichloromethane, in the presence of pyridine, at a temperature ranging from 0° C. to 25° C.
Reaction b is generally carried out in the presence of a palladium (0) (Pd2(dba)3) or palladium (II) complex such as Pd(OAc)2 in the presence of the amine HNR9R9′, cesium carbonate and racemic BINAP in an inert solvent such as toluene, at a temperature comprised between 30° C. and 60° C.
The reduction in reaction c is generally carried out with hydrogen, in the presence of Pd/charcoal, in an inert solvent such as a chlorinated solvent (dichloromethane for example), an aliphatic alcohol (methanol for example), or acetic acid, at room temperature.
Compounds represented by formula (I) wherein Z is a CR4 group, R4 is a OR8 group and R5, R6, R7 and/or X represent a cyano group;
and E is COOR1 may be prepared according to the following reaction route:
Reaction a is generally carried out in the presence of a palladium (II) complex (Pd(OAc)2) in the presence of zinc cyanide amine, zinc powder, cesium carbonate and DPPF in an inert solvent such as DMA, at a temperature of 120° C.
The reduction in reaction a is generally carried out with hydrogen, in the presence of Pd/deactivated charcoal, in an inert solvent such as a chlorinated solvent (dichloromethane for example), an aliphatic alcohol (meethanol for example), or acetic acid, at room temperature.
Compounds represented by formula (I) wherein Z is a CR4 group, R4 is a NR9R9′ group, R9 is hydrogen or arylsulfonyl and R9′ is hydrogen and E is COOR1 may be prepared according to the following reaction route:
in these formulas, R5, R6, R7, X are defined as in formula (I), E is COOR1 and SO2Ar is arylsulfonyl. Reaction a is carried out by reacting an arylsulfonylisocyanate according to the method described in J. Med. Chem., 1990, 33, 3130-3133. An inert solvent is preferably used, such as a chlorinated solvent (dichloromethane for example), at the boiling temperature of the reaction medium.
Deprotection reaction b is carried out in sulfuric acid at 0° C. When deprotection is carried out using hydrochloric acid, hydrolysis of the ester occurs and the compound in which Z is C—NR9R9′ and R9 is arylsulfonyl and R9′ is hydrogen and E is COOH is obtained.
Compounds represented by formula (I) wherein E is a CHO group may be prepared by oxidation of a compound represented by the formula:
in which Z, R3, R5, R6, R7 and X are defined as in formula (I)
This oxidation is carried out by any method of oxidizing a methyl group to an aldehyde known to those skilled in the art and allowing the rest of the molecule to remain intact, such as the method described in Tetrahedron, 1996, 52, 4659-4672. Preferably, SeO2 is used in an inert solvent such as dioxane, at a temperature of 80° C.
The methylated intermediates may be prepared according to one of the following reaction routes:
A
in these formulas, R3, R5, R6, R7 and X are defined as in formula (I) and Me is methyl.
This reaction is carried out according to the conditions described in J. Med. Chem., 1998, 41, 4062-4077 or J. Chem. Soc. 1946, 56-57. This condensation preferably takes place in acetic acid in the presence of sodium acetate at 60° C.
B—
in these formulas, R3, R5, R6, R7 and X are defined as in formula (I). This reaction is carried out as described in Org. Prep. Proced. Int, 1991, 386-387. The reaction is preferably carried out in aqueous ethanol in the presence of a base such as KOH or piperidine at the boiling temperature of the reaction medium.
in these formulas, R3, R5, R6, R7 and X are defined as in formula (I).
This reaction is carried out in the conditions described in J. Chem. Soc, 1951, 1521-1527. Preferably, formation of the enamine is carried out in methanol in the presence of HCl. The second step takes place in diphenyl ether at 250° C.
The intermediates for which Z is CR4 other than C—H and C—OH are then obtained by the methods described herein for preparing compounds represented by formula (I).
Compounds represented by formula (I) wherein E is a —CH2OH group may be prepared by reducing a corresponding compound represented by formula (I) in which E is CHO.
This reduction is carried out by any method of oxidizing a methyl group to an aldehyde known to those skilled in the art and allowing the rest of the molecule to remain intact and, preferably, by means of sodium borohydride, in an inert solvent such as methanol or ethanol, at a temperature ranging from 0° C. to 25° C.
Compounds represented by formula (I) in which E is a COOH group may also be prepared by oxidizing a corresponding compound having formula (I) in which E is CHO.
This oxidation is carrried out under the conditions described in Tetrahedron, 1996, 52, 4659-4672. It is preferably carried out in H2NSO3H in the presence of aqueous sodium hypochlorite solution, in an inert organic solvent such as THF, at room temperature.
Compounds represented by formula (I) wherein E is a COOH group may be prepared by hydrolyzing corresponding compounds having formula (I) in which E is a COOR1 group.
This reaction is carried out by any method known to those skilled in the art by which to convert an ester to the corresponding acid. Preferably the reaction occurs in acidic medium for example with hydrochloric acid in acetic acid or in alcoholic medium, at a temperature comprised between 20° C. and the boiling temperature of the reaction medium. The reaction may also be run in basic medium for example with LiOH, in an inert solvent such as water or tetrahydrofuran, at room temperature.
Compounds represented by formula (I) wherein E is a COOR1 group and R1 is alkyl may also be prepared by esterification of a corresponding compound having formula (I) in which E is a COOH group.
This esterification is carried out by any method of esterification of an acid known to those skilled in the art. In particular, an aliphatic acid (C1-C12 linear or branched) is reacted in the presence of an acid such as sulfuric acid or hydrochloric acid, at the boiling temperature of the reaction medium.
Compounds represented by formula (I) wherein E is a COOR1 group and R1 is arylalkyl may be prepared by reacting a corresponding compound having formula (I) in which E is a COOH group, with an arylalkyl halogenide.
This reaction is generally carried out in an inert solvent such as dimethylformamide, in the presence of NaH, at room temperature.
Compounds represented by formula (I) wherein E represents a CO—NHR2 group may be prepared by reacting a corresponding compound having formula (I) in which E is a COOH or COOR1 group and an amine H2NR2 in which R2 is defined as in formula (I).
This reaction is generally carried out in an inert solvent such as THF in the presence of isobutyl chloroformiate at temperatures ranging from 0° C. to 25° C.
Compounds represented by formula (I) wherein E represents a tetrazolyl group may be prepared according to the following reaction route:
in these formulaes, R3, R5, R6, R7 and X are defined as in formula (I). Me is methyl.
Reaction a is carried out according to the conditions described in Synthesis, 1983, 4, 316-319. Preferably one uses acetonitrile under reflux of the solvent.
Dehydration of the amide (reaction b) is carried out by means of phosphorus oxychloride according to the method described in J. Med. Chem., 1988, 31, 84-91. The reaction is preferably carried out in DMF at 20° C. This dehydration may also be carried out using the conditions described in Org. Prep. Proc. Int, 1994, 26, 4, 429-438 and, preferably, in dichloromethane in the presence of trifluoroacetic anhydride and triethylamine at room temperature. Reaction c is carried out in DMF in the presence of ammonium chloride at a temperature of up to 120° C. (J. Med. Chem, 1979, 22, 7, 816-823).
Compounds represented by formula (I) wherein X represents a tetrazolyl group and R1, R3, R5, R6, R7 and X are defined as in formula (I), may be prepared by reacting with sodium nitride in acetic acid medium at a temperature of up to 115° C.
Compounds represented by formula (I) wherein Z is a CR4 group, R4 is a hydrogen atom and R3 is an arylmethyl group or methyl substituted by NR9R9′ may be prepared by the following reaction route:
in these formulas, R1, R5, R6, R7, R9 and X are defined as in formula (I), R′″ is an aryl group.
The bromination reaction a is carried out as described in J. Am. Chem. Soc., 1998, 120, 1218-1222. Preferably, 1,3-dibromo-5,5-dimethylhydantoin (DBH) is used in an inert solvent such as CCl4 under reflux of the solvent.
Reaction b, in the case of aliphatic amines, is carried out according to the conditions described in Indian J. Chem. Sect B, EN 1984, 23, 1 33-39 and, preferably, in a solvent such as ethanol in the presence of NEt3 under reflux. In the case of aromatic amines, the reaction may be carried out as described in J. Chem. Soc. Chem. Comm, EN, 1992, 18, 1300-1302 or J. Med. Chem. 1991, 2209-2218 and, preferably, in acetonitrile or benzene in the presence of K2CO3 or DMF, at temperatures ranging from 50° C. to 80° C.
Reaction c is carried out under the conditions described in Tetrahedron Lett. 1999, 40, 43, 7599-7603. One preferably uses Pd(PPh3)4 in an inert solvent such as DME in the presence of Na2CO3 under reflux of the solvent.
Compounds represented by formula (I) wherein one of the substituents R3, R5, R6, R7 or X is an alcyn-1-yl, (C6-C18)aryl(C2-C12)alcyn-1-yl, (C4-C12)heteroaryl(C2-C12)alcyn-1-yl, (C2-C12) alkyl, (C6-C18)aryl(C2-C12)alkyl, (C4-C12)heteroaryl(C2-C12) alkyl group, may be prepared by reacting a corresponding compound having formula (I) in which one of the substituents R3, R5, R6, R7 or X is a halogen atom, and preferably a bromine, with a derivative of formula:
≡—R″
in which R″ represents a hydrogen atom or an alkyl group, an aryl group or a heteroaryl group possibly followed by a reduction.
This reaction is generally carried out in the presence of a palladium halogenide such as PdCl2, copper iodide, triphenylphosphine and triethylamine, in an inert solvent such as acetonitrile, at a temperature comprised between 30° C. and 60° C. The reduction is preferably carried out by means of hydrogen, in the presence of Pd/charcoal, in an inert solvent such as a chlorinated solvent (dichloromethane for example), an aliphatic alcohol (methanol for example) or acetic acid, at room temperature.
Compounds represented by formula (I) wherein one of the substituents R3, R5, R6, R7 or X is an alkyl or arylalkyl group may be prepared by reacting a corresponding compound having formula (I) in which one of the substituents R3, R5, R6, R7 or X is a halogen atom and, preferably, a bromine atom, with a derivative R′″ZnX″ in which R′″ is an alkyl or arylalkyl group and X″ is bromine or iodine.
This reaction is generally carried out in the presence of Pd(PPh3)4, in an inert solvent such as THF or DMF at a temperature ranging from 50° C. to 100° C.
Compounds represented by formula (I) wherein Z is C—R4, R4, R3, R6, R7 are hydrogen, X is OR8, R8 is benzyl, E is COOR1, R1 is benzyl and R5 is a bromine atom may be prepared by direct bromination of the corresponding compound having formula (I) in which Z is C—R4, R4, R3, R5, R6, R7 are hydrogen, X is OR8, R8 is benzyl, E is COOR1, R1 is benzyl.
This reaction is carried out as described in J. Chem. Soc, 1971, 3682-3653. It is preferably carried out with 2,4,4,6-tetrabromocyclohexa-2,5-dienone, in a chlorinated solvent such as dichloromethane at a temperature ranging from −10° C. to 25° C.
Compounds represented by formula (I) wherein Z is C—R4, R4 is hydroxyl and R5, R6, R7 are hydrogen, X is OR8, R8 is benzyl, E is COOR1, R1 is methyl and R3 is a bromine atom may be prepared by direct bromination of the corresponding compound having formula (I) in which Z is C—R4, R4, R3, R5, R6, R7 are hydrogen, X est OR8, R8 is benzyl, E is COOR1, R1 is methyl.
This reaction is preferably carried out by means of N-bromosuccinimide in the presence of diisopropylamine, in a chlorinated solvent such as dichloromethane at a temperature ranging from −10° C. to 25° C. or in carbon tetrachloride under reflux.
Compounds represented by formula (I) wherein one of the substitueants R5, R6, R7 or X is a (C1)alkyl group substituted by NR9R9′, R9 is alkyl, aryl or arylalkyl and R9′ is hydrogen, alkyl, aryl or arylalkyl may be prepared by reacting a corresponding compound in which one of the substituents R3, R5, R6, R7 or X is a CHO group with an amine corresponding to the formula HNR9R9′, R9 is alkyl, aryl or arylalkyl and R9′ is hydrogen, alkyl, aryl or arylalkyl.
The intermediates for which X represents CHO may be obtained by the hereinabove methods.
This reaction is generally carried out in the presence of NaBH4, in a protic solvent such as methanol, at a temperature of 0° C.
Compounds represented by formula (I) wherein one of the substituents R5, R6, R7 or X is a NR9R9′ group in which R9 is COR10 and R9′ is hydrogen or COR10 may be prepared by reacting a corresponding compound having formula (I) in which one of the substituents R5, R6, R7 or X is a NR9R9′ group and R9 and R9′ are hydrogen, with a derivative R10COCl in which R10 is defined as in formula (I).
This reaction is generally carried out in the presence of NEt3 in acetonitrile at room temperature.
Compounds represented by formula (I) wherein one of the substituents R5, R6, R7 or X is a NR9R9′ group and R9 is an alkyl group possibly substituted by aryl or arylalkyl and R9′ is hydrogen, alkyl, aryl or arylalkyl may be prepared by reacting a corresponding compound having formula (I) in which one of the substituents R5, R6, R7 or X is a NR9R9′ group and R9 is hydrogen and R9′ is hydrogen with an aldehyde R9″CHO in which R9″ is a hydrogen atom or an alkyl group possibly substituted by aryl or arylalkyl.
This reaction is generally carried out in the presence of NaBH4, in an inert solvent such as an aliphatic alcohol and preferably methanol, at a temperature of 0° C.
The compounds containing an OR8 where R8 is alkyl or aryl may be prepared by reacting a corresponding compound having formula (I) containing an OR8 group where R8 is hydrogen with a derivative R12Br in which R12 is an alkyl or arylalkyl group.
This reaction is carried out in a solvent such as DMF using NaH as base at room temperature.
Compounds represented by formula (I) containing a NR9R9′ group in which R9 is hydrogen and R9′ is hydrogen may be prepared by reducing a corresponding compound containing a nitro group.
This reaction is generally carried out by any known method of reducing a nitro group. Preferably hydrogen is used, in the presence of Pd/charcoal, in an inert solvent such as an aliphatic alcohol (methanol for example), at room temperature. However, in the case where a halogen is also present, the reduction of the nitro group to amino is carried out as described in J.O.C., 1985, 50, 26, 5782-5789. THF is generally used with Na2S2O4 at 60° C.
The intermediates containing a nitro group may be obtained by any of the hereinabove methods for preparing compounds represented by formula (I) from nitrated intermediates.
Compounds represented by formula (I) wherein one of the substituents R5, R6, R7 or X is iodine may be prepared by reacting a corresponding compound having formula (I) in which one of the substituents R5, 6, R7 or X is a NR9R9′ group in which R9 is hydrogen and R9′ is hydrogen, with KI.
The reaction is carried out in aqueous medium in the presence of sulfuric acid, sodium nitrite and KI at a temperature ranging from 0° C. and 70° C.
In the hereinabove methods and in the examples, room temperature means a temperature comprised between 15° C. and 25° C.
The synthesis of some compounds represented by formula (I) may require the use of protector groups for certain functions which could interfere with the reaction. Such protector groups are chosen from among groups commonly used in organic synthesis.
For protection of amines, the benzyl, diphenylmethyl or butoxycarbonyl groups may be used for example. For protection of OH, one may use benzyl, tert-butyl or trialkylsilyl groups in particular.
The compounds obtained by the methods described hereinabove are then separated and purified by conventional methods (evaporation, chromatography, distillation, and the like).
The following examples are non-limiting illustrations of the invention. In the examples, the nitrated derivatives are intermediates. FIG. 1 illustrates the activity of the inventive compounds.
To a solution of 2-methoxy-4-bromoaniline (3.2 g, 15.84 mmol) in methanol (5 ml), under an inert atmosphere, add dropwise methyl acetylene dicarboxylate (2.81 g, 19.8 mmol). Heat under reflux for 1 hour, allow to cool and filter the resulting compound. Yield: 93%. 1H-NMR (200 MHz, CDCl3): δ 9.58 (broad s, 1H, NH), 7.01-6.96 (m, 2H arom.), 6.63 (d, 1H, J=9 Hz, 1H arom.), 5.44 (s, 1H vinylic), 3.85 (s, 3H, OCH3), 3.75 (s, 3H, OCH3) 3.74 (s, 3H, OCH3).
To diphenyl ether (10 ml) heated at 250° C., add the intermediate compound methyl-2-[(4-bromo-2-methoxyphenyl)amino]but-2-enedioate 1k (1 g, 2.91 mmol), and allow to react for 5 to 15 minutes. Then add 40 ml of petroleum ether and stir for 2 hours. Filter to obtain the abovenamed product 2k. Yield: 64%. 1H-NMR (200 MHz, CDCl3): δ 9.36 (broad s, 1H, OH), 8.06 (m, 1H arom.), 7.18 (m, 1H arom.), 6.99 (m, 1H arom.), 4.05 (s, 6H, 2 OCH3).
By replacing 2-methoxy-4-bromoaniline in example 1.1 by 2-benzyloxyaniline, the intermediate product methyl-2-[(2-benzyloxyphenyl)amino]-but-2-enedioate 1a is obtained. Yield: 86%. 1H-NMR (200 MHz, CDCl3): δ 9.77 (s, 1H, NH), 7.49-7.29 (m, 5H arom.), 7.05-6.78 (m, 4H arom.), 5.41 (s, 1H vinylic), 5.15 (s, 2H, OCH2), 3.75 (s, 3H, OCH3), 3.68 (s, 3H, OCH3). Then, by replacing intermediate 1k in example 1.2 by the compound methyl-2-[(2-benzyloxyphenyl)amino]-but-2-enedioate 1a (obtained previously), the abovenamed product is obtained. Yield: 58%. 1H-NMR (300 MHz, CDCl3): δ 9.49 (broad s, 1H, OH), 7.91 (d, 1H, J=7 Hz, 1H arom.), 7.43 (m, 5H arom.), 7.26 (m, 1H arom.), 7.16 (d, 1H, J=7 Hz, 1H arom.), 6.99 (s, 1H arom.), 5.30 (s, 2H, OCH2), 4.03 (s, 3H, OCH3).
By replacing 2-methoxy-4-bromoaniline in example 1.1 by 2-benzyloxy-5-bromo-aniline, the intermediate product methyl-2-[(2-benzyloxy-5-bromo-phenyl)amino]-but-2-enedioate 1b is obtained. Yield: 81%. 1H-NMR (300 MHz, CDCl3): δ 9.72 (broad s, 1H, NH), 7.44-7.32 (m, 5H arom.), 7.08 (d, 1H, J=8 Hz, 1H arom.), 6.90 (s, 1H arom.), 6.77 (d, 1H, J=8 Hz, 1H arom.), 5.48 (s, 1H vinylic), 5.11 (s, 2H, CH2), 3.75 (s, 3H, OCH3), 3.73 (s, 3H, OCH3). Then, by replacing intermediate 1k in example 1.2 by the compound methyl-2-[(2-benzyloxy-5-bromo-phenyl)amino]-2-enedioate 1b (obtained previously), the abovenamed product methyl-4-hydroxy-5-bromo-8-benzyloxy-quinoline-2-carboxylate 2b is obtained. Yield: 71%. 1H-NMR (300 MHz, CDCl3): δ 9.37 (broad s, 1H, OH), 7.45 (m, 6H arom.), 6.94 (m, 2H arom.), 5.28 (s, 2H, OCH2), 4.02 (s, 3H, OCH3).
By replacing 2-methoxy-4-bromoaniline in example 1.1 by 2-methoxy-5-bromoaniline, the intermediate product methyl-2-[(2-methoxy-5-bromo-phenyl)amino]-but-2-enedioate 1d is obtained. Yield: 92%. 1H-NMR (200 MHz, CDCl3): δ 9.75 (broad s, 1H, NH), 7.97 (m, 1H arom.), 7.60 (d, 1H, J=2 Hz, 1H arom.), 6.93 (d, 1H, J=8 Hz, 1H arom.), 5.60 (s, 1H, H vinylic), 4.00 (s, 3H, OCH3), 3.78 (s, 3H, OCH3).
Then, by replacing intermediate 1k in example 1.2 by the compound methyl-2-[(2-methoxy-5-bromo-phenyl)amino]-but-2-enedioate 1d (obtained previously), the abovenamed product is obtained. Yield: 92%. 1H-NMR (200 MHz, CDCl3): δ 9.44 (broad s, 1H, OH), 7.34 (d, 1H, J=8 Hz, 1H arom.), 7.02 (m, 2H arom.), 4.12 (s, 3H, OCH3), 4.06 (s, 3H, OCH3).
By replacing 2-methoxy-4-bromoaniline in example 1.1 by 2-methoxy-5-methyl-aniline, the intermediate product methyl-2-[(2-methoxy-5-methyl-phenyl)amino]-but-2-enedioate 1e is obtained. Yield: 82%. 1H-NMR (200 MHz, CDCl3): δ 9.63 (broad s, 1H, NH), 6.85-6.61 (m, 3H arom.), 5.37 (s, 1H vinylic), 3.81 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 2.24 (s, 3H, CH3).
Then, by replacing intermediate 1k in example 1.2 by the compound methyl-2-[(2-methoxy-5-methyl-phenyl)amino]-but-2-enedioate 1e (obtained previously), the abovenamed product is obtained. Yield: 83%. 1H-NMR (200 MHz, CDCl3): δ 9.30 (broad s, 1H, OH), 8.39 (m, 1H arom.), 6.95-6.93 (m, 1H arom.), 6.86 (m, 1H arom.), 4.02 (s, 3H, OCH3), 3.99 (s, 3H, OCH3), 2.82 (s, 3H, CH3).
By replacing 2-methoxy-4-bromoaniline in example 1.1 by 2-methoxy-5-ethanol-aniline, the intermediate product methyl-2-[(2-methoxy-5-ethanol-phenyl)amino]-but-2-enedioate 1f is obtained in the same manner. Yield: 98%. 1H-NMR (200 MHz, CDCl3): δ 9.68 (broad s, 1H, NH), 7.02-6.81 (m, 3H arom), 5.40 (s, 1H vinylic), 4.79 (q, 1H, J=6 Hz, CH), 3.84 (s, 3H, OCH3), 3.75 (s, 6H, 2×OCH3), 1.44 (d, 3H, J=6 Hz, CH3).
Then, by replacing intermediate 1k in example 1.2 by the compound methyl-2-[(2-methoxy-5-ethanol-phenyl)amino]-but-2-enedioate 1f (obtained previously), the abovenamed product is obtained in the same manner. Yield: 20%. 1H-NMR (300 MHz, CDCl3): δ 9.71 (broad s, 1H, OH), 7.29-7.02 (m, 3H arom), 5.21 (q, 1H, J=6 Hz, CH), 4.07 (s, 3H, OCH3), 4.05 (s, 3H, OCH3), 1.60 (d, 3H, J=6 Hz, CH3).
By replacing 2-methoxy-4-bromoaniline in example 1.1 by 2-benzyloxy-5-hydroxymethyl-aniline and proceeding in the same manner, the intermediate product methyl-2-[(2-benzyloxy-5-hydroxymethyl-phenyl)amino]-but-2-enedioate 1g is obtained. Yield: 96%. 1H-NMR (200 MHz, CDCl3): δ 9.76 (broad s, 1H, NH), 7.43-7.34 (m, 5H arom.), 6.95-6.83 (m, 3H arom.), 5.42 (s, 1H vinylic), 5.13 (s, 2H, OCH2), 4.56 (d, 2H, J=6 Hz, CH2), 3.74 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 1.61 (t, 1H, J=6 Hz, OH).
Then, by replacing intermediate 1k in example 1.2 by the compound methyl-2-[(2-benzyloxy-5-hydroxymethyl-phenyl)amino]-but-2-enedioate 1g (obtained previosly), the abovenamed product is obtained in the same manner. Yield: 16%. 1H-NMR (200 MHz, CDCl3): δ 9.71 (broad s, 1H, OH), 7.74 (m, 5H arom.), 7.16-7.06 (m, 3H arom.), 5.31 (s, 2H, OCH2), 4.84 (s, 2H, CH2), 4.05 (s, 3H, OCH3).
By replacing 2-methoxy-4-bromoaniline in example 1.1 by 2-methoxy-3,5-dichloroaniline, the intermediate product methyl-2-[(2-methoxy-3,5-dichloro-phenyl)amino]-but-2-enedioate 1i is obtained. Yield: 64%. 1H-NMR (200 MHz, CDCl3): δ 9.63 (s, 1H, NH), 7.06 (d, 1H, J=2 Hz, 1H arom.), 6.71 (d, 1H, J=2 Hz, 1H arom.), 5.60 (s, 1H vinylic), 3.78 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 3.76 (s, 3H, OCH3).
Then, by replacing intermediate 1k in example 1.2 by the compound methyl-2-[(2-methoxy-3,5-dichloro-phenyl)amino]-but-2-enedioate 1i (obtained previously), the abovenamed product is obtained. Yield: 80%. 1H-NMR (300 MHz, DMSO-d6): δ 7.60 (s, 1H arom.), 6.85 (broad s, 1H arom.), 4.04 (s, 3H, OCH3), 3.95 (s, 3H, OCH3).
By reaplacing 2-methoxy-4-bromoaniline in example 1.1 by 2-benzyloxy-4-bromoaniline, the intermediate product methyl-2-[(2-benzyloxy-4-bromophenyl)amino]-but-2-enedioate 1l is obtained. Yield: 98%. 1H-NMR (200 MHz, CDCl3): δ 9.66 (broad s, 1H, NH), 7.43-7.34 (m, 5H arom.), 7.07 (d, 1H, J=2 Hz, 1H arom.), 7.03-6.98 (dd, 1H, J=2 Hz, J=8 Hz, 1H arom.), 6.65 (d, 1H, J=8 Hz, 1H arom.), 5.45 (s, 1H, H vinylic), 5.11 (s, 2H, OCH2), 3.74 (s, 3H, OCH3), 3.68 (s, 3H, OCH3).
Then, by replacing intermediate 1k in example 1.2 by the compound methyl-2-[(4-bromo-2-benzyloxyphenyl)amino]-but-2-enedioate 1l, the abovenamed product is obtained. Yield: 74%. 1H-NMR (300 MHz, CDCl3): δ 9.37 (broad s, 1H, OH), 8.07 (m, 1H arom.), 7.45 (m, 6H arom.), 6.98 (m, 1H arom.), 5.27 (s, 2H, OCH2), 4.03 (s, 3H, OCH3).
By replacing 2-methoxy-4-bromoaniline in example 1.1 by 2-methoxy-4-methyl-aniline, the intermediate product methyl-2-[(2-methoxy-4-methylphenyl)amino]-but-2-enedioate 1n is obtained. Yield: 53%. 1H-NMR (300 MHz, CDCl3): δ 9.60 (broad s, 1H, NH), 6.68 (m, 3H arom.), 5.34 (s, 1H vinylic), 3.83 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 2.32 (s, 3H, CH3).
Then, by replacing intermediate 1k in example 1.2 by the compound methyl-2-[(2-methoxy-4-methyl phenyl)amino]-but-2-enedioate 1n, the abovenamed product is obtained. Yield: 89%. 1H-NMR (300 MHz, CDCl3): δ 9.38 (broad s, 1H, OH), 7.70 (s, 1H arom.), 6.96-6.92 (m, 2H arom.), 4.03 (s, 3H, OCH3), 4.02 (s, 3H, OCH3), 2.47 (s, 3H, CH3).
By replacing 2-methoxy-4-bromoaniline in example 1.1 by 2-methoxy-4-formyl-aniline, the intermediate product methyl-2-[(2-methoxy-4-formylphenyl)amino]-but-2-enedioate 1o is obtained Yield: 81%. 1H-NMR (200 MHz, CDCl3): δ 9.85 (s, 2H, CHO and NH), 7.41-7.35 (m, 2H arom.), 6.76 (d, 1H, J=8 Hz, 1H arom.), 5.62 (s, 1H vinylic), 3.97 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 3.78 (s, 3H, OCH3).
Then, by replacing intermediate 1k in example 1.2 by the compound methyl-2-[(2-methoxy-4-formylphenyl)amino]-but-2-enedioate 1o, the abovenamed product is obtained. Yield: 96%. 1H-NMR (200 MHz, CDCl3): δ 10.03 (s, 1H, CHO), 9.52 (broad s, 1H, OH), 8.39 (m, 1H arom.), 7.59 (m, 1H arom.), 7.05 (m, 1H arom.), 4.12 (s, 3H, OCH3), 4.07 (s, 3H, OCH3).
By replacing 2-methoxy-4-bromoaniline in example 1.1 by 2-methoxy-4-nitroaniline, the intermediate product methyl-2-[(2-methoxy-4-nitro-phenyl)amino]-but-2-enedioate 1p is obtained. Yield: 78%. 1H-NMR (200 MHz, DMSO-d6): δ 9.91 (s, 1H, NH), 7.92 (m, 2H arom.), 7.02 (d, 1H, J=9 Hz, 1H arom.), 5.70 (s, 1H vinylic), 4.05 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 3.79 (s, 3H, OCH3).
Then, by replacing intermediate 1k in example 1.2 by the compound methyl-2-[(2-methoxy-4-nitro-phenyl)amino]-but-2-enedioate 1p (obtained previously), the abovenamed product is obtained. Yield: 63%. 1H-NMR (200 MHz, DMSO-d6): δ 10.50 (broad s, 1H, OH), 8.46 (d, 1H, J=2 Hz, 1H arom.), 7.96 (d, 1H, J=2 Hz, 1H arom.), 6.89 (broad s, 1H, 1H arom.), 4.16 (s, 3H, OCH3), 3.98 (s, 3H, OCH3).
By replacing 2-methoxy-4-bromoaniline in example 1.1 by 2-nitroaniline, the intermediate product methyl-2-[(2-nitro-phenyl)amino]-but-2-enedioate 1r is obtained. Yield: 34%. 1H-NMR (300 MHz, CDCl3): δ 11.12 (broad s, 1H, NH), 8.13 (d, 1H, J=8 Hz, 1H arom.), 7.46 (m, 1H, 1H arom.), 7.08 (m, 1H, 1H arom.), 6.75 (d, 1H, J=8 Hz, 1H arom.), 5.84 (s, 1H vinylic), 3.81 (s, 3H, OCH3), 3.75 (s, 3H, OCH3).
Then, by replacing intermediate 1k in example 1.2 by the compound methyl-2-[(2-nitro-phenyl)amino]-but-2-enedioate 1r (obtained previously), the abovenamed product is obtained. Yield: 58%. 1H-NMR (300 MHz, CDCl3): δ 11.79 (s, 1H, OH), 8.74 (m, 2H arom.), 7.50 (m, 1H arom.), 7.08 (s, 1H arom.), 4.09 (s, 3H, OCH3).
By replacing 2-methoxy-4-bromoaniline in example 1.1 by 2-nitro-5-methylaniline, the intermediate product methyl-2-[(2-nitro-5-methyl-phenyl)amino]-but-2-enedioate 1s is obtained. Yield: 69%. 1H-NMR (200 MHz, CDCl3): δ 11.13 (broad s, 1H, NH), 8.07 (d, 1H, J=8 Hz, 1H arom.), 6.90 (d, 1H, J=8 Hz, 1H arom.), 6.54 (s, 1H arom.), 5.80 (s, 1H vinylic), 3.88 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 2.30 (s, 3H, CH3).
Then, by replacing intermediate 1k in example 1.2 by the compound methyl-2-[(2-nitro-5-methyl-phenyl)amino]-but-2-enedioate 1s (obtained previously), the abovenamed product is obtained. Yield: 46%. 1H-NMR (200 MHz, CDCl3): δ 12.06 (broad s, 1H, OH), 8.56 (d, 1H, J=9 Hz, 1H arom.), 7.17 (d, 1H, J=9 Hz, 1H arom.), 6.99 (s, 1H arom.), 4.07 (s, 3H, OCH3), 3.00 (s, 3H, CH3).
By replacing 2-methoxy-4-bromoaniline in example 1.1 by 2-nitro-4-methylaniline, the intermediate product methyl-2-[(2-nitro-4-methyl-phenyl)amino]-but-2-enedioate 1t is obtained. Yield: 70%. 1H-NMR (200 MHz, CDCl3): δ 11.02 (broad s, 1H, NH), 7.95 (s, 1H arom.), 7.20 (d, 1H, J=7 Hz, 1H arom.), 6.70 (d, 1H, J=7 Hz, 1H arom.), 5.77 (s, 1H vinylic), 3.81 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 2.37 (s, 3H, CH3).
Then, by replacing intermediate 1k in example 1.2 by the compound methyl-2-[(2-nitro-4-methyl-phenyl)amino]-but-2-enedioate 1s (obtained previously), the abovenamed product is obtained. Yield: 23%. 1H-NMR (200 MHz, CDCl3): δ 11.65 (s, 1H, OH), 8.51 (broad s, 2H arom.), 7.01 (s, 1H arom.), 4.06 (s, 3H, OCH3), 2.53 (s, 3H, CH3).
By replacing 2-methoxy-4-bromoaniline in example 1.1 by 2-bromoaniline, the intermediate product methyl-2-[(2-bromo-phenyl)amino]-but-2-enedioate 1x is obtained. Yield: 43%. 1H-NMR (200 MHz, CDCl3): δ 9.75 (s, 1H, NH), 7.56 (d, 1H, J=8 Hz, 1H arom.), 7.19 (m, 1H arom.), 6.94 (m, 1H arom.), 6.76 (d, 1H, J=8 Hz, 1H arom.), 5.55 (s, 1H vinylic), 3.77 (s, 3H, OCH3), 3.71 (s, 3H, OCH3).
Then, by replacing intermediate 1k in example 1.2 by the compound methyl-2-[(2-bromo-phenyl)amino]-but-2-enedioate 1x (obtained previously), the abovenamed product is obtained. Yield: 94%. 1H-NMR (300 MHz, CDCl3): δ 9.37 (broad s, 1H, OH), 8.31 (d, 1H, J=7 Hz, 1H arom.), 7.90 (d, 1H, J=7 Hz, 1H arom.), 7.27 (m, 1H arom.), 7.00 (s, 1H arom.), 4.08 (s, 3H, OCH3).
By replacing 2-methoxy-4-bromoaniline in example 1.1 by 2-bromo-4-isopropylaniline, the intermediate product methyl-2-[(2-bromo-4-isopropylphenyl)amino]-but-2-enedioate 42a is obtained. Yield: 90%. 1H-NMR (200 MHz, CDCl3): δ 9.70 (s, 1H, NH), 7.43-7.42 (d, 1H, J=1.96 Hz, 1H arom.), 7.07-7.02 (dd, J=8 Hz & J=1.96 Hz, 1H arom.), 6.73-6.69 (d, J=8 Hz, 1H arom.), 5.49 (s, 1H vinylic), 3.76 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 2.95-2.75 (sept, 1H, CH(CH3)2), 1.24 and 1.20 (2s, 6H, CH(CH3)2).
Then, by replacing intermediate 1k in example 1.2 by the compound methyl-2-[(2-bromo-4-isopropylphenyl)amino]-but-2-enedioate 42a (obtained previously), the abovenamed product is obtained. Yield: 71%. 1H-NMR (300 MHz, CDCl3): δ 9.35 (broad s, 1H, OH), 8.16 (d, 1H, J=1.89 Hz, 1H arom.), 7.80 (d, 1H, J=1.86 Hz, 1H arom.), 7.27 (m, 1H arom.), 6.98 (d, J=1.89 Hz, 1H arom.), 4.06 (s, 3H, OCH3), 3.07-2.98 (sept, 1H, CH(CH3)2), 1.32 and 1.3 (2s, 6H, CH(CH3)2).
By replacing 2-methoxy-4-bromoaniline in example 1.1 by 2-benzyloxy-3,5-dichloroaniline, the intermediate product methyl-2-[(2-benzyloxy-3,5-dichlorophenyl)amino]-but-2-enedioate 44a is obtained Yield: 62%. 1H-NMR (300 MHz, CDCl3): δ 9.60 (broad s, 1H, NH), 7.44-7.28 (m, 5H arom.), 7.10 (d, 1H arom.), 6.73 (d, 1H arom.), 5.54 (s, 1H vinylic), 4.93 (s, 2H, OCH2), 3.75 (s, 3H, OCH3), 3.70 (s, 3H, OCH3).
Then, by replacing intermediate 1k in example 1.2 by the compound methyl-2-[(2-benzyloxy-3,5-dichlorophenyl)amino]-but-2-enedioate 44a (obtained previously), the abovenamed product is obtained. Yield: 48%. 1H-NMR (300 MHz, CDCl3): δ 8.98 (broad s, 1H, OH), 7.50-7.36 (m, 5H arom.), 7.34 (s, 1H arom.), 6.80 (d, 1H arom.), 5.23 (s, 2H, OCH2), 3.97 (s, 3H, OCH3).
By replacing 2-methoxybromoaniline in example 1.1 by 3-bromo-2-benzyloxyaniline, methyl-2-[(3-bromo-2-benzyloxyphenyl)amino]but-2-enedioate 50a is obtained as a yellow solid. Yield: 58%. 1H NMR (200 MHz, CDCl3): δ 9.66 (s, 1 HN), 7.53 (m, 2H, 2H arom.), 7.36 (m, 4H, 4H arom.), 6.93 (t, 1H, J=8 Hz, H5), 6.81 (dd, 1H, J=2 and 8 Hz, H arom.), 5.50 (s, 1H vinylic), 4.96 (s, 2H, CH2benz), 3.76 (s, 3H, OCH3), 3.68 (s, 3H, OCH3). By replacing intermediate 1k in example 1.2 by the compound methyl-2-[(3-bromo-2-benzyloxyphenyl)amino]but-2-enedioate 50a, the abovenamed product is obtained as a yellow solid. Yield: 42%. 1H NMR (300 MHz, CDCl3): δ 9.00 (s, 1 HO), 7.96 (d, 1H, J=8 Hz, H6), 7.43 (d, 1H, J=8 Hz, H5), 7.42 (m, 5H, 5H arom.), 6.87 (s, 1H3), 5.24 (s, 2H, CH2benz), 4.10 (s, 3H, OCH3).
By rerplacing 2-methoxy-4-bromoaniline in example 1.1 by 4-bromo-2-cyanoaniline, the intermediate product methyl-2-[(4-bromo-2-cyano-phenyl)amino]-but-2-enedioate 63a is obtained Yield: 80%. 1H-NMR (200 MHz, CDCl3): δ 9.90 (broad s, 1H, NH), 7.70-7.69 (d, 1H, J=2 Hz, 1H arom.), 7.58-7.53 (dd, 1H, J=2 Hz and 9 Hz, 1H arom.), 6.72-6.68 (d, 1H, J=9 Hz, 1H arom.), 5.80 (s, 1H vinylic), 3.79 (s, 3H, OCH3), 3.78 (s, 3H, OCH3).
Then, by replacing intermediate 1k in example 1.2 by the compound methyl-2-[(4-bromo-2-cyano-phenyl)amino]-but-2-enedioate 63a (obtained previously), the abovenamed product is obtained. Yield: 94%. 1H-NMR (200 MHz, CDCl3): δ 12.72 (broad s, 1H, OH), 8.67-8.58 (m, 2H arom.), 7.57 (s, 1H arom.), 3.97 (s, 3H, OCH3).
By replacing 2-methoxybromoaniline in example 1.1 by 5-bromo-2-nitroaniline, methyl-2-[(5-bromo-2-nitrophenyl)amino]but-2-enedioate 72a is obtained as an orange solid. Yield: 33%. 1H NMR (200 MHz, CDCl3): δ 11.13 (s, 1 HN), 8.03 (d, 1H, J=10 Hz, H3), 7.19 (dd, 1H, J=2 and 10 Hz, H4), 6.90 (d, 1H, J=2 Hz, H6), 5.94 (s, 1H vinylic), 3.82 (s, 6H, 2 OCH3).
Then, by replacing intermediate 1k in example 1.2 by the methyl-2-[(4-bromo-2-nitrophenyl)amino]but-2-enedioate 72a, the abovenamed product is obtained as a yellow solid. Yield: 28%. 1H NMR (300 MHz, CDCl3): □ 12.05 (s, 1 HO), 8.45 (d, 1H, J=9 Hz, H7), 7.70 (d, 1H, J=9 Hz, H5), 7.05 (s, 1H3), 4.09 (s, 3H, OCH3).
By replacing 2-methoxybromoaniline in example 1.1 by 4-benzyloxy-2-nitroaniline, methyl-2-[(4-benzyloxy-2-nitrophenyl)amino]but-2-eedioate 79a is obtained as a red solid. Yield: 82%. 1H NMR (300 MHz, CDCl3): δ 10.92 (s, 1 HN), 7.72 (s, 1H3), 7.42 (m, 5H arom.), 7.15 (d, 1H, J=8 Hz, H5), 6.75 (d, 1H, J=8 Hz, H6), 5.75 (s, 1H vinylic), 5.10 (s, 2H benz.), 3.81 (s, 3H, OCH3), 3.74 (s, 3H, OCH3).
Then, by replacing intermediate 1k in example 1.2 by the methyl-2-[(4-benzyloxy-2-nitrophenyl)amino]but-2-enedioate 79a, one obtains, after purification by silica chromatography (eluent: EtOAc/CH2Cl2, 92:8), the abovenamed product is obtained as an orange solid. 1H NMR (300 MHz, CDCl3): δ 11.64 (s, 1 HO), 8.40 (d, 1H, J=3 Hz, H5), 8.29 (d, 1H, J=3 Hz, H7), 7.40 (m, 5H arom.), 7.02 (s, 1H3), 5.24 (s, 2H benz.), 4.09 (s, 3H, OCH3).
By replacing 2-methoxybromoaniline in example 1.1 by 4-chloro-2-nitroaniline, methyl-2-[(4-chloro-2-nitrophenyl)amino]but-2-enedioate 117a is obtained as an orange solid. Yield: 52%. 1H NMR (200 MHz, CDCl3): δ 9.69 (s, 1 HN), 7.43 (d, 1H, J=8 Hz, H5), 7.37 (d, 1H, J=2 Hz, H3), 6.99 (dd, 1H, J=2 and 8 Hz, H5), 5.66 (s, 1H vinylic), 3.80 (s, 3H, OCH3), 3.77 (s, 3H, OCH3).
Then, by replacing intermediate 1k in example 1.2 by the methyl-2-[(4-chloro-2-nitrophenyl)amino]but-2-enedioate 117a, the abovenamed product is obtained as a yellow solid. Yield: 73%. 1H NMR (200 MHz, CDCl3): δ 10.97 (s, 1 HO), 8.44 (d, 1H, J=2 Hz, H7), 8.40 (d, 1H, J=2 Hz, H5), 7.17 (s, 1H3), 4.03 (s, 3H, OCH3).
By replacing 2-methoxybromoaniline in example 1.1 by 4-bromo-2-nitroaniline, methyl-2-[(4-bromo-2-nitrophenyl)amino]but-2-enedioate 31b is obtained as an orange solid. Yield: 49%. 1H NMR (200 MHz, CDCl3): δ 11.07 (s, 1 HN), 8.29 (d, 1H, J=2 Hz, H3), 7.55 (dd, 1H, J=2 and 9 Hz, H5), 6.63 (d, 1H, J=9 Hz, H6), 5.91 (s, 1H vinylic), 3.82 (s, 3H, OCH3), 3.78 (s, 3H, OCH3).
Then, by replacing intermediate 1k in example 1.2 by the methyl-2-[(4-bromo-2-nitrophenyl)amino]but-2-enedioate 31b, the abovenamed product is obtained as a yellow solid. Yield: 31%. 1H NMR (300 MHz, CDCl3): δ 11.67 (s, 1 HO), 8.84 (d, 1H, J=2 Hz, H7), 8.80 (d, 1H, J=2 Hz, H5), 7.07 (s, 1H3), 4.10 (s, 3H, OCH3).
By replacing 2-methoxybromoaniline in example 1.1 by 2-cyanoaniline, methyl-2-[(2-cyanophenyl)amino]but-2-enedioate 35a is obtained as a yellow solid. Yield: 87%. 1H NMR (200 MHz, CDCl3): 9.92 (s, 1 HN), 7.58 (d, 1H, J=7 Hz, H3), 7.45 (t, 1H, J=7 Hz, H 4), 7.13 (t, 1H, J=7 Hz, H5), 6.82 (d, 1H, J=7 Hz, H6), 5.73 (s, 1H vinylic), 3.78 (s, 3H, OCH3), 3.75 (s, 3H, OCH3).
Then, by replacing intermediate 1k in example 1.2 by the methyl-2-[(2-cyanophenyl)amino]but-2-enedioate 35a, the abovenamed product is obtained as a white solid. Yield: 82%. 1H NMR (300 MHz, CDCl3): δ 11.67 (s, 1 HO), 8.84 (d, 1H, J=2 Hz, H7), 8.80 (d, 1H, J=2 Hz, H5), 7.07 (s, 1H3), 4.10 (s, 3H, OCH3).
By replacing 2-methoxybromoaniline in example 1.1 by 2-fluoroaniline, methyl-2-[(2-fluorophenyl)amino]but-2-enedioate 36a is obtained as a yellow solid. Yield: 58%. 1H NMR (300 MHz, CDCl3): δ 9.60 (s, 1 HN), 7.07 (m, 2H, H5 and H3), 6.94 (t, 1H, J=8 Hz, H4), 5.54 (s, 1H vinylic), 3.77 (s, 3H, OCH3), 3.75 (s, 3H, OCH3).
Then, by replacing intermediate 1k in example 1.2 by the methyl-2-[(2-fluorophenyl)amino]but-2-enedioate 36a, the abovenamed product is obtained as a white solid. Yield: 91%. 1H NMR (200 MHz, CDCl3): δ 9.09 (s, 1 HO), 8.10 (d, 1H, J=8 Hz, H7), 7.41 (d, 1H, J=10 Hz, H5), 7.32 (dd, 1H, J=8 and 10 Hz, H6), 6.98 (s, 1H3), 4.06 (s, 3H, OCH3).
By replacing 2-methoxybromoaniline in example 1.1 by anthralinamide, methyl-2-[(2-carboxamidephenyl)amino]but-2-enedioate 37a is obtained as a white solid. Yield: 94. %. 1H NMR (300 MHz, CDCl3): δ 11.00 (s, 1 HN), 7.62 (d, 1H, J=8 Hz, H arom.), 6.36 (t, 1H, J=8 Hz, H arom.), 7.08 (t, 1H, J=8 Hz, H arom.), 6.75 (d, 1H, J=8 Hz, H arom.), 6.09 (m, 2H, CONH2), 5.60 (s, 1H vinylic), 3.80 (s, 3H, OCH3), 3.77 (s, 3H, OCH3).
Then, by replacing intermediate 1k in example 1.2 by the methyl-2-[(2-carboxamidephenyl)amino]but-2-enedioate 37a the abovenamed product is obtained as a brown solid. Yield: 78%. 1H NMR (200 MHz, CDCl3): δ 9.09 (s, 1 HO), 8.10 (d, 1H, J=8 Hz, H7), 7.41 (d, 1H, J=10 Hz, H5), 7.32 (dd, 1H, J=8 and 10 Hz, H6), 6.98 (s, 1H3), 4.06 (s, 3H, OCH3).
By replacing 2-methoxy-4-bromoaniline in example 1.1 by 2-nitro-4-phenylaniline, the intermediate product methyl-2-[(3-nitro-1,1′-biphenyl-4-yl)amino]-but-2-enedioate 86a is obtained. Yield: 83%. 1H-NMR (300 MHz, CDCl3): δ 11.18 (broad s, 1H, NH), 8.39 (s, 1H arom.), 7.72 (d, 1H, J=8 Hz, 1H arom.), 7.60-7.39 (m, 5H arom.), 6.82 (d, 1H, J=8 Hz, 1H arom.), 5.87 (s, 1H vinylic), 3.83 (s, 3H, OCH3), 3.79 (s, 3H, OCH3).
Then, by replacing intermediate 1k in example 1.2 by the compound methyl-2-[(3-nitro-1,1′-biphenyl-4-yl)amino]-but-2-enedioate 86a (obtained previously), the abovenamed product is obtained. Yield: 65%. 1H-NMR (200 MHz, CDCl3): δ 11.76 (broad s, 1H, OH), 8.98 (s, 2H arom.), 7.75-7.46 (m, 5H arom.), 7.09 (s, 1H arom.), 4.10 -(s, 3H, OCH3).
By replacing 2-methoxy-4-bromoaniline in example 1.1 by 2-benzyloxy-5-trifluoromethyl-aniline, the intermediate product methyl-2-[(2-benzyloxy-5-trifluoromethyl-phenyl)amino]-but-2-enedioate 98a is obtained. Yield: 86%. 1H-NMR (300 MHz, CDCl3): δ 9.83 (broad s, 1H, NH), 7.45-7.23 (m, 6H arom.), 6.99-76.95 (m, 2H arom.), 5.53 (s, 1H vinylic), 5.20 (s, 2H, OCH2), 3.76 (s, 3H, OCH3), 3.71 (s, 3H, OCH3).
Then, by replacing intermediate 1k in example 1.2 by the compound methyl-2-[(2-benzyloxy-5-trifluoromethyl-phenyl)amino]-but-2-enedioate 98a (obtained previously), the abovenamed product is obtained. Yield: 58%. 1H-NMR (200 MHz, CDCl3): δ 9.46 (broad s, 1H, OH), 7.67 (d, 1H, J=8 Hz, 1H arom.), 7.47-7.42 (d, 5H arom.), 7.10 (d, 1H, J=8 Hz, 1H arom.), 6.97 (s, 1H arom.), 5.36 (s, 2H, OCH2), 4.03 (s, 3H, OCH3).
By replacing 2-methoxy-4-bromoaniline in example 1.1 by 2-benzyloxy-5-trifluoromethylaniline, the intermediate product methyl-2-[(3-bromo-phenyl)amino]-but-2-enedioate 112a is obtained Yield: 83%. 1H-NMR (200 MHz, CDCl3): δ 9.62 (broad s, 1H, NH), 7.28-7.05 (m, 3H arom.), 6.83-6.78 (m, 1H arom.), 5.48 (s, 1H vinylic), 3.75 (s, 3H, OCH3), 3.74 (s, 3H, OCH3).
Then, by replacing intermediate 1k in example 1.2 by the compound methyl-[(3-bromo-phenyl)amino]-but-2-enedioate 112a (obtained previously), a mixture of the two abovenamed products is obtained. Yield: 92%. The two isomers are separated after benzylation (see example 10, compounds 112c and 112d).
To methyl-4-hydroxy-5-hydroxymethyl-8-benzyloxy-quinoline-2-carboxylate 2g (102 mg, 0.3 mmol) dissolved in degassed acetic acid, ethyl acetate or methanol (15 ml), add palladium/charcoal (10%) (30 mg) then place everything under hydrogen at atmospheric pressure overnight. Filter on celite, wash twice with CH2Cl2/MeOH: 8/2 then evaporate to dryness. Triturate in diethyl ether and filter to obtain the abovenamed product. Yield: 97%. 1H-NMR (200 MHz, DMSO-d6): δ 10.83 (broad s, 1H, OH), 9.43 (broad s, 1H, OH), 7.30-6.90 (m, 2H arom.), 6.51 (s, 1H arom.), 4.89 (s, 1H, OH), 3.97 (s, 3H, OCH3), 2.69 (s, 2H, CH2).
To methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a (0.3 mmol) dissolved in degassed acetic acid, ethyl acetate or methanol (15 ml), add palladium/charcoal (10%) (30 mg) then place everything under hydrogen at atmospheric pressure overnight. Filter on celite, wash twice with CH2Cl2/MeOH: 8/2 then evaporate to dryness. Triturate in diethyl ether and filter to obtain the abovenamed product. Yield: 100%. 1H-NMR (200 MHz, methanol-d4): δ 8.14 (s, 1H arom.), 7.95 (d, 2H, J=9 Hz, 2H arom.), 7.80 (d, 1H, J=8 Hz, 1H arom.), 4.47 (m, 1H arom.), 7.42 (d, 2H, J=9 Hz, 2H arom.), 7.22 (d, 1H, J=8 Hz, 1H arom.), 4.17 (s, 3H, OCH3), 2.46 (s, 3H, CH3).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-4-hydroxy-8-benzyloxy-5-phenyl-quinoline-2-carboxylate 18a and proceeding in the same manner, the abovenamed product is obtained. Yield: 84%. 1H-NMR (200 MHz, CDCl3): δ 9.30 (broad s, 1H, OH), 8.04 (m, 1H arom.), 7.63-7.22 (m, 6H arom.), 6.87 (s, 1H arom.), 4.02 (s, 3H, OCH3).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-4-hydroxy-6-(4-methoxy-phenyl)-8-benzyloxy-quinoline-2-carboxylate 18g and proceeding in the same manner, the abovenamed product is obtained. Yield: 95%. 1H-NMR (200 MHz, methanol-d4): δ 7.93 (m, 1H arom.), 7.65 (m, 1H arom.), 7.60 (m, 1H arom.), 7.40 (m, 1H arom.), 7.02-6.98 (m, 3H arom.), 4.07 (s, 3H, OCH3), 3.87 (s, 3H, OCH3).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-4-hydroxy-6-(3-methyl-phenyl)-8-benzyloxy-quinoline-2-carboxylate 18i and proceeding in the same manner, the abovenamed product is obtained. Yield: 51%. 1H-NMR (300 MHz, methanol-d4): δ 7.90 (m, 1H arom.), 7.54 (m, 2H arom.), 7.39 (m, 2H arom.), 7.23 (m, 1H arom.), 7.02 (m, 1H arom.), 4.10 (s, 3H, OCH3), 2.45 (s, 3H, CH3).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-8-benzyloxy-4-hydroxy-6-(pyridin-3-yl)-quinoline-2-carboxylate 18o and proceeding in the same manner, the abovenamed product is obtained. Yield: 60%. 1H-NMR (300 MHz, CDCl3): δ 9.35 (s, 1H arom.), 8.95 (m, 2H arom.), 8.17-7.96 (m, 2H arom.), 7.69 (m, 1H arom.), 7.18 (m, 1H arom.), 4.10 (s, 3H, OCH3).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-8-benzyloxy-6-benzyl-4-hydroxy-quinoline-2-carboxylate 23a and proceeding in the same manner, the abovenamed product is obtained. Yield: 95%. 1H-NMR (300 MHz, methanol-d4): δ 7.69-6.94 (m, 8H arom.), 4.09 (s, 3H, OCH3), 4.07 (s, 2H, CH2).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by ethyl-8-(benzyloxy)-3-oxo-3,4-dihydroquinoxaline-2-carboxylate 59a and proceeding in the same manner, the abovenamed product is obtained. Yield: 97%. 1H-NMR (300 MHz, methanol-d4): δ 6.63-6.58 (t, 1H, J=8 Hz, 1H arom.), 6.52-6.49 (d, 1H, J=8 Hz, 1H arom.), 6.39-6.37 (d, 1H, J=8 Hz, 1H arom.), 4.21-4.14 (q, 2H, J=7 Hz, OCH2—CH3), 1.24-1.20 (q, 3H, J=7 Hz, OCH2—CH3).
By replacing methyl-8-benzyloxy-4-(tolueene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by ethyl[8-(benzyloxy)-3-oxo-3,4-dihydroquinoxaline-2(1H)-ylilene]acetate 60a and proceeding in the same manner, the abovenamed product is obtained. Yield: 62%. 1H-NMR (200 MHz, DMSO-d6): δ 10.25 (s, 1H, OH), 9.52 (broad s, 1H, NHCO), 6.55-6.28 (m, 3H arom.), 5.18 (s, 1H, C═CH), 4.13-4.03 (q, 2H, J=7 Hz, OCH2—CH3), 1.23-1.16 (t, 3H, J=7 Hz, OCH2CH3).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by 3-ethynyl-8-nitro-4-hydroxy-quinoline-2-carboxylic acid 57b, the abovenamed product is obtained. Yield: 86%. 1H NMR (300 MHz, d6-DMSO): δ 12.02 (s, 1H, OH), 9.64 (s, 1H, OH), 8.01 (d, 1H, J=8 Hz, H arom.), 7.43 (t, 1H, J=8 Hz, 1H6), 7.34 (d, 1H, J=8 Hz, H arom.), 3.64 (s, 2H, NH2), 2.24 (dd, 2H, J=8 and 10 Hz, CH2), 1.34 (dd, 3H, J=8 and 10 Hz, CH3).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-3-phenylethynyl-8-nitro-4-hydroxy-quinoline-2-carboxylate 68a, the abovenamed product is obtained. Yield: 85%. 1H NMR (300 MHz, CDCl3): δ 9.16 (s, 1H, OH), 7.96 (d, 1H, J=8 Hz, H arom.), 7.18 (m, 7H, 7H arom.), 3.99 (s, 3H, OCH3), 3.59 (s, 2H, NH2), 3.34 (dd, 2H, J=8 and 10 Hz, CH2), 2.84 (dd, 2H, J=8 and 10 Hz, CH2).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by benzyl-3-(3′-N-(terbutoxycarbonyl)aminoprop-1′-ynyl)-8-nitro-4-hydroxy-quinoline-2-carboxylate 70b, the abovenamed product is obtained. Yield: 70%. 1H NMR (300 MHz, d6-DMSO): δ 12.14 (s, 1H, OH), 9.42 (s, 1H, OH), 7.38 (t, 1H, J=8 Hz, H6), 7.24 (d, 1H, J=8 Hz, 1H arom), 6.80 (d, 1H, J=8 Hz, 1H arom.), 5.24 (s, 2 HN), 3.52 (s, 1H, OH), 3.22 (m, 2H, CH2O), 3.35 (m, 3H, CH2), 2.41 (m, 2H, CH2), 1.80 (m, 2H, CH2).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by benzyl-3-(3′-N-(terbutoxycarbonyl)aminoprop-1′-ynyl)-8-nitro-4-hydroxy-quinoline-2-carboxylate 71b, the abovenamed product is obtained. Yield: 70%. 1H NMR (300 MHz, d6-DMSO): δ 7.50 (t, 1H, J=8 Hz, H 6), 7.24 (m, 2H, 1 OH and 1H arom), 6.86 (d, 1H, J=9 Hz, 1H arom.), 6.64 (s, 2 HN), 4.41 (m, 2H, CH2N), 3.35 (m, 3H, CH2 and HN), 1.35 (m, 2H, CH2), 1.66 (s, 9H, 3 CH3).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-5-phenyl-8-nitro-4-benzyloxy-quinoline-2-carboxylate 73a, the abovenamed product is obtained. Yield: 94%. 1H NMR (300 MHz, CDCl3): δ 10.45 (s, 1H, OH), 7.21 (m, 6H, 6H arom.), 7.12 (d, 1H, J=8 Hz, H arom.), 6.88 (d, 1H, J=8 Hz, H arom.), 4.96 (s, 2H, NH2), 3.98 (s, 3H, OCH3).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-5-phenylethynyl-8-nitro-4-benzyloxy-quinoline-2-carboxylate 74a, the abovenamed product is obtained. Yield: 76%. 1H NMR (300 MHz, CDCl3): δ 9.15 (s, 1H, OH), 7.18 (m, 7H, 7H arom.), 6.88 (d, 1H, J=8 Hz, H arom.), 4.04 (s, 3H, OCH3), 3.96 (s, 2H, NH2), 3.54 (t, 2H, J=9 Hz, CH2), 2.95 (t, 2H, J=9 Hz, CH2).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-5-(3′-benzyloxyprop-1′-ynyl)-8-nitro-4-benzyloxy-quinoline-2-carboxylate 75a, the abovenamed product is obtained. Yield: 64%. 1H NMR (200 MHz, CDCl3): δ 10.54 (s, 1H, OH), 7.32 (d, 1H, J=8 Hz, H arom.), 6.90 (d, 1H, J=8 Hz, H arom.), 6.88 (s, 1H, H3), 5.42 (s, 2H, NH2), 4.00 (s, 3H, OCH3), 3.86 (s, 1H, OH), 3.44 (m, 2H, CH2O), 2.71 (m, 4H, 2 CH2), 1.80 (m, 2H, CH2).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-5-(3′-N-(terbutoxycarbonyl)aminoprop-1′-ynyl)-8-nitro-4-benzyloxy-quinoline-2-carboxylate 76a, the abovenamed product is obtained. Yield: 79%. 1H NMR (300 MHz, CDCl3): δ 9.34 (s, 1H, OH), 7.40 (d, 1H, J=8 Hz, H arom.), 6.96 (d, 1H, J=8 Hz, H arom.), 6.90 (s, 1H, H3), 5.33 (s, 1H, NH), 4.06 (s, 3H, OCH3), 3.47 (s, 2H, NH2), 3.30 (m, 4H, 2 CH2), 1.82 (m, 2H, CH2).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-5-piperidin-1-yl-8-nitro-4-benzyloxy-quinoline-2-carboxylate 77a, the abovenamed product is obtained as a yellow solid. Yield: 82%. 1H NMR (200 MHz, CDCl3): δ 7.42 (s, 1H3), 7.22 (d, 1H, J=8 Hz, H arom.), 6.84 (d, 1H, J=8 Hz, H arom.), 5.09 (s, 2 HN), 4.00 (s, 3H, OCH3), 3.17 (m, 2H, NCH2), 2.88 (m, 2H, NCH2), 1.85 (m, 6H, 3 CH2).
By replacing methyl-4-hydroxy-5-hydroxymethyl-8-benzyloxy-quinoline-2-carboxylate 2g in example 2 by methyl-5-(N-(N-benzyl)piperazinyl)-8-nitro-4-benzyloxy-quinoline-2-carboxylate 78a, the abovenamed product is obtained as an orange solid. Yield: 61%. 1H NMR (200 MHz, d6-DMSO): δ 10.82 (s, 1H, OH), 7.40 (s, 1H3), 7.12 (d, 1H, J=8 Hz, H arom.), 6.92 (d, 1H, J=8 Hz, H arom.), 5.50 (s, 2H, H2N), 5.02 (s, 1H, NH), 3.99 (s, 3H, OCH3), 3.10 (m, 2H, NCH2), 2.98 (m, 2H, NCH2), 2.70 (m, 6H, 3 CH2), 2.51 (m, 2H, CH2).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-6-benzyloxy-8-nitro-4-hydroxy-quinoline-2-carboxylate 79b, the abovenamed product is obtained. Yield: 85%. 1H NMR (200 MHz, d6-DMSO): δ 11.10 (s, 1 OH), 9.66 (s, 1 OH), 7.33 (s, 1H3), 6.51 (d, 1H, J=2 Hz, H5), 6.44 (d, 1H, J=2 Hz, H7), 5.90 (s, 2 HN.), 3.86 (s, 3H, OCH3).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-6-phenylethynyl-8-nitro-4-benzyloxy-quinoline-2-carboxylate 118a, the abovenamed product is obtained. Yield: 92%. 1H NMR (300 MHz, CDCl3): δ 11.43 (s, 1H, OH), 7.43 (s, 1H, H arom.), 7.24 (m, 5H, 5H arom.), 7.15 (s, 1H, H arom.), 5.89 (s, 2H, NH2), 3.93 (s, 3H, OCH3), 2.95 (m, 4H, 2 CH2).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-6-(3′-benzyloxypropyn-1′-yl)-8-nitro-4-benzyloxy-quinoline-2-carboxylate 119a, the abovenamed product is obtained. Yield: 78%. 1H NMR (300 MHz, d6-DMSO): δ 11.51 (s, 1 HO), 7.40 (s, 1H3), 7.09 (d, 1H, J=2 Hz, 1H arom.), 6.77 (d, 1H, J=2 Hz, 1H arom.), 5.86 (s, 2 HN), 4.48 (s, 1 HO), 3.94 (s, 3H, OCH3), 3.42 (m, 2H, CH2O), 2.73 (m, 2H, CH2), 1.78 (m, 2H, CH2).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-6-(3′-N-(terbutoxycarbonyl)aminoprop-1′-ynyl)-8-nitro-4-benzyloxy-quinoline-2-carboxylate 121a, the abovenamed product is obtained. Yield: 73%. 1H NMR (300 MHz, DMSO-d6): δ 9.22 (s, 1 HO), 7.70 (s, 1H3), 6.97 (m, 2H arom), 4.64 (s, 2 HN), 4.02 (s, 3H, OCH3), 3.75 (s, 1 HN), 3.15 (m, 2H, CH2N), 2.70 (m, 2H, CH2), 1.84 (m, 2H, CH2), 1.66 (s, 9H, 3 CH3).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-6-(3′-pyridinylethynyl)-8-nitro-4-benzyloxy-quinoline-2-carboxylate 122a, the abovenamed product is obtained as a yellow solid. Yield: 82%. 1H NMR (200 MHz, d6-DMSO): δ 8.45 (s, 1H, H arom.), 8.40 (d, 1H, J=2 Hz, H arom.), 7.69 (d, 1H, J=5 Hz, 1H arom.), 7.34 (m, 2H, 2H arom.), 7.13 (s, 1H, 1H arom.), 6.83 (s, 1H, 1H arom.), 5.90 (s, 2 HN), 3.92 (s, 3H, OCH3), 2.97 (m, 4H, 2 CH2).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-6-(5′-cyanopent-1′-ynyl)-8-nitro-4-benzyloxy-quinoline-2-carboxylate 123a, the abovenamed product is obtained as a yellow solid. Yield: 78%. 1H NMR (200 MHz, d6-DMSO): δ 11.42 (s, 1H, OH), 7.43 (s, 1H arom.), 7.11 (s, 1H arom.), 6.79 (s, 1H arom.), 5.48 (s, H2N), 3.92 (s, 3H, OCH3), 2.65 (t, 4H, J=7 Hz, 2 CH2), 1.62 (m, 4H, 2 CH2), 1.43 (m, 2H, CH2).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-6-cyano-8-nitro-4-benzyloxy-quinoline-2-carboxylate 120a, the abovenamed product is obtained as an orange solid. Yield: 41%. 1H NMR (200 MHz, d6-DMSO): δ 12.13 (s, 1H, OH), 7.64 (s, 1H, H arom.), 7.65 (s, 1H3), 7.05 (s, 1H, H arom.), 3.95 (s, 3H, OCH3).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by 6-N-(N-methylpiperazinyl)-8-nitro-4-benzyloxy-quinoline-2-carboxylic acid hydrochloride 124a, the abovenamed product is obtained as a yellow solid. Yield: 88%. 1H NMR (200 MHz, d6-DMSO): δ 12.12 (s, 1H, OH), 11.13 (s, 1H, OH), 7.28 (s, 1H3), 6.62 (s, 1H, H arom.), 6.59 (s, 1H, H arom.), 6.29 (s, 2H, H2N), 3.42 (m, 5H, 1H and 2 NCH2), 3.30 (s, 4H, 2 CH2), 2.65 (m, 3H, CH3).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-6-(piperidin-1-yl)-8-nitro-4-benzyloxy-quinoline-2-carboxylate 125a, the abovenamed product is obtained as a yellow solid. Yield: 82%. 1H NMR (200 MHz, d6-DMSO): δ 11.02 (s, 1H, OH), 7.35 (s, 1H3), 6.71 (d, 1H, J=2 Hz, H arom.), 6.57 (d, 1H, J=2 Hz, H arom.), 6.57 (s, 2 HN), 3.91 (s, 3H, OCH3), 3.28 (m, 4H, 2 NCH2), 1.66 (m, 6H, 3 CH2).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-6-(4-benzyl-piperazin-1-yl)-8-nitro-4-benzyloxy-quinoline-2-carboxylate 126a, the abovenamed product is obtained as an orange solid. Yield: 58%. 1H NMR (200 MHz, d6-DMSO): δ 11.32 (s, 1H, OH), 7.30 (s, 1H3), 6.88 (d, 1H, J=2 Hz, H arom.), 6.62 (d, 1H, J=2 Hz, H arom.), 6.50 (s, 2H, H2N), 5.32 (s, 1H, NH), 3.96 (s, 3H, OCH3), 3.00 (m, 4H, 2 NCH2), 2.60 (m, 6H, 3 CH2).
By replacing methyl-4-hydroxy-5-hydroxymethyl-8-benzyloxy-quinoline-2-carboxylate 2g in example 2 by methyl-6-amino-8-nitro-4-benzyloxy-quinoline-2-carboxylate 32b, the abovenamed product is obtained as a yellow solid. Yield: 87%. 1H NMR (200 MHz, d6-DMSO): δ 11.82 (s, 1H, OH), 7.13 (s, 1H3), 7.03 (d, 1H, J=2 Hz, H arom.), 6.90 (d, 1H, J=2 Hz, H arom.), 5.20 (s, 2H, H2N), 5.00 (s, 2H, NH2), 3.99 (s, 3H, OCH3).
By replacing methyl-4-hydroxy-5-hydroxymethyl-8-benzyloxy-quinoline-2-carboxylate 2g in example 2 by methyl-6-(1-anilino)-8-nitro-4-benzyloxy-quinoline-2-carboxylate 33a, the abovenamed product is obtained as an orange solid. Yield: 81%. 1H NMR (200 MHz, CDCl3): δ 9.51 (s, 1H, OH), 7.48 (m, 2H, 2H arom.), 7.68 (s, 1H3), 7.40 (m, 3H, 3H arom.), 7.20 (m, 2H, 2H arom.), 5.74 (s, 1H, 1NH), 5.40 (s, 2H, NH2), 4.01 (s, 3H, OCH3).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-6-(N-piperidinyl)-8-nitro-4-benzyloxy-quinoline-2-carboxylate 34c, the abovenamed product is obtained as a yellow solid. Yield: 32%. 1H NMR (300 MHz, d6-DMSO): δ 10.26 (s, 1H, OH), 7.42 (m, 6H, 6H arom.), 6.98 (d, 1H, J=2 Hz, H arom.), 6.48 (s, 1H3), 5.32 (s, 2 HN).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-4-(N-methylamino)-8-amino-quinoline-2-carboxylate 38c, the abovenamed product is obtained as a yellow solid. Yield: 82%. 1H NMR (300 MHz, d6-DMSO): δ 9.46 (s, 1H, OH), 7.82 (d, 1H, J=8 Hz, 1H arom.), 7.49 (t, 1H, J=8 Hz, 1H6), 7.28 (d, 1H, J=8 Hz, H arom.), 7.15 (s, 1H3), 3.15 (s, 3 HN).
By replacing methyl-4-hydroxy-5-hydroxymethyl-8-benzyloxy-quinoline-2-carboxylate 2g in example 2 by 3-(N-morpholinomethyl)-8-benzyloxy-4-hydroxy-quinoline-2-carboxylic acid 39a, the abovenamed product is obtained as a beige solid. Yield: 30%. 1H NMR (200 MHz, d6-DMSO): δ 12.05 (s, 1H, OH), 11.03 (s, 1H, OH), 10.30 (s, 1H, OH), 7.55 (d, 1H, J=8 Hz, 1H arom.), 7.20 (m, 2H, 2H arom.), 4.51 (s, 2H, CH2N), 3.75 (m, 8H, 4 CH2).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by 3-(N-pyrrolidinomethyl)-8-benzyloxy-4-hydroxy-quinoline-2-carboxylic acid 40a, the abovenamed product is obtained as a beige solid. Yield: 30%. 1H NMR (200 MHz, d6-DMSO): δ 11.00 (s, 1H, OH), 10.69 (s, 1H, OH), 10.37 (s, 1H, OH), 7.56 (dd, 1H, J=2 and 8 Hz, 1H arom.), 7.16 (m, 2H, 2H arom.), 4.57 (s, 2H, CH2N), 3.37 (m, 4H, 2 CH2), 1.88 (m, 4H, 2 CH2).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-8-dimethylamino-4-benzyloxy-quinoline-2-carboxylate 41a, the abovenamed product is obtained as a yellow solid. Yield: 74%. 1H NMR (300 MHz, CDCl3): δ 9.77 (s, 1H, OH), 8.05 (dd, 1H, J=2 and 8 Hz, 1H arom.), 7.45 (dd, 1H, J=2 and 8 Hz, H arom.), 7.31 (t, 1H, J=8 Hz, 1H6), 6.96 (s, 1H3), 4.03 (s, 3H, OCH3), 2.78 (s, 6H, 2 NCH3).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-4-hydroxy-8-nitro-6-phenyl-quinoline-2-carboxylate 86b and proceeding in the same manner, the abovenamed product is obtained. Yield: 98%. 1H-NMR (200 MHz, CDCl3): δ 11.44 (broad s, 1H, OH), 7.73-7.40 (m, 7H arom.), 7.23 (s, 1H arom.), 6.07 (broad s, 2H, NH2), 3.95 (s, 3H, OCH3).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-8-benzyloxy-4-(4-benzyl-piperazin-1-yl)-quinoline-2-carboxylate 87a and proceeding in the same manner, the abovenamed product is obtained. Yield: 93%. 1H-NMR (200 MHz, CDCl3): δ 7.51-7.48 (m, 3H arom.), 7.17-7.12 (m, 1H arom.), 3.95 (s, 3H, OCH3), 3.29 (broad s, 2H, NH2), 3.28-3.25 (m, 4H, CH2—N—CH2), 3.15-3.13 (m, 4H, CH2—N—CH2).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-8-nitro-4-phenyl-quinoline-2-carboxylate 92b and proceeding in the same manner, the abovenamed product is obtained. Yield: 93%. 1H-NMR (200 MHz, CDCl3): δ 8.07 (s, 1H arom.), 7.53-7.21 (m, 7H arom.), 6.92 (d, 1H, J=8 Hz, 1H arom.), 4.05 (s, 3H, OCH3).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-8-amino-4-(hex-1-ynyl)-quinoline-2-carboxylate 93a and proceeding in the same manner, the abovenamed product is obtained. Yield: 93%. 1H-NMR (200 MHz, CDCl3): δ 7.97(s, 1H arom.), 7.45-7.32 (m, 2H arom.), 6.92 (d, 1H, J=8 Hz, 1H arom.), 5.20 (broad s, 2H, NH2), 4.03 (s, 3H, OCH3), 3.05 (t, 2H, J=7 Hz, CH2), 1.77-1.74 (m, 2H, CH2), 1.36-1.31(m, 6H, 3×CH2), 0.90 (t, 3H, J=7 Hz, CH3).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-8-amino-4-phenylethynyl-quinoline-2-carboxylate 94a and proceeding in the same manner, the abovenamed product is obtained. Yield: 90%. 1H-NMR (300 MHz, CDCl3): δ 7.97 (s, 1H arom.), 7.45-7.22 (m, 7H arom.), 6.94 (d, 1H, J=8 Hz, 1H arom.), 5.19 (broad s, 2H, NH2), 4.03 (s, 3H, OCH3), 3.41-3.36 (m, 2H, CH2), 3.33-3.04 (m, 2H, CH2).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-8-nitro-4-(3-tert-butoxycarbonylamino-prop-1-ynyl)-quinoline-2-carboxylate 95a and proceeding in the same manner, the abovenamed product is obtained. Yield: 79%. 1H-NMR (300 MHz, CDCl3): δ 7.97 (s, 1H arom.), 7.43-7.27 (m, 2H arom.), 6.93 (d, 1H, J=8 Hz, 1H arom.), 5.30 (broad s, 1H, NH), 4.03 (s, 3H, OCH3), 3.27-3.24 (m, 2H, CH2), 3.09 (t, 2H, J=6 Hz, CH2), 2.01-1.95 (m, 2H, CH2), 1.46 (s, 9H, (CH3)3).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-4-(3-benzyloxy-prop-1-ynyl)-8-nitro-quinoline-2-carboxylate 96a and proceeding in the same manner, the abovenamed product is obtained. Yield: 48%. 1H-NMR (200 MHz, CDCl3): δ 8.01(s, 1H arom.), 7.43-7.27 (m, 2H arom.), 6.93 (d, 1H, J=8 Hz, 1H arom.), 5.18 (broad s, 2H, NH2), 4.03 (s, 3H, OCH3), 3.81-3.76 (m, 2H, CH2), 3.19 (t, 2H, J=6 Hz, CH2), 2.08-2.01 (m, 2H, CH2).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-4-(3-acetyl-aminoprop-1-ynyl)-8-nitro-quinoline-2-carboxylate 97a and proceeding in the same manner, the abovenamed product is obtained. Yield: 54%. 1H-NMR (200 MHz, CDCl3): δ 7.97(s, 1H arom.), 7.45-7.27 (m, 2H arom.), 6.95 (d, 1H, J=8 Hz, 1H arom.), 6.67 (s, 1H, NH), 5.25 (broad s, 2H, NH2), 4.38 (s, 2H, NCH2), 4.03 (s, 3H, OCH3), 2.41 (s, 3H, COCH3).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-8-benzyloxy-4-(morpholin-1-yl)-quinoline-2-carboxylate 99a and proceeding in the same manner, the abovenamed product is obtained. Yield: 92%. 1H-NMR (300 MHz, CDCl3): δ 7.64 (s, 1H arom.), 7.47 (m, 2H arom.), 7.18 (s, 1H arom.), 4.04 (s, 3H, OCH3), 4.01-3.99 (m, 4H, CH2—O—CH2), 3.34-3.31 (m, 4H, CH2—N—CH2).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-8-benzyloxy-4-(piperidin-1-yl)-quinoline-2-carboxylate 100a and proceeding in the same manner, the abovenamed product is obtained. Yield: 89%. 1H-NMR (200 MHz, CDCl3): δ 7.57 (s, 1H arom.), 7.45-7.42 (m, 2H arom.), 7.23 (m, 1H arom.), 4.04 (s, 3H, OCH3), 3.36-3.31 (m, 4H, CH2—N—CH2), 1.86-1.71 (m, 6H, 3×CH2).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-8-nitro-4-(pipeeridin-1-yl)-quinoline-2-carboxylate 101a and proceeding in the same manner, the abovenamed product is obtained. Yield: 77%. 1H-NMR (200 MHz, CDCl3): δ 7.59 (s, 1H arom.), 7.33-7.27 (s, 1H arom.), 6.88 (d, 1H, J=8 Hz, 1H arom.), 5.13 (broad s, 2H, NH2), 4.02 (s, 3H, OCH3), 3.25-3.21 (m, 4H, CH2—N—CH2), 1.90-1.68 (m, 6H, 3×CH2).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-4-benzyloxy-8-(4-benzyl-piperazin-1-yl)-quinoline-2-carboxylate 105a and proceeding in the same manner, the abovenamed product is obtained. Yield: 95%. 1H-NMR (200 MHz, CDCl3): δ 9.30 (broad s, 1H, OH), 7.84-7.81 (m, 1H arom.), 7.50-7.42 (m, 2H arom.), 6.99 (broad s, 1H arom.), 3.95 (s, 3H, OCH3), 3.32-3.25 (m, 8H, 4×CH2).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-8-benzyloxy-4-(4-methyl-piperazin-1-yl)-quinoline-2-carboxylate 110a and proceeding in the same manner, the abovenamed product is obtained. Yield: 81%. 1H-NMR (200 MHz, CDCl3): δ 9.65 (broad s, 1H, OH), 7.55-7.44 (m, 3H arom.), 7.16-7.12 (m, 1H arom.), 4.03 (s, 3H, OCH3), 3.29-3.25 (m, 4H, CH2—N—CH2), 2.67-2.63 (m, 4H, CH2—N—CH2), 2.31 (s, 3H, NCH3).
By replacing methyl-8-benzyloxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15a in example 2 by methyl-7-acetylamino-4-benzyloxy-quinoline-2-carboxylate 116a and proceeding in the same manner, the abovenamed product is obtained. Yield: 82%. 1H-NMR (200 MHz, CDCl3): δ 12.06 (broad s, 1H, OH), 10.36 (broad s, 1H, NH), 8.46 (s, 1H arom.), 8.02 (d, 1H, J=8 Hz, 1H arom.), 7.34 (d, 1H, J=8 Hz, 1H arom.), 6.60 (s, 1H arom.), 3.96 (s, 3H, OCH3), 2.14 (s, 3H, COCH3).
Dissolve 172 mg (0.443 mmol) of methyl-4-hydroxy-5-bromo-8-benzyloxy-quinoline-2-carboxylate 2b in 3 ml of dichloromethane and add 0.18 ml (1.33 mmol) of dimethylaniline. Add 239 mg (1.79 mmol) of aluminium chloride powder and stir at room temperature for 1 to 2 hours. Evaporate to dryness, add 15 ml of 1 N hydrochloric acid and triturate. Filter the precipitate, triturate in 15 ml of diethyl ether and filter. One obtains 110 mg (0.37 mmol) of the abovenamed product. Yield: 84%. 1H-NMR (300 MHz, DMSO-d6): δ 11.44 (broad s, 1H, OH), 9.59 (broad s, 1H, OH), 7.40 (m, 1H arom.), 7.04 (m, 1H arom.), 6.56 (m, 1H arom.), 3.96 (s, 3H, OCH3).
By replacing methyl-4-hydroxy-5-bromo-8-benzyloxy-quinoline-2-carboxylate 2b in example 3 by methyl-4-hydroxy-6-bromo-8-benzyloxyquinoline-2-carboxylate 2l and proceeding in the same manner, the abovenamed product is obtained. Yield: 93%. 1H-NMR (300 MHz, DMSO-d6): δ 7.67 (s, 1H arom.), 7.27 (s, 1H arom.), 7.00 (broad s, 1H arom.).
By replacing methyl-4-hydroxy-5-bromo-8-benzyloxy-quinoline-2-carboxylate 2b in example 3 by methyl-4-hydroxy-6-(4-chloro-phenyl)-8-benzyloxy-quinoline-2-carboxylate 18k and proceeding in the same manner, the abovenamed product is obtained. Yield: 80%. 1H-NMR (200 MHz, methanol-d4): δ 8.04 (m, 1H arom.), 7.75-7.51 (m, 6H arom.), 4.15 (s, 3H, OCH3).
By replacing methyl-4-hydroxy-5-bromo-8-benzyloxy-quinoline-2-carboxylate 2b in example 3 by methyl-4-hydroxy-6-(3,4-dichloro-phenyl)-8-benzyloxy-quinoline-2-carboxylate 18m and proceeding in the same manner, the abovenamed product is obtained. Yield: 91%. 1H-NMR (200 MHz, DMSO-d6): δ 7.97 (s, 1H arom.), 7.82 (m, 1H arom.), 7.74 (m, 2H arom.), 7.47 (m, 1H arom.), 7.06 (m, 1H arom.), 4.14 (s, 3H, OCH3).
By replacing methyl-4-hydroxy-5-bromo-8-benzyloxy-quinoline-2-carboxylate 2b in example 3 by benzyl-8-benzyloxy-5-bromo-quinoline-2-carboxylate 5b and proceeding in the same manner, the abovenamed product is obtained. Yield: 93%. 1H-NMR (300 MHz, DMSO-d6): δ 13.04 (broad s, 1H, COOH), 10.52 (broad s, 1H, OH), 8.62 (d, 1H, J=9 Hz, 1H arom.), 8.28 (d, 1H, J=9 Hz, 1H arom.), 7.97(d, 1H, J=8 Hz, 1H arom.), 7.19 (d, 1H, J=8 Hz, 1H arom.).
By replacing methyl-4-hydroxy-5-bromo-8-benzyloxy-quinoline-2-carboxylate 2b in example 3 by methyl-8-benzyloxy-5,7-dichloro-4-hydroxyquinoline-2-carboxylate 44b and proceeding in the same manner, the abovenamed product is obtained. Yield: 88%. 1H-NMR (200 MHz, DMSO-D6): δ 7.57 (m, 1H arom.), 7.29 (m, 1H arom.), 3.96 (s, 3H, OCH3).
By replacing methyl-4-hydroxy-5-bromo-8-benzyloxy-quinoline-2-carboxylate 2b in example 3 by methyl-8-benzyloxy-3-bromo-4-hydroxyquinoline-2-carboxylate 52a and proceeding in the same manner, the abovenamed product is obtained. Yield: 80%. 1H-NMR (300 MHz, DMSO-D6): δ 11.07 (broad s, 2H, 2 OH), 7.60-7.57 (dd, J=1 Hz and J=8 Hz, 1H arom.), 7.29-7.24 (t, J=7.8 Hz, 1H arom.), 7.20-7.17 (dd, J=1 Hz and J=8 Hz, 1H arom.), 3.93 (s, 3H, OCH3).
By replacing methyl-4-hydroxy-5-bromo-8-benzyloxy-quinoline-2-carboxylate 2b in example 3 by methyl-8-benzyloxy-3,7-dibromo-4-hydroxyquinoline-2-carboxylate 56a and proceeding in the same manner, the abovenamed product is obtained. Yield: 85%. 1H-NMR (300 MHz, DMSO-D6): δ 12.40 (broad s, 1H, OH), 10.67 (broad s, 1H, OH), 7.60-7.52 (m, 2H arom.), 3.94 (s, 3H, OCH3).
By replacing methyl-4-hydroxy-5-bromo-8-benzyloxy-quinoline-2-carboxylate 2b in example 3 by methyl-8-benzyloxy-4-(3-benzoyl-aminoprop-1-yl)-quinoline-2-carboxylate 85c and proceeding in the same manner, the abovenamed product is obtained. Yield: 85%. 1H-NMR (200 MHz, CDCl3): 8.49 (s, 1H, OH.), 8.06 (s, 1H arom.), 7.76-7.20 (m, 8H arom.), 6.21 (broad s, 1H, NH), 4.05 (s, 3H, OCH3), 3.67-3.57 (m, 2H, CH2), 3.23 (t, 2H, J=7.8 Hz, CH2), 2.19-2.12 (m, 2H, CH2).
Dissolve methyl-4-hydroxy-8-nitro-quinoline-2-carboxylate 2r (295 mg, 1.21 mmol) in methanol (10 ml). Add Pd/C 10% (18 mg) and hydrogenate under atmospheric pressure for 2 hours at room temperature. Filter the solution on celite and evaporate the filtrate. Purify the crude reaction product by silica gel column chromatography, eluent: Hex/EtOAc, 1/1 then EtOAc. Yield: 93%. 1H-NMR (200 MHz, DMSO-d6): δ 7.37-7.28 (m, 3H arom.), 5.96 (s, 1H arom.), 3.93 (s, 3H, OCH3).
By replacing methyl-4-hydroxy-8-nitro-quinoline-2-carboxylate in example 4 by methyl-4-hydroxy-5-methyl-8-nitro-quinoline-2-carboxylate 2s, and proceeding in the same manner, the abovenamed product is obtained. Yield: 68%. 1H-NMR (200 MHz, DMSO-d6): δ 11.31 (broad s, 1H, OH), 7.04 (broad s, 1H arom.), 7.01 (d, 1H, J=8 Hz, 1H arom.), 6.81 (d, 1H, J=8 Hz, 1H arom.), 5.68 (s, 2H, NH2), 3.90 (s, 3H, OCH3), 2.60 (s, 3H, CH3).
By replacing methyl-4-hydroxy-8-nitro-quinoline-2-carboxylate in example 4 by methyl-4-hydroxy-6-methyl-8-nitro-quinoline-2-carboxylate 2t and proceeding in the same manner, the abovenamed product is obtained. Yield: 46%. 1H-NMR (200 MHz, DMSO-d6): δ 7.36 (s, 1H arom.), 7.09 (s, 1H arom.), 6.75 (s, 1H arom.), 5.88 (s, 2H, NH2), 3.91 (s, 3H, OCH3), 2.02 (s, 3H, CH3).
By replacing methyl-4-hydroxy-8-nitro-quinoline-2-carboxylate in example 4 by methyl-4-hydroxy-8-meethoxy-6-nitro-quinoline-2-carboxylate 2p and proceeding in the same manner, the abovenamed product is obtained. Yield: 93%. 1H-NMR (300 MHz, CDCl3): δ 6.85 (d, 1H, J=2 Hz, 1H arom.), 6.79 (s, 1H arom.), 6.53 (d, 1H, J=2 Hz, 1H arom.), 3.95 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.84 (broad s, 2H, NH2).
By replacing methyl-4-hydroxy-8-nitro-quinoline-2-carboxylate in example 4 by methyl-4-chloro-8-nitro-quinoline-2-carboxylate 8c and proceeding in the same manner, the abovenamed product is obtained. Yield: 18%. 1H-NMR (300 MHz, CDCl3): δ 8.15 (m, 2H arom.), 7.43 (m, 1H arom.), 7.16 (d, 1H, J=8 Hz, 1H arom.), 6.95 (d, 1H, J=8 Hz, 1H arom.), 5.18 (broad s, 2H, NH2), 4.04 (s, 3H, OCH3).
By replacing methyl-4-hydroxy-8-nitro-quinoline-2-carboxylate in example 4 by methyl-8-nitro-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15c and proceeding in the same manner, the abovenamed product is obtained. Yield: 73%. 1H-NMR (300 MHz, CDCl3): δ 8.19 (s, 1H arom.), 7.87 (d, 2H, J=7 Hz, 2H arom.), 7.63 (broad s, 1H, NH), 7.38 (m, 1H, 1H arom.), 7.26 (d, 2H, J=7 Hz, 2H arom.), 7.03 (broad d, 1H, J=8 Hz, 1H arom.), 6.90 (d, 1H, J=8 Hz, 1H arom.), 5.24 (broad s, 2H, NH2), 4.02 (s, 3H, OCH3), 2.36 (s, 3H, CH3).
By replacing methyl-4-hydroxy-8-nitro-quinoline-2-carboxylate 2r in example 4 by methyl-4-(N-methylamino)-8-amino-quinoline-2-carboxylate 132b, the abovenamed product is obtained. Yield: 96%. 1H NMR (200 MHz, CDCl3): δ 7.32 (t, 1H, J=8 Hz, H6), 7.27 (s, 1H, H3), 6.93 (d, 1H, J=8 Hz, H arom.), 6.90 (d, 1H, J=8 Hz, H arom.), 5.10 (s, 3H, NH2 and NH), 4.02 (s, 3H, OCH3), 3.15 (d, 3H, J=3 Hz, CH3).
Suspend methyl-4-hydroxy-6-amino-8-methoxy-quinoline-2-carboxylate 2q (126 mg, 0.51 mmol) in ice-water (2 ml). Add 0.3 ml of concentrated sulfuric acid. At 0° C., add sodium nitrite (39 mg, 0.57 mmol). Allow to stand at this temperature for 1 hour. Then add dropwise potassium iodide (115 mg, 0.69 mmol) dissolved in 2 ml of water. Heat the reaction medium at 70° C. for 1 hour. Extract the aqueous medium with methylene chloride. Dry on Na2SO4, filter, and evaporate the organic solvents. The crude reaction product is purified by silica gel column chromatography, eluent, CH2Cl2/MeOH: 9/1. Yield: 55%. 1H-NMR (200 MHz, CDCl3): δ 9.33 (broad s, 1H, OH), 8.26 (d, 1H, J=2 Hz, 1H arom.), 7.31 (d, 1H, J=2 Hz, 1H arom.), 6.98 (s, 1H, H arom.), 3.89 (s, 3H, OCH3), 3.70 (s, 3H, OCH3).
In a flask, mix potassium iodide (340 mg, 2.05 mmol), phosphoric acid (410 mg, 4.18 mmol) and methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k (160 mg, 0.52 mmol). Heat this mixture at 60° C. so as to form a slurry then add 5 drops of 85% phosphoric acid in water. Heat at 160° C. for 36 hours. Allow to cool and add 10 ml of water. Stir under cold for 30 minutes then filter the precipitate. Wash the precipitate with isopropanol. Yield: 79%. 1H-NMR (300 MHz, DMSO-d6): δ 11.08 (broad s, 3H, COOH and 2×OH), 7.67 (s, 1H arom.), 7.27 (s, 1H arom.), 7.00 (broad s, 1H arom.).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 6 by methyl-4-hydroxy-5-methyl-8-methoxy-quinoline-2-carboxylate 2e and proceeding in the same manner, the abovenamed product is obtained. Yield: 96%. 1H-NMR (300 MHz, DMSO-d6): δ 10.54 (broad s, 1H, COOH), 7.01-6.94 (m, 2H arom.), 6.73 (s, 1H arom.), 2.68 (s, 3H, CH3).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 6 by methyl-4-hydroxy-5,7-dichloro-8-methoxy-quinoline-2-carboxylate 2i and proceeding in the same manner, the abovenamed product is obtained. Yield: 82%. 1H-NMR (200 MHz, DMSO-d6): δ 12.51 (broad s, 1H, COOH), 10.81 (broad s, 2H, 2×OH), 7.65 (s, 1H arom.), 7.43 (broad s, 1H arom.).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 6 by methyl-4-hydroxy-6-iodo-8-methoxy-quinoline-2-carboxylate 2j and proceeding in the same manner, the abovenamed product is obtained. Yield: 54%. 1H-NMR (300 MHz, DMSO): δ 11.06 (broad s, 1H, COOH), 7.87 (s, 1H arom.), 7.39 (s, 1H arom.), 6.90 (broad s, 1H arom.).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 6 by methyl-4-hydroxy-6-methyl-8-methoxy-quinoline-2-carboxylate 2n and proceeding in the same manner, the abovenamed product is obtained. Yield: 95%. 1H-NMR (300 MHz, DMSO-d6): δ 7.37 (m, 1H arom.), 7.02 (m, 1H arom.), 6.97 (s, 1H arom.), 2.39 (s, 3H, CH3).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 6 by methyl-8-methoxy-4-phenyl-quinoline-2-carboxylate 9b and proceeding in the same manner, the abovenamed product is obtained. Yield: 62%. 1H-NMR (200 MHz, DMSO-d6): δ 12.90 (broad s, 1H, COOH), 10.31 (broad s, 1H, OH), 8.01 (s, 1H arom.), 7.64-7.59 (m, 6H arom.), 7.40-7.25 (m, 2H arom.).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 6 by methyl-8-methoxy-4-(4-chlorophenyl)-quinoline-2-carboxylate 9c and proceeding in the same manner, the abovenamed product is obtained. Yield: 53%. 1H-NMR (300 MHz, DMSO-d6): δ 12.59 (broad s, 1H, COOH), 10.33 (broad s, 1H, OH), 8.02 (s, 1H arom.), 7.70-7.62 (m, 5H arom.), 7.37-7.26 (m, 2H arom.).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 6 by methyl-4-hydroxy-6-phenyl-8-methoxy-quinoline-2-carboxylate 18f and proceeding in the same manner, the abovenamed product is obtained. Yield: 99%. 1H-NMR (200 MHz, DMSO-d6): δ 7.81-7.71 (m, 3H arom.), 7.52-7.45 (m, 4H arom.), 6.98 (s, 1H arom.).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 6 by methyl-4-hydroxy-8-methoxy-6-propyl-quinoline-2-carboxylate 18r and proceeding in the same manner, the abovenamed product is obtained. Yield: 34%. 1H-NMR (200 MHz, DMSO-d6): δ 7.38 (s, 1H arom.), 7.03 (s, 2H arom.), 2.65 (t, 2H, CH2), 1.63 (m, 2H, CH2), 0.92 (t, 3H, CH3).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 6 by methyl-8-methoxy-5-phenyl-quinoline-2-carboxylate 18t and proceeding in the same manner, the abovenamed product is obtained. Yield: 65%. 1H-NMR (200 MHz, DMSO-d6): δ 11.15 (broad s, 1H, COOH), 8.43 (d, 1H, J=9 Hz, 1H arom.), 8.17 (d, 1H, J=9 Hz, 1H arom.), 7.63-7.47 (m, 6H arom.), 7.31 (d, 1H, J=8 Hz, 1H arom).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 6 by methyl-4-hydroxy-8-meethoxy-6-phenethyl-quinoline-2-carboxylate 21a and proceeding in the same manner, the abovenamed product is obtained. Yield: 61%. 1H-NMR (300 MHz, DMSO-d6): δ 7.40 (d, 1H, J=2 Hz, 1H arom.), 7.29-7.14 (m, 5H arom.), 7.07 (d, 1H, J=2 Hz, 1H arom.), 6.96 (s, 1H arom.), 2.99-2.90 (m, 4H, 2CH2).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 6 by methyl-4-hydroxy-8-methoxy-6-heptyl-quinoline-2-carboxylate 21b and proceeding in the same manner, the abovenamed product is obtained. Yield: 48%. 1H-NMR (200 MHz, DMSO-d6): δ 7.37 (s, 1H arom.), 7.02 (s, 2H arom.), 2.67 (t, 2H, CH2), 1.60 (m, 2H, CH2), 1.28 (m, 8H, 4×CH2), 0.85 (m, 3H, CH3).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 6 by methyl-6-(benzylamino-methyl)-4-hydroxy-8-methoxy-quinoline-2-carboxylate 25a and proceeding in the same manner, the abovenamed product is obtained. Yield: 67%. 1H-NMR (200 MHz, DMSO-d6): δ 7.76 (s, 1H arom.), 7.45 (m, 5H arom.), 7.27 (m, 1H arom.), 6.99 (m, 1H arom.), 4.21 (m, 4H, 2×CH2).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 6 by methyl-5-(4-chlorophenyl)-8-methoxydroxy-quinoline-2-carboxylate 81a and proceeding in the same manner, the abovenamed product is obtained. Yield: 60%. 1H-NMR (200 MHz, DMSO-d6): δ 13.05 (broad s, 1H, CO2H), 10.40 (broad s, 1H, OH), 8.42 (d, 1H, J=9 Hz, 1H arom.), 8.18 (d, 1H, J=9 Hz, 1H arom.), 7.65-7.49 (m, 5H arom.), 7.32 (d, 1H, J=8 Hz, 1H arom).
Dissolve methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 2u (150 mg, 0.69 mmol) in 2 N HCl solution in water (10 ml). Heat at 60° C. overnight. Allow to cool and filter the precipitate. Yield: 60%. 1H-NMR (200 MHz, D2O): δ 7.52 (d, 1H, J=8 Hz, 1H arom.), 7.17 (m, 1H arom.), 6.99 (d, 1H, J=8 Hz, 1H arom.), 6.93 (s, 1H arom.).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 2u in example 7 by methyl-4,8-dihydroxy-6-(3-tert-butoxycarbonylamino-propyl)-quinoline-2-carboxylate 21c and proceeding in the same manner, the abovenamed product is obtained. Yield: 92%. 1H-NMR (200 MHz, DMSO-d6): δ 10.73 (broad s, 1H, COOH), 8.01 (broad s, 3H, NH3+), 7.44 (s, 1H arom.), 7.11 (s, 2H arom.), 2.80 (m, 4H, 2CH2), 1.92 (m, 2H, CH2).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 2u in example 7 by methyl-4,8-dihydroxy-6-(3-hydroxy-propyl)-quinoline-2-carboxylate 21d and proceeding in the same manner, the abovenamed product is obtained. Yield: 50%. 1H-NMR (200 MHz, DMSO-d6): δ 7.59 (m, 1H arom.), 7.11 (m, 2H arom.), 3.60 (m, 2H, CH2), 2.74 (m, 2H, CH2), 1.94 (m, 2H, CH2).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 2u in example 7 by methyl-4,8-dihydroxy-6-(4-methoxy-phenyl)-quinoline-2-carboxylate 18h and proceeding in the same manner, the abovenamed product is obtained. Yield: 90%. 1H-NMR (300 MHz, DMSO-d6): δ 7.83 (s, 1H arom.), 7.71-7.68 (m, 2H arom.), 7.55 (m, 1H arom.), 7.29 (s, 1H arom.), 7.09-7.06 (m, 2H arom.), 3.82 (s, 3H, OCH3).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 2u in example 7 by methyl-4,8-dihydroxy-6-(3-methyl-phenyl)-quinoline-2-carboxylate 18j and proceeding in the same manner, the abovenamed product is obtained. Yield: 90%. 1H-NMR (200 MHz, DMSO-d6): δ 7.81 (m, 1H arom.), 7.55-7.35 (m, 4H arom.), 7.25 (m, 1H arom.), 7.06 (s, 1H arom.), 2.43 (s, 3H, CH3).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 2u in example 7 by methyl-4-hydroxy-6-(4-chloro-phenyl)-8-benzyloxy-quinoline-2-carboxylate 18k and proceeding in the same manner, the abovenamed product is obtained. Yield: 70%. 1H-NMR (200 MHz, DMSO-d6): δ 7.79 (m, 1H arom.), 7.76-7.72 (m, 2H arom.), 7.58-7.54 (m, 2H arom.), 7.48 (m, 1H arom.), 6.92 (broad s, 1H arom.).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 2u in example 7 by methyl-8-benzyloxy-6-(3,4-dichloro-phenyl)-4-hydroxy-quinoline-2-carboxylate 18m and proceeding in the same manner, the abovenamed product is obtained. Yield: 80%. 1H-NMR (200 MHz, DMSO-d6): δ 7.97 (m, 1H arom.), 7.82 (m, 1H arom.), 7.74 (m, 2H arom.), 7.47 (m, 1H arom.), 7.06 (broad s, 1H arom.).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 2u in example 7 by methyl-8-benzyloxy-4-hydroxy-6-(pyridin-3-yl)-quinoline-2-carboxylate 18o and proceeding in the same manner, the abovenamed product is obtained. Yield: 70%. 1H-NMR (200 MHz, DMSO-d6): δ 8.90 (s, 1H arom.), 8.59 (m, 1H arom.), 8.15-8.09 (m, 1H arom.), 7.82 (m, 1H arom.), 7.55-7.45 (m, 2H arom.), 6.82 (m, 1H arom.).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 2u in example 7 by methyl-4,8-dihydroxy-5-phenyl-quinoline-2-carboxylate 18b and proceeding in the same manner, the abovenamed product is obtained. Yield: 83%. 1H-NMR (300 MHz, DMSO-d6): δ 11.01(broad s, 1H, OH), 9.93 (broad s, 1H, OH), 7.24-7.10 (m, 6H arom.), 6.79 (m, 1H arom.), 6.40 (s, 1H arom.).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate in example 7 by methyl-4,8-dihydroxy-5-bromo-quinoline-2-carboxylate 2c and proceeding in the same manner, the abovenamed product is obtained. Yield: 85%. 1H-NMR (200 MHz, DMSO-d6): δ 7.49 (d, 1H, J=8 Hz, 1H arom.), 7.04 (d, 1H, J=8 Hz, 1H arom.), 6.84 (s, 1H arom.).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate in example 7 by methyl-8-methoxy-5-bromo-quinoline-2-carboxylate 5c and proceeding in the same manner, the abovenamed product is obtained. Yield: 88%. 1H-NMR (200 MHz, DMSO-d6): δ 13.2 (broad s, 1H, COOH), 8.59 (d, 1H, J=9 Hz, 1H arom.), 8.26 (d, 1H, J=9 Hz, 1H arom.) 7.99 (d, 1H, J=8 Hz, 1H arom.), 7.25 (d, 1H, J=8 Hz, 1H arom.), 4.04 (s, 3H, OCH3).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate in example 7 by methyl-4,8-dihydroxy-5-hydroxymethyl-quinoline-2-carboxylate 2h and proceeding in the same manner, the abovenamed product is obtained. Yield: 82%. 1H-NMR (300 MHz, DMSO-d6): δ 7.13-7.07 (m, 2H arom.), 6.98 (s, 1H arom.), 2.72 (s, 2H, CH2).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate in example 7 by methyl-4-hydroxy-5-methyl-8-amino-quinoline-2-carboxylate 2v and proceeding in the same manner, the abovenamed product is obtained. Yield: 56%. 1H-NMR (200 MHz, DMSO-d6): δ 11.36 (broad s, 1H, COOH), 7.37 (broad s, 1H arom.), 7.00 (d poorly resolved, 1H arom.), 6.74 (d poorly resolved, 1H arom.), 2.67 (s, 3H, CH3).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate in example 7 by methyl-4-hydroxy-6-methyl-8-amino-quinoline-2-carboxylate 2w and proceeding in the same manner, the abovenamed product is obtained. Yield: 67%. 1H-NMR (200 MHz, DMSO): δ 11.45 (broad s, 1H, COOH), 7.37 (broad s, 1H arom.), 7.02 (s, 1H arom.), 6.68 (s, 1H arom.), 2.34 (s, 3H, CH3).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate in example 7 by methyl-4-hydroxy-8-bromo-quinoline-2-carboxylate 2x and proceeding in the same manner, the abovenamed product is obtained. Yield: 32%. 1H-NMR (200 MHz, DMSO-d6): δ 8.13 (m, 2H arom.), 7.42 (m, 1H arom.), 7.07 (m, 1H arom.).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 2u in example 7 by methyl-8-hydroxy-4-phenethyl-quinoline-2-carboxylate 13a and proceeding in the same manner, the abovenamed product is obtained. Yield: 65%. 1H-NMR (300 MHz, DMSO-d6): δ 10.14 (broad s, 1H, COOH), 7.75(m, 1H arom.), 7.67-6.58 (m, 2H arom.), 7.22-7.17 (m, 3H arom.), 6.96 (m, 3H arom.), 3.45-3.34 (m, 4H, 2×CH2).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 2u in example 7 by methyl-8-hydroxy-4-(3-tert-butoxycarbonylamino-propyl)-quinoline-2-carboxylate 13b and proceeding in the same manner, the abovenamed product is obtained. Yield: 83%. 1H-NMR (300 MHz, DMSO-d6): δ 10.26 (broad s, 1H, COOH), 8.07 (broad s, 3H, NH3+), 8.03 (s, 1H arom.), 7.67 (m, 2H arom.), 7.22 (s, 1H arom.), 3.47 (m, 2H, CH2), 2.93 (m, 2H, CH2), 2.05 (m, 2H, CH2).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 2u in example 7 by methyl-8-hydroxy-4-(3-hydroxy-propyl)-quinoline-2-carboxylate 13c and proceeding in the same manner, the abovenamed product is obtained. Yield: 83%. 1H-NMR (200 MHz, methanol-d4): δ 8.12 (s, 1H arom.), 7.73-7.60 (m, 2H arom.), 7.20 (s, 1H arom.), 3.72 (m, 2H, CH2), 3.34 (m, 2H, CH2), 2.03 (m, 2H, CH2).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate in example 7 by methyl-4-amino-8-hydroxy-quinoline-2-carboxylate 17a and proceeding in the same manner, the abovenamed product is obtained. Yield: 48%. 1H-NMR (300 MHz, methanol-d4): δ 7.94 (d, 1H, J=8 Hz, 1H arom.), 7.73 (m, 1H arom.), 7.58 (s, 1H arom.), 7.51 (d, 1H, J=8 Hz, 1H arom.).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate in example 7 by methyl-4,8-diamino-quinoline-2-carboxylate 17b and proceeding in the same manner, the abovenamed product is obtained. Yield: 62%. 1H-NMR (200 MHz, DMSO-d6): δ 7.53-7.40 (m, 2H arom.), 7.20 (s, 1H arom.), 7.16 (d, 1H, J=9 Hz, 1H arom.).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate in example 7 by methyl-4-hydroxy-8-(2H-tetrazol-5-yl)-quinoline-2-carboxylate 62a and proceeding in the same manner, the abovenamed product is obtained. Yield: 64%. 1H-NMR (200 MHz, DMSO-d6+D2O): δ 8.48-8.38 (m, 2H arom.), 7.56-7.48 (m, 1H arom.), 6.75 (s, 1H arom.).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 3u in example 7 by methyl-3-phenylethyl-8-amino-4-hydroxy-quinoline-2-carboxylate 68b, the abovenamed product is obtained. Yield: 92%. 1H NMR (300 MHz, CDCl3): δ 12.14 (s, 1H, OH), 9.16 (s, 1H, OH), 7.36 (d, 1H, J=8 Hz, H arom.), 7.22 (m, 6H, 7H arom.), 6.89 (d, 1H, J=8 Hz, H arom.), 4.68 (s, 2H, NH2), 3.21 (dd, 2H, J=8 and 10 Hz, CH2), 2.78 (dd, 2H, J=8 and 10 Hz, CH2).
By replacing methyl 4-hydroxy-8-amino-quinoline-2-carboxylate 3u in example 7 by 3-(3′-N-(terbutoxycarbonyl)aminopropyl)-8-amino-4-hydroxy-quinoline-2-carboxylic 71b, the abovenamed product is obtained. Yield: 82%. 1H NMR (300 MHz, d6-DMSO): δ 7.50 (t, 1H, J=8 Hz, H6), 7.24 (m, 2H, 1 OH and 1H arom), 6.86 (d, 1H, J=9 Hz, 1H arom.), 6.64 (s, 2 HN), 4.41 (m, 2H, CH2N), 3.35 (m, 3H, CH2 and HN), 1.35 (m, 2H, CH2), 1.66 (s, 9H, 3 CH3).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 3u in example 7 by methyl-5-phenylethyl-8-amino-4-hydroxy-quinoline-2-carboxylate 74b, the abovenamed product is obtained. Yield: 84%. 1H NMR (300 MHz, CDCl3): δ 9.15 (s, 1H, OH), 7.24 (m, 7H, 7H arom.), 7.04 (d, 1H, J=8 Hz, H arom.), 6.93 (d, 1H, J=8 Hz, H arom.), 4.96 (s, 2H, NH2), 3.42 (t, 2H, J=9 Hz, CH2), 2.83 (t, 2H, J=9 Hz, CH2).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 3u in example 7 by methyl-5-(3′-hydroxypropyl)-8-amino-4-hydroxy-quinoline-2-carboxylate 75b, the abovenamed product is obtained. Yield: 46%. 1H NMR (200 MHz, CDCl3): δ 11.48 (s, 1H, 1 OH), 10.65 (s, 1H, OH), 7.18 (d, 1H, J=8 Hz, H arom.), 7.02 (s, 1H, H3), 6.80 (d, 1H, J=8 Hz, H arom.), 5.65 (s, 2H, NH2), 3.24 (m, 2H, CH2O), 2.62 (m, 4H, 2 CH2), 1.71 (m, 2H, CH2).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 3u in example 7 by methyl-5-(3′-N-(terbutoxycarbonyl)aminoprop-1′-ynyl)-8-nitro-4-benzyloxy-quinoline-2-carboxylate 76b, the abovenamed product is obtained. Yield: 71%. 1H NMR (300 MHz, CDCl3): δ 12.17 ‘s, 1H, OH), 9.22 (s, 1 HO), 8.75 (s, 3 HN), 7.14 (d, 1H, J=8 Hz, H arom.), 7.06 (s, 1H3), 6.89 (d, 1H, J=8 Hz, H arom.), 4.49 (s, 2 HN), 2.69 (m, 2H, CH2N), 2.50 (m, 2H, CH2), 1.71 (m, 2H, CH2).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 3u in example 7 by methyl-5-(piperidin-1-yl)-8-amino-4-hydroxy-quinoline-2-carboxylate 77b, the abovenamed product is obtained as a yellow solid. Yield: 61%. 1H NMR (200 MHz, CDCl3): δ 8.76 (s, 1H, OH), 7.44 (s, 1H3), 7.12 (d, 1H, J=8 Hz, H arom.), 6.94 (d, 1H, J=8 Hz, H arom.), 5.39 (s, 2 HN), 2.97 (m, 2H, NCH2), 2.77 (m, 2H, NCH2), 1.69 (m, 6H, 3 CH2).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 3u in example 7 by methyl-piperazin-1-yl-8-amino-4-hydroxy-quinoline-2-carboxylate 78b, the abovenamed product is obtained as an orange solid Yield: 72%. 1H NMR (200 MHz, d6-DMSO): δ 12.24 (s, 1H, OH), 10.82 (s, 1H, OH), 8.12 (s, 2H, NH2+), 7.32 (s, 1H3), 7.15 (d, 1H, J=8 Hz, H arom.), 6.81 (d, 1H, J=8 Hz, H arom.), 5.12 (s, 2H, H2N), 2.81 (m, 2H, NCH2), 2.78 (m, 2H, NCH2), 2.21 (m, 6H, 3 CH2), 2.14 (m, 2H, CH2).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 3u in example 7 by methyl-6-benzyloxy-8-nitro-4-hydroxy-quinoline-2-carboxylate 79c, the abovenamed product is obtained. Yield: 69%. 1H NMR (200 MHz, d6-DMSO): δ 11.01 (s, 1 OH), 9.57 (s, 1 OH), 7.15 (s, 1H3), 6.28 (d, 1H, J=2 Hz, H5), 6.16 (d, 1H, J=2 Hz, H7), 5.60 (s, 2 HN).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 3u in example 7 by methyl-6-chloro-8-amino-4-hydroxy-quinoline-2-carboxylate 117c, the abovenamed product is obtained. Yield: 78%. 1H NMR (200 MHz, d6-DMSO): δ 9.13 (m, 4H, 2 OH and NH2), 7.48 (s, 1H3), 7.19 (d, 1H, J=2 Hz, H5), 6.86 (d, 1H, J=2 Hz, H7).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 3u in example 7 by methyl-6-phenylethy-8-amino-4-hydroxy-quinoline-2-carboxylate 118b, the abovenamed product is obtained. Yield: 79%. 1H NMR (200 MHz, d6-DMSO): δ 13.24 (s, 1H, OH), 10.73 (s, 1H, OH), 7.24 (m, 6H, 6H arom.), 7.10 (s, 1H, H arom.), 6.83 (s, 1H, H arom.), 5.24 (s, 2H, NH2), 2.90 (s, 4H, 2 CH2).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 3u in example 7 by methyl-6-(3′-hydroxypropyl)-8-amino-4-hydroxy-quinoline-2-carboxylate 119b, the abovenamed product is obtained. Yield: 64%. 1H NMR (200 MHz, d6-DMSO): δ 12.14 (s, 1H, OH), 10.21 (s, 1 HO), 7.19 (d, 1H, J=2 Hz, 1H arom.), 7.08 (s, 1H3), 6.97 (d, 1H, J=2 Hz, 1H arom.), 5.16 (s, 2 HN), 4.18 (s, 1 HO), 3.21 (m, 2H, CH2O), 2.51 (m, 2H, CH2), 1.70 (m, 2H, CH2).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 3u in example 7 by methyl-6-(3′-N-(terbutoxycarbonyl)aminopropyl)-8-amino-4-hydroxy-quinoline-2-carboxylate 121b, the abovenamed product is obtained. Yield: 52%. 1H NMR (200 MHz, d6-DMSO): δ 8.00 (m, 4H, OH and NH3+), 7.37 (m, 1H, H arom), 7.35 (m, 1H, H arom), 7.03 (s, 1H3), 2.78 (m, 4H, CH2 and H2N), 2.50 (m, 2H, CH2), 1.94 (m, 2H, CH2).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 3u in example 7 by methyl-6-(pyridin-3-yl)ethyl-8-amino-4-hydroxy-quinoline-2-carboxylate 122b, the abovenamed product is obtained as a yellow solid. Yield: 78%. 1H NMR (200 MHz, d6-DMSO): δ 12.15 (s, 1H, OH), 10.45 (s, 1H, OH), 8.37 (s, 1H, H arom.), 8.40 (d, 1H, J=2 Hz, H arom.), 7.49 (d, 1H, J=4 Hz, 1H arom.), 7.15 (m, 3H, 3H arom.), 6.68 (s, 1H, 1H arom.), 5.41 (s, 2 UN), 2.80 (m, 4H, 2 CH2).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 3u in example 7 by methyl-6-(N-piperidinyl)-8-amino-4-hydroxy-quinoline-2-carboxylate 126b, the abovenamed product is obtained as a yellow solid. Yield: 62%. 1H NMR (200 MHz, d6-DMSO): δ 13.42 (s, 1H, OH), 10.32 (s, 1H, OH), 7.01 (d, 1H, J=2 Hz, H arom.), 6.88 (s, 1H3), 6.61 (d, 1H, J=2 Hz, H arom.), 5.97 (s, 2 HN), 2.88 (m, 4H, 2 NCH2), 1.62 (m, 6H, 3 CH2).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 3u in example 7 by methyl-6-(N-piperazinyl)-8-amino-4-hydroxy-quinoline-2-carboxylate 125b, the abovenamed product is obtained as a brown solid. Yield: 48%. 1H NMR (200 MHz, d6-DMSO): δ 10.96 (s, 1H, OH), 6.98 (d, 1H, J=2 Hz, H arom.), 6.86 (s, 1H3), 6.72 (d, 1H, J=2 Hz, H arom.), 5.90 (s, 2H, H2N), 2.89 (m, 4H, 2 NCH2), 2.20 (m, 6H, 3 CH2).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 3u in example 7 by methyl-6,8-diamino-4-hydroxy-quinoline-2-carboxylate 32c, the abovenamed product is obtained as a purple solid. Yield: 61%. 1H NMR (200 MHz, d6-DMSO): δ 12.42 (s, 1 H, OH), 11.82 (s, 1H, OH), 8.00 (s, 3H, NH3+), 7.23 (d, 1H, H arom.), 7.01 (s, 1H3), 6.83 (d, 1H, H arom.), 5.20 (s, 2H, H2N).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 3u in example 7 by methyl-6-(1-anilino)-8-amino-4-hydroxy-quinoline-2-carboxylate 33b, the abovenamed product is obtained as an orange solid. Yield: 81%. 1H NMR (200 MHz, CDCl3): δ 13.14 (s, 1H, OH), 9.51 (s, 1H, OH), 8.24 (s, 1H, 2NH+), 7.78 (m, 1H, 1H arom.), 7.45 (s, 1H3), 7.36 (m, 4H, 4H arom.), 7.20 (m, 2H, 2H arom.), 4.72 (s, 2H, NH2).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 2u in example 7 by methyl-8-amino-4-phenyl-quinoline-2-carboxylate 92c and proceeding in the same manner, the abovenamed product is obtained. Yield: 93%. 1H-NMR (200 MHz, DMSO-d6): δ 7.97 (s, 1H arom.), 7.61-7.51 (m, 6H arom.), 7.26 (d, 2H, J=8 Hz, 2H arom.), 3.70 (broad s, 2H, NH2).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 2u in example 7 by methyl-8-amino-4-(hex-1-yl)-quinoline-2-carboxylate 93b and proceeding in the same manner, the abovenamed product is obtained. Yield: 90%. 1H-NMR (200 MHz, DMSO-d6): δ 9.50 (broad s, 1H, OH), 7.96 (s, 1H arom.), 7.58-7.55 (m, 2H arom.), 7.24-7.20 (m, 1H arom.), 3.10 (t, 2H, J=7 Hz, CH2), 1.69-1.66 (m, 2H, CH2), 1.31-1.23 (m, 6H, 3×CH2), 0.96 (t, 3H, J=7 Hz, CH3).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 2u in example 7 by methyl-8-amino-4-(2-phenyleth-1-yl)-quinoline-2-carboxylate 94b and proceeding in the same manner, the abovenamed product is obtained. Yield: 72%. 1H-NMR (200 MHz, DMSO-d6): δ 7.98 (s, 1H arom.), 7.55-7.17 (m, 8H arom.), 3.45-3.37 (m, 2H, CH2), 3.07-2.99(m, 2H, CH2).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 2u in example 7 by methyl-8-amino-4-(3-tert-butoxycarbonylamino-prop-1-yl)-quinoline-2-carboxylate 95b and proceeding in the same manner, the abovenamed product is obtained. Yield: 84%. 1H-NMR (200 MHz, DMSO-d6): δ 8.13 (broad s, 3H, N+H3), 8.03 (s, 1H arom.), 7.62-7.59 (m, 2H arom.), 7.28-7.26 (m, 1H arom.), 3.19 (t, 2H, J=7 Hz, CH2), 2.93 (t, 2H, J=7 Hz, CH2), 2.04-1.99 (m, 2H, CH2).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 2u in example 7 by methyl-8-amino-4-(3-hydroxy-prop-1-yl)-quinoline-2-carboxylate 96b and proceeding in the same manner, the abovenamed product is obtained. Yield: 95%. 1H-NMR (200 MHz, DMSO-d6): δ 8.03 (s, 1H arom.), 7.62-7.59 (m, 2H arom.), 7.28-7.26 (m, 1H arom.), 6.15 (broad s, 3H, N+H3), 3.51 (t, 2H, J=7 Hz, CH2), 3.15 (t, 2H, J=7 Hz, CH2), 1.89-1.82 (m, 2H, CH2).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 2u in example 7 by methyl-4-(3-acetyl-aminoprop-1-ynyl)-8-amino-quinoline-2-carboxylate 97b and proceeding in the same manner, the abovenamed product is obtained. Yield: 84%. 1H-NMR (200 MHz, DMSO-d6): δ 8.01(s, 1H arom.), 7.66-7.57 (m, 2H arom.), 7.30 (d, 1H, J=8 Hz, 1H arom.), 6.93 (s, 1H, NH), 6.69 (broad s, 2H, NH2), 4.58 (s, 2H, NCH2), 2.34 (s, 3H, COCH3).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 2u in example 7 by methyl-8-hydroxy-4-(morpholin-1-yl)-quinoline-2-carboxylate 99b and proceeding in the same manner, the abovenamed product is obtained. Yield: 90%. 1H-NMR (300 MHz, DMSO-d6): δ 11.10 (broad s, 2H, OH), 7.56-754 (m, 3H arom.), 7.29-7.27 (m, 1H arom.), 3.89-3.87 (m, 4H, CH2—O—CH2), 3.55-3.53 (m, 4H, CH2—N—CH2).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 2u in example 7 by methyl-8-hydroxy-4-(morpholin-1-yl)-quinoline-2-carboxylate 100b and proceeding in the same manner, the abovenamed product is obtained. Yield: 85%. 1H-NMR (200 MHz, DMSO-d6): δ 11.09 (broad s, 1H, OH), 8.84 (broad s, 1H, OH), 7.56-7.48 (m, 3H arom.), 7.33-7.29 (m, 1H arom.), 3.62-3.60 (m, 4H, CH2—N—CH2), 1.82-1.78 (m, 6H, 3×CH2).
By replacing methyl-4-hydroxy-5-hydroxymethyl-8-benzyloxy-quinoline-2-carboxylate 2g in example 2 by methyl-8-amino-4-(piperidin-1-yl)-quinoline-2-carboxylate 101b and proceeding in the same manner, the abovenamed product is obtained. Yield: 95%. 1H-NMR (200 MHz, DMSO-d6): δ 9.75 (broad s, 4H, NH2+2×OH), 7.69-7.53 (m, 4H arom.), 3.33-3.30 (m, 4H, CH2—N—CH2), 1.77-1.59 (m, 6H, 3×CH2).
By replacing methyl-4-hydroxy-5-hydroxymethyl-8-benzyloxy-quinoline-2-carboxylate 2g in example 2 by methyl-4-hydroxy-8-(piperazin-1-yl)-quinoline-2-carboxylate 108a and proceeding in the same manner, the abovenamed product is obtained. Yield: 89%. 1H-NMR (200 MHz, DMSO-d6): δ 9.47 (broad s, 2H, NH+OH), 7.91 (d, 1H, J=8 Hz, 1H arom.), 7.59 (d, 1H, J=8 Hz, 1H arom.), 7.44 (t, 1H, J=8 Hz, 1H arom.), 6.84 (s, 1H arom.), 3.39-3.32 (m, 4H, CH2—N—CH2), 3.29-3.26 (m, 4H, CH2—N—CH2).
By replacing methyl-4-hydroxy-5-hydroxymethyl-8-benzyloxy-quinoline-2-carboxylate 2g in example 2 by methyl-8-hydroxy-4-(4-methyl-piperazin-1-yl)-quinoline-2-carboxylate 110b and proceeding in the same manner, the abovenamed product is obtained. Yield: 65%. 1H-NMR (300 MHz, DMSO-d6): δ 11.38 (broad s, 1H, COOH), 7.62-7.48 (m, 3H arom.), 7.21 (m, 1H arom), 3.86-3.82 (m, 2H, CH2), 3.29-3.26 (m, 6H, 3×CH2), 2.86 (s, 3H, NCH3).
By replacing methyl-4-hydroxy-5-hydroxymethyl-8-benzyloxy-quinoline-2-carboxylate 2g in example 2 by methyl-4-hydroxy-8-phenylethyl-quinoline-2-carboxylate 111a and proceeding in the same manner, the abovenamed product is obtained. Yield: 90%. 1H-NMR (200 MHz, DMSO-d6): δ 9.54 (broad s, 2H, OH), 8.01 (d, 1H, J=8 Hz, 1H arom.), 7.60 (d, 1H, J=8 Hz, 1H arom.), 7.45-7.14 (m, 7H arom.), 3.41 (t, 2H, J=6.5 Hz, CH2), 2.98 (t, 2H, J=6.5 Hz, CH2).
Dissolve methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate 2a (300 mg, 0.97 mmol) in a 1:1 mixture of THF/water (20 ml). To this solution add lithium hydroxide hydrate (216 mg, 5.1 mmol). Allow to stand at room temperature overnight. Evaporate the THF then cool the medium to 0° C. Acidify to pH 2 with concentrated hydrochloric acid solution. Filter the precipitate formed. Yield: 30%. 1H-NMR (200 MHz, DMSO-d6): δ 8.90 (very broad s, 2H, COOH, OH), 7.70-7.29 (m, 8H arom.), 6.67 (s, 1H arom.), 5.40 (s, 2H, OCH2).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate in example 8 by methyl 8-amino-quinoline-2-carboxylate 5f and proceeding in the same manner, the abovenamed product is obtained. Yield: 85%. 1H-NMR (300 MHz, DMSO-d6): δ 12.84 (broad s, 1H, COOH), 8.37 (d, 1H, J=8 Hz, 1H arom.), 8.06 (d, 1H, J=8 Hz, 1H arom.), 7.44 (m, 1H arom.), 7.12 (d, 1H, J=7 Hz, 1H arom.), 6.90 (d, 1H, J=7 Hz, 1H arom.), 6.57 (broad s, 2H, NH2).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate in example 8 by- methyl 8-benzylamino-4-hydroxy-quinoline-2-carboxylate 29a and proceeding in the same manner, the abovenamed product is obtained. Yield: 69%. 1H-NMR (300 MHz, DMSO-d6): δ 11.60 (very broad s, 2H, COOH and OH), 7.96 (broad s, 1H, NH), 7.44-6.61 (m, 9H arom.), 4.55 (s, 2H, OCH2).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate in example 8 by methyl-8-hydroxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15b and proceeding in the same manner, the abovenamed product is obtained. Yield: 62%. 1H-NMR (200 MHz, MeOD): δ 8.25 (s, 1H, H arom.), 7.97 (m, 3H arom.), 7.55 (m, 3H arom.), 7.35 (d, 1H, J=7 Hz, H arom.), 2.54 (s, 3H, CH3).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate in example 8 by methyl-8-bromo-4-hydroxy-6-isopropyl-quinoline-2-carboxylate 42b and proceeding in the same manner, the abovenamed product is obtained. Yield: 68%. 1H-NMR (300 MHz, DMSO): δ 8.09 (d, 1H, J=1.86 Hz, H arom.), 7.98 (d, 1H, J=1.86 Hz, 1H, H arom.), 7.6 (broad s, 1H arom.), 3.15-3.02 (sept, 1H, CH(CH3)2), 1.29 and 1.26 (2s, 6H, CH(CH3)2).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate in example 8 by methyl-5,7-dichloro-4,8-dihydroxy-quinoline-2-carboxylate 44c and proceeding in the same manner, the abovenamed product is obtained. Yield: 79%. 1H-NMR (300 MHz, DMSO): δ 10.90 (broad s, 1H, OH), 7.64 (s, 1H arom.), 7.42 (broad s, 1H arom.).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate in example 8 by methyl-8-benzyloxy-6-bromo-4-hydroxy-quinoline-2-carboxylate 3k and proceeding in the same manner, the abovenamed product is obtained. Yield: 79%. 1H-NMR (300 MHz, DMSO): δ 7.76 (d, 1H arom.), 7.61-7.57 (m, 3H arom.), 7.49-7.40 (m, 3H arom.), 6.72 (broad s, 1H arom.), 5.42 (s, 2H, OCH2).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate in example 8 by methyl-8-benzyloxy-7-bromo-4-hydroxy-quinoline-2-carboxylate 50b and proceeding in the same manner, the abovenamed product is obtained. Yield: 70%. 1H-NMR (200 MHz, DMSO): δ 7.83-7.79 (d, 1H arom.), 7.70-7.65 (d, 1H arom.), 7.63-7.52 (m, 2H arom.), 7.47-7.34 (m, 3H arom.), 6.85 (broad s, 1H arom.), 5.32 (s, 2H, OCH2).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate in example 8 by methyl-3-bromo-4,8-dihydroxy-quinoline-2-carboxylate 52b and proceeding in the same manner, the abovenamed product is obtained. Yield: 44%. 1H-NMR (200 MHz, DMSO): δ 12.02 (broad s, 1H, CO2H), 10.94 (s, 1H, OH), 7.60-7.59 (dd, 1H, J=1 Hz and J=8 Hz, 1H arom.), 7.29-7.21 (t, 1H, J=8 Hz, 1H arom.), 7.17-7.12 (dd, 1H, J=1 Hz and J=8 Hz, 1H arom.).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate in example 8 by methyl-8-benzyloxy-3-bromo-4-hydroxy-quinoline-2-carboxylate 52b and proceeding in the same manner, the abovenamed product is obtained. Yield: 63%. 1H-NMR (300 MHz, DMSO): δ 12.06 (broad s, 1H, CO2H), 7.70-7.68 (m, 1H arom.), 7.58-7.55 (m, 2H arom.), 7.45-7.30 (m, 5H arom.), 5.40 (s, 2H, OCH2).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate in example 8 by methyl-3,7-dibromo-4,8-dihydroxy-quinoline-2-carboxylate 56b and proceeding in the same manner, the abovenamed product is obtained. Yield: 72%. 1H-NMR (300 MHz, DMSO): δ 12.26 (broad s, 1H, CO2H or OH), 10.62 (broad s, 1H, OH), 7.64-7.48 (m, 2H arom.).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate in example 8 by ethyl-8-hydroxy-3-oxo-3,4-dihydroquinoxaline-2-carboxylate 59b and proceeding in the same manner, the abovenamed product is obtained. Yield: 62%. 1H-NMR (200 MHz, DMSO): δ 13.82 (broad s, 1H, COOH), 12.84 (broad s, 1H, NH), 10.46 (s, 1H, OH), 7.46 (t, 1H, J=8 Hz, 1H arom.), 6.79-6.75 (d, 2H, J=8 Hz, 2H arom.).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate in example 8 by ethyl[8-(hydroxy)-3-oxo-3,4-dihydroquinoxaline-2(1H)-ylilene]acetate 60b and proceeding in the same manner, the abovenamed product is obtained. Yield: 65%. 1H-NMR (200 MHz, DMSO-d6): δ 12.19 (s, 1H, OH), 9.84 (broad s, 1H, NHCO), 7.30-7.22 (t, 1H, J=8 Hz, 1H arom.), 6.71-6.67 (d, 1H, J=8 Hz, 1H arom.), 6.69-6.65 (d, 1H, J=8 Hz, 1H arom.), 2.41 (s, 2H, CH2).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate in example 8 by methyl-6-bromo-8-cyano-4-hydroxy-quinoline-2-carboxylate 63b and proceeding in the same manner, the abovenamed product is obtained. Yield: 68%. 1H-NMR (200 MHz, DMSO-d6): δ 12.83 (broad s, 2H, COOH and OH), 8.64-8.58 (m, 2H arom.), 7.51 (s, 1H arom.).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate in example 8 by methyl-8-cyano-4-hydroxy-6-phenyl-quinoline-2-carboxylate 64a and proceeding in the same manner, the abovenamed product is obtained. Yield: 65%. 1H-NMR (200 MHz, DMSO-d6): δ 12.80 (broad s, 2H, COOH and OH), 8.77-8.65 (m, 2H arom.), 7.93-7.89 (m, 2H arom.), 7.60-7.48 (m, 4H arom.).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate in example 8 by methyl-8-cyano-4-hydroxy-6-phenethyl-quinoline-2-carboxylate 65c and proceeding in the same manner, the abovenamed product is obtained. Yield: 84%. 1H-NMR (200 MHz, DMSO-d6+TFA): δ 8.24 (s, 2H arom.), 7.47 (s, 1H arom.), 7.24 (m, 5H arom.), 3.18-2.99 (m, 4H, PhCH2—CH2).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate in example 8 by methyl-3-bromo-8-cyano-4-hydroxyquinoline-2-carboxylate 66a and proceeding in the same manner, the abovenamed product is obtained. Yield: 57%. 1H-NMR (200 MHz, DMSO-d6): δ 8.52-8.48 (m, 1H arom.), 8.37-8.34 (m, 1H arom.), 7.69-7.61 (m, 1H arom.).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate in example 8 by benzyl-4-benzyloxy-8-cyano-3-phenylethynyl-quinoline-2-carboxylate 67b and proceeding in the same manner, the abovenamed product is obtained. Yield: 56%. 1H-NMR (300 MHz, DMSO-d6): δ 8.86-8.83 (m, 1H arom.), 8.47-8.44 (m, 1H arom.), 8.20-8.18 (m, 2H arom.), 7.98 (m, 1H arom.), 7.61-7.53 (m, 3H arom.).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate in example 8 by methyl-8-cyano-6-ethyl-4-hydroxy-quinoline-2-carboxylate 69c and proceeding in the same manner, the abovenamed product is obtained. Yield: 60%. 1H-NMR (200 MHz, MeOD): δ 8.31 (m, 1H arom.), 8.13 (m, 1H arom.), 7.17 (m, 1H arom.), 2.89-2.84 (m, 2H, CH2—CH3), 1.39-1.34 (m, 3H, CH2—CH3).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate 2a in example 8 by methyl-8-fluoro-4-hydroxy-quinoline-2-carboxylate 36b, the abovenamed product is obtained. Yield: 91%. 1H NMR (300 MHz, d6-DMSO): δ 11.61 (s, 1 OH), 10.81 (s, 1 OH), 7.93 (d, 1H, J=8 Hz, 1H5), 7.62 (t, 1H, J=8 Hz, H6), 7.48 (d, 1H, J=2 Hz, H7), 7.07 (s, 1H3).
By replacing the compound in example 8 by methyl-8-carboxamide-4-hydroxy-quinoline-2-carboxylate 37b, the abovenamed product is obtained as a white solid. Yield: 90%. 1H NMR (200 MHz, d6-DMSO): δ 14.70 (s, 1 OH), 13.28 (s, 1 OH), 8.50 (s, 1H, 1 NH), 8.32 (d, 1H, J=8 Hz, H arom.), 8.29 (d, 1H, J=8 Hz, H arom.), 7.99 (s, 1H, 1 NH), 7.49 (t, 1H, J=8 Hz, H6), 6.69 (s, 1H3).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate 2a in example 8 by methyl-3-bromo-4-hydroxy-quinoline-2-carboxylate 45b, the abovenamed product is obtained as a white solid. Yield: 51%. 1H NMR (200 MHz, d6-DMSO): δ 7.40 (d, 1H, J=8 Hz, H7), 7.21 (t, 1H, J=8 Hz, H6), 6.98 (d, 1H, J=8 Hz, H5), 3.9 (s, 2H, 2 HN).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate 2a in example 8 by methyl-8-cyano-4-hydroxy-quinoline-2-carboxylate 35b, the abovenamed product is obtained as a white solid. Yield: 93%. 1H NMR (200 MHz, d6-DMSO): δ 13.19 (s, 1 OH), 12.80 (s, 1 OH), 8.45 (d, 1H, J=8 Hz, H7), 8.37 (d, 1H, J=8 Hz, H5), 7.71 (t, 1H, J=8 Hz, H6), 7.50 (s, 1H3).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate 2a in example 8 by methyl-5-phenyl-8-amino-4-hydroxy-quinoline-2-carboxylate 73b, the abovenamed product is obtained as a yellow solid. Yield: 78%. 1H NMR (300 MHz, CDCl3): δ 11.91 (s, 1H, OH), 9.95 (s, 1H, OH), 7.21 (m, 5H, 5H arom.), 7.18 (d, 1H, J=8 Hz, H arom.), 7.10 (d, 1H, J=8 Hz, H arom.), 7.00 (s, 1H, H3), 5.23 (s, 2H, NH2).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate 2a in example 8 by methyl-6-(5′-cyanopentyl)-8-amino-4-hydroxy-quinoline-2-carboxylate 123b, the abovenamed product is obtained as a yellow solid. Yield: 78%. 1H NMR (200 MHz, d6-DMSO): δ 12.58 (s, 1H, OH), 11.40 (s, 1H, OH), 7.28 (s, 1H arom.), 6.89 (s, 1H arom.), 6.78 (s, 1H arom.), 5.02 (s, H2N), 2.60 (t, 4H, J=7 Hz, 2 CH2), 1.61 (m, 4H, 2 CH2), 1.40 (m, 2H, CH2).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate 2a in example 8 by methyl-6-cyano-8-nitro-4-hydroxy-quinoline-2-carboxylate 120b, the abovenamed product is obtained. Yield: 42%. 1H NMR (300 MHz, d6-DMSO): δ 12.01 (s, 1 OH), 6.28 (s, 1H, H5), 7.24 (s, 1H3), 6.86 (s, 1H, H7), 6.63 (s, 2 HN).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate 2a in example 8 by methyl-6-(4-methyl-piperazin-1-yl)-8-nitro-4-benzyloxy-quinoline-2-carboxylate 124a, the abovenamed product is obtained. Yield: 86%. 1H-NMR (300 MHz, d6-DMSO): δ 11.96 (s, 1 OH), 8.30 (d, 1H, J=2 Hz, 1H arom.), 7.70 (s, 1H3), 7.50 (m, 6H, 6H arom.), 6.63 (s, 2H, CH2benz.), 3.68 (m, 4H, 2 CH2N), 3.34 (m, 5H, 1H and 2 CH2N).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate 2a in example 8 by methyl-8-dimethylamino-4-hydroxy-quinoline-2-carboxylate 41c, the abovenamed product is obtained. Yield: 66%. 1H NMR (200 MHz, d6-DMSO): 8.23 (d, 2H, J=8 Hz, 2H arom.), 7.75 (t, 1H, J=8 Hz, 1H6), 7.51 (s, 1H, H3), 3.26 (s, 6H, 2 NCH3).
By replacing mehtyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate 2a in example 8 by methyl-4-(3-benzoyl-aminoprop-1-yl)-8-hydroxy-quinoline-2-carboxylate 85d and proceeding in the same manner, the abovenamed product is obtained. Yield: 93%. 1H-NMR (300 MHz, DMSO-d6): δ 12.81(s, 1H, COOH), 10.18 (broad s, 1H, OH), 8.55 (t, 1H, J=5.6 Hz, NHCO), 8.08 (s, 1H arom.), 7.85-7.18 (m, 8H arom.), 3.39-3.31 (m, 4H, CH2), 1.99-1.95 (m, 2H, CH2).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate 2a in example 8 by methyl-8-amino-4-hydroxy-6-phenyl-quinoline-2-carboxylate 86c and proceeding in the same manner, the abovenamed product is obtained. Yield: 82%. 1H-NMR (300 MHz, DMSO-d6): δ 12.58 (s, 1H, COOH), 11.65 (broad s, 1H, OH), 7.73 (s, 1H arom.), 7.73 (s, 1H arom.), 7.51-7.41 (m, 5H arom.), 7.18 (s, 1H arom.), 6.62 (broad s, 2H, NH2).
Dissolve sodium hydroxide (630 mg, 15.8 mmol) in 60 ml of methanol. Add to this solution 2-amino-3-benzyloxy-4-bromobenzaldehyde (600 mg, 1.96 mmol) and pyruvic acid (0.27 ml, 3.88 mmol). Heat this mixture at 60° C. overnight under a nitrogen atmosphere. Allow to cool and evaporate the methanol. Take up the oily red residue in water and wash with ethyl acetate. Take up the organic phase, adjust to pH 2 with concentrated hydrochloric acid solution. Filter the precipitate formed. Yield: 85%. 1H-NMR (300 MHz, DMSO): δ 13.57 (broad s, 1H, COOH), 8.61 (d, 1H, J=8 Hz, 1H arom.), 8.19 (d, 1H, J=8 Hz, 1H arom.), 7.90 (d, 1H, J=9 Hz, 1H arom.), 7.78 (d, 1H, J=9 Hz, 1H arom.), 7.68 (m, 2H arom.), 7.39 (m, 3H arom.), 5.61 (s, 2H, OCH2).
In a dry flask under argon, dissolve 7-bromo-8-benzyloxy-quinoline-2-carboxylic acid 4c (300 mg, 0.84 mmol) in 10 ml of dry DMF. At room temperature add NaH (37 mg, 0.93 mmol). Stir for 10 minutes, then add dropwise to this mixture benzyl bromide (0.11 ml, 0.92 mmol). Run the reaction overnight then evaporate the DMF. Take up the oily residue in ethyl acetate and wash with water. Dry the organic phases on Na2SO4, filter and evaporate the solvents. Purify the crude reaction product by silica gel column chromatography, eluent: Hex/EtOAc, 4/1 and 3/1. Yield: 85%. 1H-NMR (200 MHz, CDCl3): δ 8.25 (m, 2H arom.), 7.78 (d, 1H, J=9 Hz, 1H arom.), 7.61 (m, 4H arom.), 7.49 (d, 1H, J=9 Hz, 1H arom.), 7.36 (m, 6H arom.), 5.65 (s, 2H, OCH2), 5.53 (s, 2H, OCH2).
By replacing 7-bromo-8-benzyloxy-quinoline-2-carboxylic acid 4c in example 10 by 8-hydroxy-quinoline-2-carboxylic acid and proceeding in the same manner, the abovenamed product is obtained. Yield: 78%. 1H-NMR (200 MHz, CDCl3): δ 8.25 (m, 2H arom.), 8.23-7.52 (m, 5H arom.), 7.39-7.38 (m, 7H arom.), 7.14 (m, 1H arom.), 5.51 (s, 2H, OCH2), 5.43 (s, 2H, OCH2).
By replacing 7-bromo-8-benzyloxy-quinoline-2-carboxylic acid 4c in example 10 by methyl-4-hydroxy-8-bromo-quinoline carboxylate 42b and proceeding in the same manner, the abovenamed product is obtained. Yield: 88%. 1H-NMR (200 MHz, CDCl3): δ 8.31-8.26 (dd, 1H arom.), 8.13-8.09 (dd, 1H arom.), 7.75 (s, 1H arom.), 7.52-7.3540 (m, 6H arom.), 5.38 (s, 2H, OCH2), 4.08 (s, 3H, OCH3).
By replacing 7-bromo-8-benzyloxy-quinoline-2-carboxylic acid 4c in example 10 by 8-bromo-4-hydroxy-quinoline-2-carboxylic acid 3x, and by doubling the quantities of NaH and benzyl bromide and proceeding in the same manner, the abovenamed product is obtained. Yield: 88%. 1H-NMR (200 MHz, CDCl3): δ 8.29-8.25 (dd, 1H arom.), 8.13-8.09 (dd, 1H arom.), 7.71 (s, 1H arom.), 7.59-7.35 (m, 1H arom.), 5.53 (s, 2H, OCH2), 5.37 (s, 2H, OCH2).
By replacing 7-bromo-8-benzyloxy-quinoline-2-carboxylic acid 4c in example 10 by 8-benzyloxy-6-bromo-4-hydroxy-quinoline-2-carboxylic acid 46a, and by doubling the quantities of NaH and benzyl bromide and proceeding in the same manner, the abovenamed product is obtained. Yield: 61%. 1H-NMR (200 MHz, CDCl3): δ 8.00 (d, 1H arom.), 7.71 (s, 1H arom.), 7.64-7.34 (m, 15H arom.), 7.27-7.25 (d, 1H arom.), 5.48 (s, 2H, OCH2), 5.36 (s, 2H, OCH2), 5.34 (s, 2H, OCH2).
By replacing 7-bromo-8-benzyloxy-quinoline-2-carboxylic acid 4c in example 10 by 8-benzyloxy-7-bromo-4-hydroxy-quinoline-2-carboxylic acid 50c, and by doubling the quantities of NaH and benzyl bromide and proceeding in the same manner, the abovenamed product is obtained. Yield: 99%. 1H-NMR (300 MHz, CDCl3): δ 7.90-7.87 (d, 1H arom.), 7.72-7.68 (d, 1H arom.), 7.71 (s, 1H arom.), 7.65-7.28 (m, 15H arom.), 5.58 (s, 2H, OCH2), 5.51 (s, 2H, OCH2), 5.36 (s, 2H, OCH2).
By replacing 7-bromo-8-benzyloxy-quinoline-2-carboxylic acid 4c in example 10 by 8-benzyloxy-3-bromo-4-hydroxy-quinoline-2-carboxylic acid 53a, and by doubling the quantities of NaH and benzyl bromide and proceeding in the same manner, the abovenamed product is obtained. Yield: 99%. 1H-NMR (300 MHz, CDCl3): δ 7.62-7.31 (m, 17H arom.), 7.12-7.09 (d, 1H arom.), 5.51 (s, 2H, OCH2), 5.43 (s, 2H, OCH2), 5.23 (s, 2H, OCH2).
By replacing 7-bromo-8-benzyloxy-quinoline-2-carboxylic acid 4c in example 10 by methyl-6-bromo-8-cyano-4-hydroxy-quinoline-2-carboxylate 63b and proceeding in the same manner, the abovenamed product is obtained. Yield: 96%. 1H-NMR (300 MHz, CDCl3): δ 8.63-8.62 (d, 1H, J=2 Hz, 1H arom.), 8.23-8.22 (d, 1H, J=2 Hz, 1H arom.), 7.80 (s, 1H arom.), 7.50-7.44 (m, 5H arom.), 5.39 (s, 2H, OCH2), 4.08 (s, 3H, OCH3).
By replacing 7-bromo-8-benzyloxy-quinoline-2-carboxylic acid 4c in example 10 by 3-bromo-8-cyano-4-hydroxy-quinoline-2-carboxylic acid 66b and proceeding in the same manner, the abovenamed product is obtained. Yield: 87%. 1H-NMR (200 MHz, CDCl3): δ 8.62-8.58 (m, 1H arom.), 8.03-8.00 (m, 1H arom.), 7.52-7.40 (m, 6H arom.), 5.56 (s, 2H, OCH2).
By replacing 7-bromo-8-benzyloxy-quinoline-2-carboxylic acid in example 10 by methyl-5-bromo-8-nitro-4-hydroxy-quinoline-2-carboxylate 72b, the abovenamed product is obtained. Yield: 94%. 1H NMR (200 MHz, CDCl3): δ 7.98 (d, 1H, J=8 Hz, H7), 7.85 (s, 1H3), 7.82 (d, 1H, J=8 Hz, H5), 7.61 (m, 2H arom.), 7.50 (m, 3H arom.), 5.46 (s, 2H benz.), 4.07 (s, 3H, OCH3).
By replacing 7-bromo-8-benzyloxy-quinoline-2-carboxylic acid in example 10 by methyl-6-bromo-8-nitro-4-hydroxy-quinoline-2-carboxylate 31b, the abovenamed product is obtained. Yield: 95%. 1H NMR (300 MHz, CDCl3): δ 8.65 (d, 1H, J=2 Hz, H7), 8.21 (d, 1H, J=2 Hz, H5), 7.83 (s, 1H3), 7.53 (m, 5H arom.), 5.44 (s, 2H benz.), 4.08 (s, 3H, OCH3).
By replacing 7-bromo-8-benzyloxy-quinoline-2-carboxylic acid in example 10 by methyl-4-(toluene-4-sulfonamino)-8-nitro-quinoline-2-carboxylate 15c and benzyl bromide by iodomethane, the abovenamed product is obtained. Yield: 89%. 1H NMR (200 MHz, CDCl3): δ 8.73 (dd, 1H, J=2 and 9 Hz, H arom.), 8.16 (dd, 1H, J=2 and 8 Hz, H arom.), 7.81 (dd, 1H, J=8 and 9 Hz, H6), 7.56 (s, 1H, H3), 7.52 (AB, 2H, J=7 Hz, 2H tosyl), 7.35 (AB, 2H, J=7 Hz, 2H tosyl), 4.01 (s, 3H, OCH3), 3.30 (s, 3H, CH3 tosyl), 2.50 (s, 3H, CH3).
By replacing 7-bromo-8-benzyloxy-quinoline-2-carboxylic acid in example 10 by methyl-4-benzyloxy-8-amino-quinoline-2-carboxylate and benzyl bromide by methyl iodide, the abovenamed product is obtained. Yield: 25%. 1H NMR (200 MHz, CDCl3): δ 7.82 (dd, 1H, J=2 and 9 Hz, H arom.), 7.65 (s, 1H, H3), 7.5 (m, 6H, 6H arom.), 7.09 (dd, 1H, J=2 and 8 Hz, H6), 5.32 (s, 2H, CH2benz.), 4.03 (s, 3H, OCH3), 3.19 (s, 6H, 2 NCH3).
Dissolve 0.74 g (2 mmol) of benzyl-8-benzyloxy-quinoline-2-carboxylate 5a in 25 ml of dichloromethane. Cool to −10° C. and add by small spatula tips, without allowing the temperature to rise above −5° C., 0.90 g (2.2 mmol) of 2,4,4,6-tetrabromocyclohexa-2,5-dienone. Allow to return to room temperature and stir overnight. Evaporate to dryness and perform chromatography on a silica gel column, eluent: EtOAc/Hex: 1/3 to obtain the abovenamed product. Yield: 86%. 1H-NMR (200 MHz, CDCl3): δ 8.66 (d, 1H, J=9 Hz, 1H arom.), 8.33 (d, 1H, J=9 Hz, 1H arom.) 7.81 (d, 1H, J=8 Hz, 1H arom.), 7.56 (m, 4H arom.), 7.40-7.30 (m, 6H arom.), 7.06 (d, 1H, J=8 Hz, 1H arom.), 5.55 (s, 2H, OCH2), 5.45 (s, 2H, OCH2).
By replacing benzyl-8-benzyloxy-quinoline-2-carboxylate 5a in example 11 by methyl-8-methoxy-quinoline-2-carboxylate and proceeding in the same manner, the abovenamed product is obtained. Yield: 89%. 1H-NMR (200 MHz, CDCl3): δ 8.63 (d, 1H, J=9 Hz, 1H arom.), 8.31 (d, 1H, J=9 Hz, 1H arom.) 7.82 (d, 1H, J=8 Hz, 1H arom.), 6.97 (d, 1H, J=8 Hz, 1H arom.), 4.09 (s, 3H, OCH3), 4.04 (s, 3H, OCH3).
Dissolve 0.932 g (4 mmol) of methyl-4-hydroxy-8-methoxy-quinoline-2-carboxylate in 2 ml of POCl3 and heat under reflux for 2 hours. Allow to cool and pour on a water-ice mixture. Extract twice with EtOAc, wash with saturated NaCl solution, dry on Na2SO4 and evaporate to dryness. Chromatograph on a silica column, eluent: CH2Cl2 to obtain the abovenamed product. Yield: 67%. 1H-NMR (200 MHz, CDCl3): δ 8.33 (s, 1H arom.), 7.85 (d, 1H, J=8 Hz, 1H arom.), 7.85 (t, 1H, J=8 Hz, 1H arom.), 7.16 (d, 1H, J=8 Hz, 1H arom.), 4.11 (s, 3H, OCH3), 4.06 (s, 3H, OCH3).
By replacing methyl-4-hydroxy-8-methoxy-quinoline-2-carboxylate in example 12 by methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate 2a and proceeding in the same manner, the abovenamed product is obtained. Yield: 73%. 1H-NMR (200 MHz, CDCl3): δ 8.32 (s, 1H arom.), 7.83 (d, 1H, J=9 Hz, 1H arom.), 7.60-7.36 (m, 6H arom.), 7.17 (d, 1H, J=9 Hz, 1H arom.), 5.46 (s, 2H, OCH2), 4.06 (s, 3H, OCH3).
By replacing methyl-4-hydroxy-8-methoxy-quinoline-2-carboxylate in example 12 by methyl-4-hydroxy-8-nitro-quinoline-2-carboxylate 2r and proceeding in the same manner, the abovenamed product is obtained. Yield: 100%. 1H-NMR (300 MHz, CDCl3): δ 8.53 (d, 1H, J=8 Hz, 1H arom.), 8.40 (s, 1H arom.), 8.17 (d, 1H, J=8 Hz, 1H arom.), 7.84 (m, 1H arom.), 4.07 (s, 3H, OCH3).
Dissolve 1.11 g (3.8 mmol) of methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate 2a in 30 ml of dichloromethane. Add 2.2 ml (26 mmol) of pyridine. Cool to 0° C. and add by small amounts 5 ml (30 mmol) of triflic anhydride. Allow to return to room temperature and stir for 2 hours. Add a saturated NH4Cl solution and extract with dichloromethane. Wash with saturated NaCl solution, dry on Na2SO4 and evaporate to dryness. Chromatograph on a silica gel column, eluent: EtOAc/Hex: 1/4 to obtain the abovenamed product. Yield: 73%. 1H-NMR (200 MHz, CDCl3): δ 8.20 (s, 1H arom.), 7.68-7.24 (m, 8H arom.), 5.48 (s, 2H, OCH2), 4.08 (s, 3H, OCH3).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate 2a in example 13 by methyl-4-hydroxy-8-nitro-quinoline-2-carboxylate 2r and proceeding in the same manner, the abovenamed product is obtained. Yield: 55%. 1H-NMR (200 MHz, CDCl3): δ 8.38-8.23 (m, 3H arom.), 7.93 (t, 1H, J=8 Hz, 1H arom.), 4.09 (s, 3H, OCH3).
Dissolve 300 mg (0.77 mmol) of methyl-4-hydroxy-6-bromo-8-benzyloxy-quinoline-2-carboxylate 2l in 7 ml of degassed dimethylformamide. Add 40 mg (0.035 mmol) of tetrakistriphenylphosphine palladium (0), 383 mg (1.7 mmol, 2.2 eq) of tripotassium phosphate, 235 mg (1.55 mmol, 2 eq) of 4-methoxybenzene boronic acid. Heat at 115° C. for 16 hours, add water plus ice, stir for 1 hour then filter. Chromatograph the solid on a silica gel column, eluent: CH2Cl2/EtOAc: 9/1 to obtain the abovenamed product. Yield: 30%. 1H-NMR (200 MHz, CDCl3): δ 9.46 (broad s, 1H, OH), 8.1 (m, 1H arom.), 7.60-7.39 (m, 8H arom.), 7.01-6.97 (m, 3H arom.), 5.36 (s, 2H, OCH2), 4.04 (s, 3H, OCH3), 3.87 (s, 3H, OCH3).
Starting with methyl-4-hydroxy-5-bromo-8-benzyloxy-quinoline-2-carboxylate 2b and replacing in example 14 4-methoxybenzene boronic acid by benzene boronic acid and proceeding in the same manner, the abovenamed product is obtained. Yield: 49%. 1H-NMR (200 MHz, DMSO-d6): δ 9.55 (broad s, 1H, OH), 7.62-7.04 (m, 11H arom.), 7.02 (d, 1H, J=8 Hz, 1H arom.), 6.54 (s, 1H arom.), 5.44 (s, 2H, OCH2), 4.08 (s, 3H, OCH3).
Starting with methyl-8-benzyloxy-6-bromo-4-hydroxyquinoline-2-carboxylate 2k and replacing in example 14 4-methoxybenzene boronic acid by par 3-methylbenzene boronic acid and proceeding in the same manner, the abovenamed product is obtained. Yield: 30%. 1H-NMR (200 MHz, CDCl3): δ 9.47 (broad s, 1H, OH), 8.15 (m, 1H arom.), 7.73-7.30 (m, 9H arom.), 7.21-7.17 (m, 1H arom.), 7.01 (m, 1H arom.), 5.36 (s, 2H, OCH2), 4.04 (s, 3H, OCH3), 2.43 (s, 3H, CH3).
Starting with methyl-8-benzyloxy-6-bromo-4-hydroxyquinoline-2-carboxylate 2l and replacing in example 14 4-methoxybenzene boronic acid by 3,4-dichlorobenzene boronic acid and proceeding in the same manner, the abovenamed product is obtained. Yield: 50%. 1H-NMR (300 MHz, CDCl3): δ 9.47 (broad s, 1H, OH), 8.05 (s, 1H arom.), 7.92 (s, 1H arom.), 7.76-7.72 (m, 3H arom.), 7.60-7.58 (m, 2H arom.), 7.47-7.45 (m, 3H arom.), 6.60 (s, 1H arom.), 5.51 (s, 2H, OCH2), 4.04 (s, 3H, OCH3).
Starting with methyl-8-benzyloxy-6-bromo-4-hydroxyquinoline-2-carboxylate 2l and replacing in example 14 4-methoxybenzene boronic acid by 3-pyridine boronic acid 1,3-propanediol cyclic ester and proceeding in the same manner, the abovenamed product is obtained. Yield: 56%. 1H-NMR (200 MHz, CDCl3): δ 8.97 (broad s, 1H, OH), 8.58 (m, 1H arom.), 8.17 (m, 1H arom.), 7.94 (m, 1H arom.), 7.74 (m, 1H arom.), 7.58-7.47 (m, 7H arom.), 6.56 (s, 1H arom.), 5.52 (s, 2H, OCH2), 4.04 (s, 3H, OCH3).
Starting with methyl-8-benzyloxy-6-bromo-4-hydroxyquinoline-2-carboxylate 2l and replacing in example 14 4-methoxybenzene boronic acid by 4-chlorobenzene boronic acid and proceeding in the same manner, the abovenamed product is obtained. Yield: 90%. 1H-NMR (300 MHz, CDCl3): δ 9.50 (broad s, 1H, OH), 8.10 (m, 2H arom.), 7.71-7.64 (m, 2H arom.), 7.56-7.35 (m, 7H arom.), 7.02 (m, 1H arom.), 5.36 (s, 2H, OCH2), 4.04 (s, 3H, OCH3).
Starting with methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2l and replacing in example 14 4-methoxybenzene boronic acid by benzene boronic acid and proceeding in the same manner, the abovenamed product is obtained. Yield: 50%. 1H-NMR (300 MHz, CDCl3): δ 9.46 (broad s, 1H, OH), 7.90 (m, 1H arom.), 7.80 (m, 2H arom.), 7.60 (m, 1H arom.), 7.61-7.53 (m, 3H arom.), 6.73 (m, 1H arom.), 4.14 (s, 3H, OCH3), 4.06 (s, 3H, OCH3).
By replacing in example 14 4-methoxybenzene boronic acid by methylethylene catecholborane and proceeding in the same manner the abovenamed product is obtained. Yield: 70%. 1H-NMR (200 MHz, CDCl3): δ 9.45 (broad s, 1H, OH), 7.79 (m, 1H arom.), 7.12 (m, 1H arom.), 6.96 (m, 1H arom.), 6.45-6.36 (m, 2H vinylic), 4.05 (s, 3H, OCH3), 4.03 (s, 3H, OCH3), 1.94-1.91 (d, 3H, CH3).
Starting with benzyl-8-methoxy-5-bromo-quinoline-2-carboxylate 5c and replacing in example 14 4-methoxybenzene boronic acid by benzene boronic acid and proceeding in the same manner, the abovenamed product is obtained. Yield: 59%. 1H-NMR (300 MHz, CDCl3): δ 8.38 (d, 1H, J=9 Hz, 1H arom.), 8.19 (d, 1H, J=9 Hz, 1H arom.), 7.56-7.44 (m, 6H arom.), 7.16 (d, 1H, J=8 Hz, 1H arom.), 4.14 (s, 3H, OCH3), 4.07 (s, 3H, OCH3).
Starting with methyl-4-chloro-8-methoxy-quinoline-2-carboxylate 8a and replacing in example 14 4-methoxybenzene boronic acid by benzene boronic acid and proceeding in the same manner, the abovenamed product is obtained. Yield: 55%. 1H-NMR (300 MHz, CDCl3): δ 8.19 (m, 1H arom.), 7.55-7.52 (m, 7H arom.), 7.11 (m, 1H arom.), 4.13 (s, 3H, OCH3), 4.07 (s, 3H, OCH3).
Starting with methyl-4-chloro-8-methoxy-quinoline-2-carboxylate 8a and replacing in example 14 4-methoxybenzene boronic acid by 4-chlorobenzene boronic acid and proceeding in the same manner, the abovenamed product is obtained. Yield: 87%. 1H-NMR (200 MHz, CDCl3): δ 8.16 (s, 1H arom.), 7.56-7.48 (m, 7H arom.), 7.11 (m, 1H arom.), 4.13 (s, 3H, OCH3), 4.07 (s, 3H, OCH3).
Starting with methyl-8-benzyloxy-6-bromo-4-hydroxyquinoline-2-carboxylate 2l and replacing in example 14 4-methoxybenzene boronic acid by furan-2-boronic acid and proceeding in the same manner, the abovenamed product is obtained. Yield: 59%. 1H-NMR (300 MHz, CDCl3): δ 9.45 (broad s, 1H, OH), 8.18 (s, 1H arom.), 7.54-7.40 (m, 7H arom.), 6.98 (d, J=1.89 Hz, 1H arom.), 6.78 (d, J=3.45 Hz, 1H arom.), 6.51 (dd, J=1.86 Hz and J=3.42 Hz, 1H arom.), 5.35 (s, 2H, OCH2), 4.03 (s, 3H, OCH3).
Starting with benzyl-4,8-dibenzyloxy-6-bromoquinoline-2-carboxylate 46b and replacing in example 14 4-methoxybenzene boronic acid by 2-chloropheenyl boronic acid and proceeding in the same manner, the abovenamed product is obtained. Yield: 80%. 1H-NMR (200 MHz, CDCl3): δ 7.87-7.86 (d, 1H arom.), 7.74 (s, 1H arom.), 7.62-7.28 (m, 20H arom.), 5.51 (s, 2H, OCH2), 5.42 (s, 2H, OCH2), 5.36 (s, 2H, OCH2).
Starting with benzyl-4,8-dibenzyloxy-6-bromoquinoline-2-carboxylate 46b and replacing in example 14 4-methoxybenzene boronic acid by 3-chlorophenyl boronic acid and proceeding in the same manner, the abovenamed product is obtained. Yield: 63%. 1H-NMR (200 MHz, CDCl3): δ 8.00-7.99 (d, 1H arom.), 7.74 (s, 1H arom.), 7.68-7.28 (m, 20H arom.), 5.50 (s, 2H, OCH2), 5.47 (s, 2H, OCH2), 5.39 (s, 2H, OCH2).
Starting with benzyl-4,8-dibenzyloxy-7-bromoquinoline-2-carboxylate 50d and replacing in example 14 4-methoxybenzene boronic acid by benzene boronic acid and proceeding in the same manner, the abovenamed product is obtained. Yield: 60%. 1H-NMR (300 MHz, CDCl3): δ 8.10-8.07 (d, 1H arom.), 7.72 (s, 1H arom.), 7.66-7.37 (m, 16H arom.), 7.18-7.15 (m, 5H arom.), 5.52 (s, 2H, OCH2), 5.39 (s, 2H, OCH2), 5.21 (s, 2H, OCH2).
Starting with benzyl-4,8-dibenzyloxy-6-bromoquinoline-2-carboxylate 46b and replacing in example 14 4-methoxybenzene boronic acid by 2-methoxyphenyl boronic acid and proceeding in the same manner, the abovenamed product is obtained. Yield: 70%. 1H-NMR (200 MHz, CDCl3): δ 7.96 (d, 1H arom.), 7.70 (s, 1H arom.), 7.57-7.33 (m, 20H arom.), 5.51 (s, 2H, OCH2), 5.43 (s, 2H, OCH2), 5.36 (s, 2H, OCH2), 3.72 (s, 3H, OCH3).
Starting with benzyl-4,8-dibenzyloxy-3-bromoquinoline-2-carboxylate 53b and replacing in example 14 4-methoxybenzene boronic acid by benzene boronic acid and proceeding in the same manner, the abovenamed product is obtained. Yield: 20%. 1H-NMR (300 MHz, CDCl3): δ 7.74-7.71 (d, 1H arom.), 7.56-7.28 (m, 17H arom.), 7.10-7.07 (m, 5H arom.), 5.47 (s, 2H, OCH2), 5.13 (s, 2H, OCH2), 4.60 (s, 2H, OCH2).
Starting with methyl-6-bromo-8-cyano-4-hydroxy-quinoline-2-carboxylate 63b and replacing in example 14 4-methoxybenzene boronic acid by benzene boronic acid and proceeding in the same manner, the abovenamed product is obtained. Yield: 84%. 1H-NMR (300 MHz, DMSO6): δ 12.60 (broad s, 1H, OH), 8.78 (s, 1H arom.), 8.66 (s, 1H arom.), 7.68-7.48 (m, 5H arom.), 6.77 (s, 1H arom.), 3.98 (s, 3H, OCH3).
By replacing methyl-4-hydroxy-6-bromo-8-benzyloxy-quinoline-2-carboxylate 2k in example 14 by methyl-5-bromo-8-nitro-4-benzyloxy-quinoline-2-carboxylate 72c and by replacing 4-methoxybenzene boronic acid by phenyl boronic acid, the abovenamed product is obtained. Yield: 74%. 1H NMR (200 MHz, CDCl3): δ 8.00 (d, 1H, J=8 Hz, H7), 7.42 (d, 1H, J=8 Hz, H5), 7.24 (m, 8H, 8H arom.), 7.73 (m, 2H, 2H arom.), 5.01 (s, 2H benz.), 5.04 (s, 2H, 2H benz.).
By replacing methyl-4-hydroxy-6-bromo-8-benzyloxy-quinoline-2-carboxylate 2k in example 14 by benzyl-7-iodo-8-amino-4-benzyloxy-quinoline-2-carboxylate 34c and by replacing 4-methoxybenzene boronic acid by phenyl boronic acid, the abovenamed product is obtained. Yield: 61%. 1H NMR (200 MHz, CDCl3): δ 7.61 (d, 1H, J=8 Hz, H7), 7.57 (s, 1H arom.), 7.48 (m, 5H arom.), 7.41 (m, 11H arom.), 5.49 (s, 2H benz.), 5.37 (s, 4H, 2 NH and 2H benz.).
Starting with methyl-8-methoxy-5-bromo-quinoline-2-carboxylate 5c and replacing in example 14 4-methoxybenzene boronic acid by 3-chlorobenzene boronic acid and proceeding in the same manner, the abovenamed product is obtained. Yield: 74%. 1H-NMR (300 MHz, CDCl3): δ 8.32 (d, 1H, J=9 Hz, 1H arom.), 8.19 (d, 1H, J=9 Hz, 1H arom.), 7.53-7.36 (m, 5H arom.), 7.15 (d, 1H, J=8 Hz, 1H arom.), 4.14 (s, 3H, OCH3), 4.07 (s, 3H, OCH3).
Starting with benzyl-4,8-dibenzyloxy-6-bromoquinoline-2-carboxylate 46b and replacing in example 14 4-methoxybenzene boronic acid by 3,5-dichlorobenzene boronic acid and proceeding in the same manner, the abovenamed product is obtained. Yield: 45%. 1H-NMR (200 MHz, CDCl3): δ 7.97 (s, 1H arom.), 7.74 (s, 1H arom.), 7.63-7.36 (m, 19H arom.), 5.50 (s, 2H, OCH2), 5.47 (s, 2H, OCH2), 5.30 (s, 2H, OCH2).
Starting with benzyl-4,8-dibenzyloxy-6-bromoquinoline-2-carboxylate 46b and replacing in example 14 4-methoxybenzene boronic acid by 4-fluorobenzene boronic acid and proceeding in the same manner, the abovenamed product is obtained. Yield: 67%. 1H-NMR (300 MHz, CDCl3): δ 7.97 (s, 1H arom.), 7.73 (s, 1H arom.), 7.59-7.13 (m, 20H arom.), 5.50 (s, 2H, OCH2), 5.46 (s, 2H, OCH2), 5.38 (s, 2H, OCH2).
Starting with methyl-8-nitro-4-trifluoromethanesulfonyloxy-quinoline-2-carboxylate 92a and replacing in example 14 4-methoxybenzene boronic acid by benzene boronic acid and proceeding in the same manner, the abovenamed product is obtained. Yield: 47%. 1H-NMR (200 MHz, CDCl3): δ 8.27 (s, 1H arom.), 8.23-8.10 (m, 2H arom.), 7.71-7.54 (m, 6H arom.), 4.07 (s, 3H, OCH3).
Dissolve 300 mg (0.96 mmol) of methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in 8 ml of degassed acetonitrile. Add 33 mg (0.17 mmol) of copper iodide, 19 mg (0.107 mmol, 0.11 eq) of palladium(II) chloride, 65 mg (0.247 mmol, 0.25 mmol) of triphenylphosphine, 352 μl (9.6 mmol, 10 eq) of phenylacetylene and 1.84 ml of triethylamine. Heat at 50° C. for 16 hours, evaporate to dryness and chromatograph using as eluent: CH2Cl2/EtOAc: 9/1 to obtain the abovenamed product. Yield: 68%. 1H-NMR (200 MHz, CDCl3): δ 9.42 (broad s, 1H, OH), 8.11 (s, 1H arom.), 7.56 (m, 2H arom.), 7.39-7.37 (m, 3H arom.), 7.20 (s, 1H arom.), 6.98 (s, 1H arom.), 4.08 (s, 3H, OCH3), 4.05 (s, 3H, OCH3).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by methyl-8-benzyloxy-4-trifluoromethanesulfonyloxy-quinoline-2-carboxylate 11, the abovenamed product is obtained. Yield: 52%. 1H-NMR (200 MHz, CDCl3): δ 8.40 (s, 1H arom), 7.98 (d, 1H, J=9 Hz, 1H arom.), 7.70-7.58 (m, 5H arom.), 7.46-7.36 (m, 6H arom.), 7.16 (d, 1H, J=8 Hz, 1H arom.), 5.47 (s, 2H, OCH2), 4.08 (s, 3H, OCH3).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by methyl-8-benzyloxy-4-trifluoromethanesulfonyloxy-quinoline-2-carboxylate 11 and by replacing phenylacetylene by N-Boc propargylamine and proceeding in the same manner, the abovenamed product is obtained. Yield: 34%. 1H-NMR (200 MHz, CDCl3): δ 8.28 (m, 1H arom.), 7.85 (d, 1H, J=8 Hz, 1H arom.), 7.82-7.34 (m, 6H arom.), 7.13 (d, 1H, J=8 Hz, 1H arom.), 5.45 (s, 2H, OCH2), 4.90 (broad s, 1H, NH), 4.31 (d, 2H, J=6 Hz, CH2), 4.05 (s, 3H, OCH3), 1.49 (s, 9H, (CH3)3).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by methyl-8-benzyloxy-4-trifluoromethanesulfonyloxy-quinoline-2-carboxylate 11 and by replacing phenylacetylene by O-benzyl propargylic alcohol and proceeding in the same manner, the abovenamed product is obtained. Yield: 68%. 1H-NMR (300 MHz, CDCl3): δ 8.32 (s, 1H arom.), 7.86 (d, 1H, J=8 Hz, 1H arom.), 7.54-7.34 (m, 11H arom.), 7.14 (d, 1H, J=8 Hz, 1H arom.), 5.45 (s, 2H, OCH2), 4.76 (s, 2H, OCH2), 4.57 (s, 2H, OCH2), 4.06 (s, 3H, OCH3).
By replacing phenylacetylene in example 15 by 1-heptyne and proceeding in the same manner, the abovenamed product is obtained. Yield: 47%. 1H-NMR (200 MHz, CDCl3): δ 9.38 (broad s, 1H, OH), 7.96 (m, 1H arom.), 7.07 (m, 1H arom.), 6.96 (m, 1H arom.), 4.05 (s, 3H, OCH3), 4.03 (s, 3H, OCH3), 2.42 (t, 2H, CH2), 1.56 (m, 2H, CH2), 1.42 (m, 4H, 2×CH2), 0.94 (t, 3H, CH3).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by methyl-4-hydroxy-6-bromo-8-benzyloxy-quinoline-2-carboxylate 2l and by replacing phenylacetylene by N-Boc propargylamine and proceeding in the same manner, the abovenamed product is obtained. Yield: 70%. 1H-NMR (300 MHz, CDCl3): δ 9.42 (broad s, 1H, OH), 7.99 (m, 1H arom.), 7.45 (m, 5H arom.), 7.16 (m, 1H arom.), 6.96 (m, 1H arom.), 5.27 (s, 2H, OCH2), 4.18-4.15 (s, 2H, CH2), 4.02 (s, 3H, OCH3), 1.45 (s, 9H, (CH3)3).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by methyl-4-hydroxy-6-bromo-8-benzyloxy-quinoline-2-carboxylate 2l and by replacing phenylacetylene by O-benzyl propargylic alcohol and proceeding in the same manner, the abovenamed product is obtained. Yield: 73%. 1H-NMR (300 MHz, CDCl3): δ 9.41 (broad s, 1H, OH), 8.04 (m, 1H arom.), 7.45-7.38 (m, 10H arom.), 7.19 (m, 1H arom.), 6.96 (m, 1H arom.), 5.27 (s, 2H, OCH2), 4.69 (s, 2H, OCH2), 4.42 (s, 2H, OCH2), 4.03 (s, 3H, OCH3).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by benzyl-4-benzyloxy-8-bromo-quinoline-2-carboxylate 47a and by replacing phenylacetylene by 1-hexyne and proceeding in the same manner, the abovenamed product is obtained. Yield: 55%. 1H-NMR (300 MHz, CDCl3): δ 8.21-8.19 (d, 1H arom.), 7.90-7.87 (d, 1H arom.), 7.70 (s, 1H arom.), 7.58-7.38 (m, 11H arom.), 5.50 (s, 2H, OCH2), 5.35 (s, 2H, OCH2), 2.62-2.57 (t, 2H, CC—CH2), 1.69-1.51 (m, 4H, CH2—CH2—CH3), 0.99-0.94 (t, 3H, CH2—CH3).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by benzyl-4,8-dibenzyloxy-6-bromoquinoline-2-carboxylate 46b and by replacing phenylacetylene by O-benzyl propargylic alcohol and proceeding in the same manner, the abovenamed product is obtained. Yield: 95%. 1H-NMR (300 MHz, CDCl3): δ 7.98-7.97 (d, 1H arom.), 7.72 (s, 1H arom.), 7.56-7.33 (m, 20H arom.), 7.18-7.17 (d, 1H arom.), 5.49 (s, 2H, OCH2), 5.36 (s, 2H, OCH2), 5.34 (s, 2H, OCH2), 4.68 (s, 2H, CH2—OCH2), 4.43 (s, 2H, CH2—OCH2).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by benzyl-4,8-dibenzyloxy-7-bromoquinoline-2-carboxylate 50c and by replacing phenylacetylene by O-benzyl propargylic alcohol and proceeding in the same manner, the abovenamed product is obtained. Yield: 38%. 1H-NMR (200 MHz, CDCl3): δ 7.97-7.92 (d, 1H arom.), 7.69 (s, 1H arom.), 7.57-7.23 (m, 21H arom.), 5.68 (s, 2H, OCH2), 5.51 (s, 2H, OCH2), 5.35 (s, 2H, OCH2), 4.69 (s, 2H, CH2—OCH2), 4.48 (s, 2H, CH2—OCH2).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by benzyl-4,8-dibenzyloxy-7-bromo-quinoline-2-carboxylate 50c, the abovenamed product is obtained. Yield: 58%. 1H-NMR (200 MHz, CDCl3): δ 7.99-7.94 (d, 1H arom.), 7.69-7.27 (m, 22H arom.), 5.73 (s, 2H, OCH2), 5.52 (s, 2H, OCH2), 5.36 (s, 2H, OCH2).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by methyl-6-bromo-8-cyano-4-benzyloxy-quinoline-2-carboxylate 65a, the abovenamed product is obtained. Yield: 66%. 1H-NMR (300 MHz, CDCl3): δ 8.60 (d, 1H, J=2 Hz, 1H arom.), 8.26-8.25 (d, 1H, J=2 Hz, 1H arom.), 7.80 (s, 1H arom.), 7.60-7.39 (m, 10H arom.), 5.40 (s, 2H, OCH2), 4.09 (s, 3H, OCH3).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by benzyl-3-bromo-4-benzyloxy-8-cyano-quinoline-2-carboxylate 67a, the abovenamed product is obtained. Yield: 9%. 1H-NMR (200 MHz, CDCl3): δ 8.63-8.58 (m, 1H arom.), 8.17-8.13 (m, 1H arom.), 7.97-7.41 (m, 11H arom.), 5.61 (s, 2H, OCH2).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by methyl-6-bromo-8-cyano-4-benzyloxy-quinoline-2-carboxylate 65a, the abovenamed product is obtained. Yield: 27%. 1H-NMR (300 MHz, CDCl3): δ 9.24 (broad s, 1H, OH), 8.60 (m, 1H arom.), 8.02 (m, 1H arom.), 7.01 (m, 1H arom.), 4.08 (s, 3H, OCH3), 0.27 (s, 9H, Si(CH3)3).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by methyl-3-bromo-8-nitro-4-hydroxy-quinoline-2-carboxylate 45a and by replacing phenylacetylene by trimethylsilylacetylene, the abovenamed product is obtained. Yield: 46%. 1H NMR (200 MHz, CDCl3): δ 8.65 (dd, 1H, J=1 and 8 Hz, H arom.), 8.12 (dd, 1H, J=1 and 8 Hz, H arom.), 7.83 (t, 1H, J=8 Hz, H arom.), 7.80 (m, 1H, OH), 4.14 (s, 3H, CH3).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by methyl-3-bromo-8-nitro-4-hydroxy-quinoline-2-carboxylate 45a, the abovenamed product is obtained. Yield: 63%. 1H NMR (300 MHz, CDCl3): δ 8.65 (dd, 1H, J=2 and 8 Hz, H arom.), 8.11 (dd, 1H, J=2 and 8 Hz, H arom.), 7.85 (m, 2H, H arom. and OH), 7.55 (m, 3H arom.), 4.16 (s, 3H, OCH3).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by benzyl-3-bromo-8-nitro-4-hydroxy-quinoline-2-carboxylate and by replacing phenylacetylene by 3-benzyloxyprop-1-yne, the abovenamed product is obtained. Yield: 43%. 1H NMR (300 MHz, CDCl3): δ 8.54 (d, 1H, J=8 Hz, H arom.), 8.10 (d, 1H, J=8 Hz, H arom.), 7.81 (t, 1H, J=8 Hz, H6), 7.40 (m, 10H, 10H arom.), 5.57 (s, 2H, CH2benz.), 4.80 (s, 2H, CH2benz.), 4.70 (s, 2H, CH2O).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by benzyl-3-bromo-8-nitro-4-hydroxy-quinoline-2-carboxylate and by replacing phenylacetylene by 3-N-(terbutoxycarbonyl)aminoprop-1-yne, the abovenamed product is obtained. Yield: 43%. 1H NMR (300 MHz, CDCl3): δ 8.48 (d, 1H, J=8 Hz, H arom.), 8.08 (d, 1H, J=8 Hz, H arom.), 7.76 (t, 1H, J=8 Hz, H arom.), 7.46 (m, 5H arom.), 5.54 (s, 2H, CH2benz.), 5.05 (s, 1H, 1 NH), 4.63 (d, 2H, J=6 Hz, CH2N), 1.49 (s, 9H, 3 CH3).
By replacing methyl-4-hydroxy-6-bromo-8-mehoxy-quinoline-2-carboxylate 2k in example 15 by methyl-5-bromo-8-nitro-4-benzyloxy-quinoline-2-carboxylate 72c, the abovenamed product is obtained. Yield: 97%. 1H NMR (200 MHz, CDCl3): δ 8.03 (d, 1H, J=8 Hz, H7), 7.90 (d, 1H, J=8 Hz, H6), 7.86 (s, 1H3), 7.56 (m, 2H arom.), 7.32 (m, 6H arom.), 7.05 (m, 2H arom.), 5.46 (s, 2H benz.), 4.08 (s, 3H, OCH3).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by methyl-5-bromo-8-nitro-4-benzyloxy-quinoline-2-carboxylate 72c and by replacing phenylacetylene by 3-benzyloxyprop-1-yne, the abovenamed product is obtained. Yield: 59%. 1H NMR (200 MHz, CDCl3): δ 7.94 (d, 1H, J=8 Hz, 1H arom.), 7.79 (s, 1H3), 7.74 (d, 1H, J=8 Hz, 1H arom.), 7.51 (m, 2H arom.), 7.32 (m, 8H arom.), 5.33 (s, 2H benz.), 4.49 (s, 2H benz.), 4.04 (s, 3H, OCH3), 3.83 (s, 2H, CH2O).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by methyl-5-bromo-8-nitro-4-benzyloxy-quinoline-2-carboxylate 72c and by replacing phenylacetylene by 3-N-(terbutoxycarbonyl)aminoprop-1-yne, the abovenamed product is obtained. Yield: 89%. 1H NMR (200 MHz, CDCl3): δ 7.92 (d, 1H, J=8 Hz, 1H arom.), 7.79 (s, 1H3), 7.72 (d, 1H, J=8 Hz, 1H arom.), 7.57 (m, 2H arom.), 7.49 (m, 3H arom.), 5.33 (AB, 2H, H=6 Hz, 2H benz.), 4.05 (m, 1 HN), 4.04 (s, 3H, OCH3), 3.65 (d, 2H, J=6 Hz, CH2N), 1.44 (s, 9H, 3 CH3).
By replacing methyl-4-hydroxy-6-bromo-8-meethoxy-quinoline-2-carboxylate 2k in example 15 by methyl-6-bromo-8-nitro-4-benzyloxy-quinoline-2-carboxylate 31e, the abovenamed product is obtained. Yield: 85%. 1H NMR (300 MHz, CDCl3): δ 8.58 (d, 1H, J=2 Hz, 1H arom.), 8.20 (d, 1H, J=2 Hz, 1H arom.), 7.80 (s, 1H3), 7.49 (m, 5H arom.), 5.41 (s, 2H benz.), 4.07 (s, 3H, OCH3).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by methyl-6-bromo-8-nitro-4-benzyloxy-quinoline-2-carboxylate 31e and by replacing phenylacetylene by 3-benzyloxyprop-1-yne, the abovenamed product is obtained. Yield: 87%. 1H NMR (300 MHz, CDCl3): δ 8.51 (d, 1H, J=2 Hz, 1H arom.), 8.07 (d, 1H, J=2 Hz, 1H arom.), 7.79 (s, 1H3), 7.44 (m, 10H arom.), 5.39 (s, 2H benz.), 4.69 (s, 2H benz.), 4.69 (s, CH2O), 4.02 (s, 3H, OCH3).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by methyl-6-bromo-8-nitro-4-benzyloxy-quinoline-2-carboxylate 31e and by replacing phenylacetylene by 3-N-(terbutoxycarbonyl)aminoprop-1-yne, the abovenamed product is obtained. Yield: 87%. 1H NMR (200 MHz, CDCl3): δ 8.48 (d, 1H, J=2 Hz, 1H arom.), 8.06 (d, 1H, J=2 Hz, 1H arom.), 7.78 (s, 1H3), 7.50 (m, 5H arom.), 5.38 (s, 2H benz.), 4.82 (m, 1 HN), 4.19 (d, 2H, J=5 Hz, CH2N), 4.04 (s, 3H, OCH3), 1.68 (s, 9H, 3 CH3).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by methyl-6-bromo-8-nitro-4-benzyloxy-quinoline-2-carboxylate 31e and by replacing phenylacetylene by 3-pyridylacetylene, the abovenamed product is obtained. Yield: 95%. 1H NMR (300 MHz, CDCl3): δ 8.83 (s, 1H arom.), 8.63 (m, 2H arom.), 8.20 (d, 1H, J=2 Hz, 1H arom.), 7.87 (dt, 1H, J=2 and 8 Hz, 1H arom.), 7.82 (s, 1H arom.), 7.48 (m, 5H arom.), 7.34 (dd, 1H, J=5 and 8 Hz, 1H arom.), 5.42 (s, 2H benz.), 4.06 (s, 3H, OCH3).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by methyl-6-bromo-8-nitro-4-benzyloxy-quinoline-2-carboxylate 31e and by replacing phenylacetylene by 5-cyanopent-1-yne, the abovenamed product is obtained. Yield: 91%. 1H NMR (200 MHz, CDCl3): δ 8.46 (s, 1H arom.), 8.06 (s, 1H arom.), 7.78 (s, 1H arom.), 7.49 (m, 5H arom.), 5.39 (s, 2H benz.), 4.04 (s, 3H, OCH3), 2.64 (m, 4H, 2 CH2), 2.01 (t, 2H, J=7 Hz, CH2).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by benzyl-8-benzyloxy-5-bromoquinoline-2-carboxylate 5b, the abovenamed product is obtained. Yield: 68%. 1H-NMR (200 MHz, CDCl3): δ 8.85-8.80 (d, 1H arom.), 8.35-8.31 (d, 1H arom.), 8.30-7.38 (m, 16H arom.), 7.15-7.11 (d, 1H arom.), 5.53 (s, 2H, OCH2), 5.46 (s, 2H, OCH2).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by methyl-8-benzyloxy-4-trifluoromethanesulfonyloxy-quinoline-2-carboxylate 11 and by replacing phenylacetylene by 1-hexyne and proceeding in the same manner, the abovenamed product is obtained. Yield: 84%. 1H-NMR (200 MHz, CDCl3): δ 8.26 (s, 1H arom.), 7.87 (d, 1H, J=8 Hz, 1H arom.), 7.57-7.27 (m, 6H arom.), 7.12 (d, 1H, J=8 Hz, 1H arom.), 5.45 (s, 2H, OCH2), 4.05 (s, 3H, OCH3), 2.60 (t, 2H, J=8 Hz, CH2), 1.75-1.54 (m, 4H, 2×CH2), 1.01 (t, 3H, J=7 Hz, CH3).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by methyl-8-benzyloxy-4-trifluoromethanesulfonyloxy-quinoline-2-carboxylate 11 and by replacing phenylacetylene by 5-benzyloxy-pent-1-ynyl and proceeding in the same manner, the abovenamed product is obtained. Yield: 84%. 1H-NMR (200 MHz, CDCl3): δ 8.24 (s, 1H arom.), 7.3 (d, 1H, J=7 Hz, 1H arom.), 7.54-7.27 (m, 11H arom.), 7.12 (d, 1H, J=8 Hz, 1H arom.), 5.44 (s, 2H, OCH2), 4.57 (s, 2H, OCH2), 4.05 (s, 3H, OCH3), 3.69 (t, 2H, J=6 Hz, CH2), 2.74 (t, 2H, J=7 Hz, CH2), 2.05-1.98 (m, 2H, CH2).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by methyl-8-benzyloxy-4-hydroxy-7-bromo-quinoline-2-carboxylate 50c and by replacing phenylacetylene by N-Boc propargylamine and proceeding in the same manner, the abovenamed product is obtained. Yield: 47%. 1H-NMR (200 MHz, CDCl3): δ 9.13 (broad s, 1H, OH), 7.94 (d, 1H, J=8 Hz, 1H arom.), 7.40-7.28 (m, 6H arom.), 6.86 (s, 1H arom.), 5.42 (s, 2H, OCH2), 4.23 (d, 2H, J=6 Hz, 2H, NHCH2), 3.98 (s, 3H, OCH3), 1.47 (s, 9H, (CH3)3).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by benzyl-4,8-dibenzyloxy-7-bromoquinoline-2-carboxylate 50c and by replacing phenylacetylene by 1-hexyne and proceeding in the same manner, the abovenamed product is obtained. Yield: 63%. 1H-NMR (200 MHz, CDCl3): δ 7.90 (d, 1H, J=8 Hz, 1H arom.), 7.66-7.28 (m, 17H arom.), 5.61 (s, 2H, OCH2), 5.51 (s, 2H, OCH2), 5.34 (s, 2H, OCH2), 2.52 (t, 2H, J=7 Hz, CH2), 1.62-1.53 (m, 4H, 2×CH2), 0.96 (t, 3H, J=7 Hz, CH3).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by methyl-8-nitro-4-trifluoromethanesulfonyloxy-quinoline-2-carboxylate 92a and by replacing phenylacetylene by 1-hexyne and proceeding in the same manner, the abovenamed product is obtained. Yield: 45%. 1H-NMR (200 MHz, CDCl3): δ 8.15 (s, 1H arom.), 7.58-7.41 (m, 2H arom.), 6.96 (d, 1H, J=8 Hz, 1H arom.), 5.18 (broad s, 2H, NH2), 4.03 (s, 3H, OCH3), 2.59 (t, 2H, J=7 Hz, CH2), 1.74-1.49 (m, 4H, 2×CH2), 0.99 (t, 3H, J=7 Hz, CH3).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by methyl-8-nitro-4-trifluoromethanesulfonyloxy-quinoline-2-carboxylate 92a and proceeding in the same manner, the abovenamed product is obtained. Yield: 48%. 1H-NMR (200 MHz, CDCl3): δ 8.33 (s, 1H arom.); 7.73-7.45 (m, 7H arom.), 7.01 (d, 1H, J=8 Hz, 1H arom.), 5.18 (broad s, 2H, NH2), 4.03 (s, 3H, OCH3).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by methyl-8-nitro-4-trifluoromethanesulfonyloxy-quinoline-2-carboxylate 92a and by replacing phenylacetylene by N-Boc propargylamine and proceeding in the same manner, the abovenamed product is obtained. Yield: 67%. 1H-NMR (200 MHz, CDCl3): δ 8.52 (d, 1H, J=8 Hz, 1H arom.), 8.34 (s, 1H arom.), 8.13 (d, 1H, J=8 Hz, 1H arom.), 7.76 (t, 1H, J=8 Hz, 1H arom.), 4.98 (broad s, 2H, NH2), 4.34 (d, 2H, J=6 Hz, 2H, NHCH2), 3.91 (s, 3H, OCH3), 1.51 (s, 9H, (CH3)3).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by methyl-8-nitro-4-trifluoromethanesulfonyloxy-quinoline-2-carboxylate 92a and by replacing phenylacetylene by O-benzyl propargylic alcohol and proceeding in the same manner, the abovenamed product is obtained. Yield: 40%. 1H-NMR (200 MHz, CDCl3): δ 8.52 (d, 1H, J=8 Hz, 1H arom.), 8.38 (s, 1H arom.), 8.13 (d, 1H, J=8 Hz, 1H arom.), 7.77 (t, 1H, J=8 Hz, 1H arom.), 7.42-7.36 (m, 5H arom.), 4.76 (s, 2H, OCH2), 4.59 (s, 2H, OCH2), 4.06 (s, 3H, OCH3).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by methyl-8-nitro-4-trifluoromethanesulfonyloxy-quinoline-2-carboxylate 92a and by replacing phenylacetylene by N-acetyl propargylamine and proceeding in the same manner, the abovenamed product is obtained. Yield: 55%. 1H-NMR (200 MHz, CDCl3): δ 8.30 (d, 1H, J=8 Hz, 1H arom.), 8.15 (s, 1H arom.), 8.07 (d, 1H, J=8 Hz, 1H arom.), 7.75 (t, 1H, J=8 Hz, 1H arom.), 6.70 (s, H, NH), 4.49 (s, 2H, CH2), 4.02 (s, 3H, OCH3), 2.38 (s, 3H, COCH3).
By replacing methyl-4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k in example 15 by methyl-8-bromo-4-benzyloxy-quinoline-2-carboxylate 47a and proceeding in the same manner, the abovenamed product is obtained. Yield: 48%. 1H-NMR (200 MHz, CDCl3): δ 8.29 (d, 1H, J=8 Hz, 1H arom.), 8.04 (d, 1H, J=8 Hz, 1H arom.), 7.76-7.39 (m, 11H arom.), 7.38 (s, 1H arom.), 5.38 (broad s, 2H, NH2), 4.09 (s, 3H, OCH3).
To methyl-4-hydroxy-6-bromo-8-benzyloxy-quinoline-2-carboxylate 2l (282 mg, 0.726 mmol) in degassed tetrahydrofuran (10 ml), add benzyl zincic bromide (0.5 M/THF, 7.26 ml) and tetrakistriphenylphosphine palladium (0). Heat at 50° C. for 4 hours, wash with 2 N hydrochloric acid, wash with water and with a saturated sodium chloride solution. Dry on sodium sulfate, filter and evaporate to dryness. Triturate in diethyl ether, filter to obtain the abovenamed product. Yield: 49%. 1H-NMR (300 MHz, methanol-d4): δ 7.84 (m, 1H arom.), 7.70-7.15 (m, 10H arom.), 7.03 (m, 1H arom.), 6.96 (m, 1H arom.), 5.35 (s, 2H, OCH2), 4.08 (m, 5H, OCH3 and CH2).
To methyl-8-benzyloxy-6-(3-benzyloxy-prop-1-ynyl)-4-hydroxy-quinoline-2-carboxylate 20d (132 mg, 0.246 mmol) dissolved in degassed dichloromethane, methanol or acetic acid (15 ml), add palladium/charcoal (10%) (30 mg) and place under hydrogen at 30 psi overnight. Filter on celite, wash twice with CH2Cl2/MeOH 8/2 then evaporate to dryness. Triturate in diethyl ether and filter to obtain the abovenamed product. Yield: 95%. 1H-NMR (200 MHz, methanol-d4): δ 7.56 (s, 1H arom.), 7.02 (m, 2H arom.), 4.06 (s, 3H, OCH3), 3.60 (t, 2H, CH2), 2.77 (m, 2H, CH2), 1.89 (m, 2H, CH2).
By replacing methyl-8-benzyloxy-6-(3-benzyloxy-prop-1-ynyl)-4-hydroxyquinoline-2-carboxylate 20d in example 17 by methyl-8-benzyloxy-6-(3-tert-butoxycarbonylamino-prop-1-ynyl)-4-hydroxyquinoline-2-carboxylate 20c and proceeding in the same manner, the abovenamed product is obtained. Yield: 70%. 1H-NMR (300 MHz, CDCl3): δ 9.68 (broad s, 1H, OH), 7.60 (m, 1H arom.), 7.08 (m, 1H arom.), 6.98 (m, 1H arom.), 4.83 (broad s, 1H, NH), 4.03 (s, 3H, OCH3), 3.11 (m, 2H, CH2), 2.64 (m, 2H, CH2), 1.79 (m, 2H, CH2), 1.44 (s, 9H, (CH3)3).
By replacing methyl-8-benzyloxy-6-(3-benzyloxy-prop-1-ynyl)-4-hydroxyquinoline-2-carboxylate 20d in example 17 by methyl-4-hydroxy-8-methoxy-6-phenylethynyl-quinoline-2-carboxylate 20a and proceeding in the same manner, the abovenamed product is obtained. Yield: 72%. 1H-NMR (300 MHz, CDCl3): δ 9.38 (broad s, 1H, OH), 7.78 (m, 1H arom.), 7.31-7.17 (m, 5H arom.), 6.98 (m, 1H arom.), 6.76 (m, 1H arom.), 4.04 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 3.01 (m2, 4H, 2CH2).
By replacing methyl-8-benzyloxy-6-(3-benzyloxy-prop-1-ynyl)-4-hydroxyquinoline-2-carboxylate 20d in example 17 by methyl-4-hydroxy-8-methoxy-6-(hept-1-ynyl)-quinoline-2-carboxylate 20b and proceeding in the same manner, the abovenamed product is obtained. Yield: 74%. 1H-NMR (200 MHz, CDCl3): δ 9.38 (broad s, 1H, OH), 7.71 (m, 1H arom.), 6.97-6.93 (m, 2H arom.), 4.03 (s, 6H, 2×OCH3), 2.75-2.67 (m, 2H, CH2), 1.72 (m, 2H, CH2), 1.31 (m, 8H, 4×CH2), 0.88 (m, 3H, CH3).
By replacing methyl-8-benzyloxy-6-(3-benzyloxy-prop-1-ynyl)-4-hydroxyquinoline-2-carboxylate 20d in example 17 by methyl-4-hydroxy-8-methoxy-6-propenyl-quinoline-2-carboxylate 18q and proceeding in the same manner, the abovenamed product is obtained. Yield: 82%. 1H-NMR (200 MHz, CDCl3): δ 9.38 (broad s, 1H, OH), 7.70 (m, 1H arom.), 6.96-6.92 (m, 2H arom.), 4.03 (s, 6H, OCH3), 2.73-2.65 (t, 2H, CH2), 1.76-1.65 (m, 2H, CH2), 0.99-0.92 (t, 3H, CH3).
By replacing methyl-8-benzyloxy-6-(3-benzyloxyprop-1-ynyl)-4-hydroxyquinoline-2-carboxylate 20d in example 17 by methyl-8-benzyloxy-4-phenylethynyl-quinoline-2-carboxylate 12a and proceeding in the same manner, the abovenamed product is obtained. Yield: 88%. 1H-NMR (300 MHz, CDCl3): δ 8.60 (broad s, 1H, OH), 8.01 (m, 1H arom.), 7.56 (m, 1H arom.), 7.30-7.22 (m, 7H arom.), 4.05 (s, 3H, OCH3), 3.42(t, 2H, J=8 Hz, CH2), 3.10(t, 2H, J=8 Hz, CH2).
By replacing methyl-8-benzyloxy-6-(3-benzyloxyprop-1-ynyl)-4-hydroxyquinoline-2-carboxylate 20d in example 17 by methyl-8-benzyloxy-4-(3-tert-butoxycarbonylaminoprop-1-ynyl)-quinoline-2-carboxylate 12b and proceeding in the same manner, the abovenamed product is obtained. Yield: 90%. 1H-NMR (300 MHz, CDCl3): δ 8.07 (s, 1H arom.), 7.54-7.28 (m, 3H arom.), 4.05 (s, 3H, OCH3), 3.26 (m, 2H, CH2), 3.14 (m, 2H, CH2), 2.10 (m, 2H, CH2), 1.46 (s, 9H, (CH3)3).
By replacing methyl-8-benzyloxy-6-(3-benzyloxyprop-1-ynyl)-4-hydroxyquinoline-2-carboxylate 20d in example 17 by methyl-8-benzyloxy-4-(3-benzyloxyprop-1-ynyl)-quinoline-2-carboxylate 12c and proceeding in the same manner, the abovenamed product is obtained. Yield: 95%. 1H-NMR (200 MHz, CDCl3): δ 8.6 (broad s, 1H, OH), 8.11 (m, 1H arom.), 7.69-7.07 (m, 3H arom.), 4.05 (s, 3H, OCH3), 3.56 (t, 2H, J=8 Hz, CH2), 3.24 (t, 2H, J=8 Hz, CH2), 3.10 (t, 2H, J=8 Hz, CH2).
By replacing methyl-8-benzyloxy-6-(3-benzyloxyprop-1-ynyl)-4-hydroxyquinoline-2-carboxylate 20d in example 17 by Benzyl-4-benzyloxy-8-(hex-1-ynyl)-quinoline-2-carboxylate 47b and proceeding in the same manner, the abovenamed product is obtained. Yield: 70%. 1H-NMR (300 MHz, DMSO-d6): δ 8.03-8.01 (m, 1H arom.), 7.66-7.62 (m, 1H arom.), 7.46-7.44 (m, 1H arom.), 7.05 (s, 1H arom.), 3.11-3.09 (t, 2H, Ph-CH2), 1.69 (m, 2H, CH2), 1.34 (m, 6H, 3CH2), 0.88 (m, 3H, CH3).
By replacing methyl-8-benzyloxy-6-(3-benzyloxyprop-1-ynyl)-4-hydroxyquinoline-2-carboxylate 20d in example 17 by benzyl-4,8-dibenzyloxy-6-(3-benzyloxy-prop-1-ynyl)-quinoline-2-carboxylate 49a and proceeding in the same manner, the abovenamed product is obtained. Yield: 71%. 1H-NMR (200 MHz, DMSO-d6): δ 7.38 (s, 1H arom.), 7.02 (s, 1H arom.), 6.86 (s, 1H arom.), 3.45-3.39 (t, 2H, CH2), 2.69 (t, 2H, CH2), 1.76 (t, 2H, CH2).
By replacing methyl-8-benzyloxy-6-(3-benzyloxyprop-1-ynyl)-4-hydroxyquinoline-2-carboxylate 20d in example 17 by benzyl-4,8-dibenzyloxy-7-(3-benzyloxy-prop-1-ynyl)-quinoline-2-carboxylate 54a and proceeding in the same manner, the abovenamed product is obtained. Yield: 50%. 1H-NMR (200 MHz, DMSO-d6): δ 7.55 (d, 1H arom.), 7.12-7.09 (d, 1H arom.), 6.58 (s, 1H arom.), 3.50-3.42 (t, 2H, CH2), 2.78-2.74 (t, 2H, CH2), 1.77-1.72 (t, 2H, CH2).
By replacing methyl-8-benzyloxy-6-(3-benzyloxyprop-1-ynyl)-4-hydroxyquinoline-2-carboxylate 20d in example 17 by benzyl-4,8-dibenzyloxy-7-phenylethynyl-quinoline-2-carboxylate 55a and proceeding in the same manner, the abovenamed product is obtained. Yield: 87%. 1H-NMR (300 MHz, DMSO-d6): δ 9.95 (broad s, 1H, CO2H), 7.55-7.52 (d, 1H arom.), 7.38-7.19 (m, 7H arom.), 3.11-2.94 (m, 4H, Ph-CH2—CH2).
By replacing methyl-8-benzyloxy-6-(3-benzyloxyprop-1-ynyl)-4-hydroxyquinoline-2-carboxylate 20d in example 17 by methyl-4-benzyloxy-8-cyano-6-phenylethynyl-quinoline-2-carboxylate 65b and proceeding in the same manner, the abovenamed product is obtained. Yield: 8%. 1H-NMR (200 MHz, CDCl3): δ 9.19 (broad s, 1H, OH), 8.40 (m, 1H arom.), 7.71 (m, 1H arom.), 7.33-7.12 (m, 5H arom.), 7.02 (s, 1H arom.), 4.08 (s, 3H, OCH3), 3.07-2.98 (m, 4H, Ph-CH2—CH2).
By replacing methyl-8-benzyloxy-6-(3-benzyloxyprop-1-ynyl)-4-hydroxyquinoline-2-carboxylate 20d in example 17 by methyl-8-cyano-6-ethynyl-4-hydroxy-quinoline-2-carboxylate 69b and proceeding in the same manner, the abovenamed product is obtained. Yield: 82%. 1H-NMR (200 MHz, MeOD): δ 8.20 (m, 1H arom.), 7.99 (m, 1H arom.), 6.98 (m, 1H arom.), 3.98 (s, 3H, OCH3), 2.78 (m, 2H, CH2—CH3), 1.26-1.23 (m, 3H, CH2—CH3).
By replacing methyl-8-benzyloxy-6-(3-benzyloxyprop-1-ynyl)-4-hydroxyquinoline-2-carboxylate 20d in example 17 by benzyl-4-benzyloxy-8-(hex-1-ynyl)-quinoline-2-carboxylate 47a and proceeding in the same manner, the abovenamed product is obtained. Yield: 70%. 1H-NMR (300 MHz, DMSO-d6): δ 8.03-8.01 (m, 1H arom.), 7.66-7.62 (m, 1H arom.), 7.46-7.44 (m, 1H arom.), 7.05 (s, 1H arom.), 3.11-3.09 (t, 2H, Ph-CH2), 1.69 (m, 2H, CH2), 1.34 (m, 6H, 3CH2), 0.88 (m, 3H, CH3).
By replacing methyl-8-benzyloxy-6-(3-benzyloxyprop-1-ynyl)-4-hydroxyquinoline-2-carboxylate 20d in example 17 by methyl-4,8-dibenzyloxy-6-(3-benzyloxy-prop-1-ynyl)-quinoline-2-carboxylate 49a and proceeding in the same manner, the abovenamed product is obtained. Yield: 71%. 1H-NMR (200 MHz, DMSO-d6): δ 7.38 (s, 1H arom.), 7.02 (s, 1H arom.), 6.86 (s, 1H arom.), 3.45-3.39 (t, 2H, CH2), 2.69 (t, 2H, CH2), 1.76 (t, 2H, CH2).
By replacing methyl-8-benzyloxy-6-(3-benzyloxyprop-1-ynyl)-4-hydroxyquinoline-2-carboxylate 20d in example 17 by benzyl-4,8-dibenzyloxy-7-(3-benzyloxy-prop-1-ynyl)-quinoline-2-carboxylate 54a and proceeding in the same manner, the abovenamed product is obtained. Yield: 50%. 1H-NMR (200 MHz, DMSO-d6): δ 7.55 (d, 1H arom.), 7.12-7.09 (d, 1H arom.), 6.58 (s, 1H arom.), 3.50-3.42 (t, 2H, CH2), 2.78-2.74 (t, 2H, CH2), 1.77-1.72 (t, 2H, CH2).
By replacing methyl-8-benzyloxy-6-(3-benzyloxyprop-1-ynyl)-4-hydroxyquinoline-2-carboxylate 20d in example 17 by benzyl-4,8-dibenzyloxy-7-phenylethynyl-quinoline-2-carboxylate 55a and proceeding in the same manner, the abovenamed product is obtained. Yield: 87%. 1H-NMR (300 MHz, DMSO-d6): δ 9.95 (broad s, CO2H), 7.55-7.52 (d, 1H arom.), 7.38-7.19 (m, 7H arom.), 3.11-2.94 (m, 4H, Ph-CH2—CH2).
By replacing methyl-8-benzyloxy-6-(3-benzyloxy-prop-1-ynyl)-4-hydroxy-quinoline-2-carboxylate 20d in example 17 by benzyl-8-benzyloxy-5-phenylethynyl-quinoline-2-carboxylate 80a and proceeding in the same manner, the abovenamed product is obtained. Yield: 55%. 1H-NMR (300 MHz, DMSO-d6): δ 10.15 (s, 1H, OH), 7.25-7.18 (m, 9H arom.), 2.82-2.61 (m, 4H arom.).
By replacing methyl-8-benzyloxy-6-(3-benzyloxy-prop-1-ynyl)-4-hydroxy-quinoline-2-carboxylate 20d in example 17 by methyl-8-benzyloxy-4-(hex-1-ynyl)-quinoline-2-carboxylate 83a and proceeding in the same manner, the abovenamed product is obtained. Yield: 67%. 1H-NMR (200 MHz, DMSO-d6): δ 8.17 (s, 1H arom.), 7.58-7.32 (m, 7H arom.), 7.10 (d, 1H, J=8 Hz, 1H arom.), 5.45 (s, 2H, OCH2), 4.05 (s, 3H, OCH3), 3.10 (t, 2H, J=8 Hz, CH2), 1.79-1.70 (m, 2H, CH2), 1.39-1.27 (m, 6H, CH2), 0.90 (t, 3H, J=7 Hz, CH3).
By replacing methyl-8-benzyloxy-6-(3-benzyloxy-prop-1-ynyl)-4-hydroxy-quinoline-2-carboxylate 20d in example 17 by methyl-8-benzyloxy-4-(5-benzyloxy-pent-1-ynyl)-quinoline-2-carboxylate 84a and proceeding in the same manner, the abovenamed product is obtained. Yield: 97%. 1H-NMR (200 MHz, DMSO-d6): δ 8.02 (s, 1H arom.), 7.53-7.333 (m, 7H arom.), 6.76 (d, 1H, J=8 Hz, 1H arom.), 4.51 (s, 2H, OCH2), 4.05 (s, 3H, OCH3), 3.49 (t, 2H, J=8 Hz, CH2), 3.11 (t, 2H, J=8 Hz, CH2), 1.77-1.65 (m, 6H, 3×CH2).
By replacing methyl-8-benzyloxy-6-(3-benzyloxy-prop-1-ynyl)-4-hydroxyquinoline-2-carboxylate 20d in example 17 by methyl-8-benzyloxy-4-(3-tert-butoxycarbonylaminoprop-1-ynyl)-quinoline-2-carboxylate 12b and proceeding in the same manner, the abovenamed product is obtained. Yield: 93%. [H-NMR (300 MHz, CDCl3): δ 8.07 (s, 1H arom.), 7.59-7.27 (m, 7H arom.), 7.09 (d, 1H, J=8 Hz, 1H arom.), 5.45 (s, 2H, OCH2), 4.65 (broad s, 1H, NH), 4.05 (s, 3H, OCH3), 3.29-3.09 (m, 4H, CH2), 2.02 (d, 2H, J=7.6 Hz, CH2), 1.47 (s, 9H, (CH3)3).
By replacing methyl-8-benzyloxy-6-(3-benzyloxy-prop-1-ynyl)-4-hydroxyquinoline-2-carboxylate 20d in example 17 by methyl-8-benzyloxy-7-(3-tert-butoxycarbonylamino-prop-1-ynyl)-4-hydroxy-quinoline-2-carboxylate 90a and proceeding in the same manner, the abovenamed product is obtained. Yield: 95%. 1H-NMR (300 MHz, CDCl3): δ 9.75 (broad s, 1H, OH), 7.82 (d, 1H, J=8 Hz, 1H arom.), 7.12 (d, 1H, J=8 Hz, 1H arom.), 7.04 (s, 1H arom.), 5.09 (broad s, 1H, NH), 4.04 (s, 3H, OCH3), 3.12-3.08 (m, 2H, CH2), 2.87-2.82 (m, 2H, CH2), 1.92-1.90 (m, 2H, CH2), 1.53 (s, 9H, (CH3)3).
By replacing methyl-8-benzyloxy-6-(3-benzyloxy-prop-1-ynyl)-4-hydroxyquinoline-2-carboxylate 20d in example 17 by benzyl-4,8-dibenzyloxy-7-(hex-1-ynyl)-quinoline-2-carboxylate 91a and proceeding in the same manner, the abovenamed product is obtained. Yield: 50%. 1H-NMR (200 MHz, CDCl3): δ 9.90 (broad s, 1H, OH), 7.58-7.22 (m, 2H arom.), 7.22 (s, 1H arom.), 2.75-2.71 (m, 2H, CH2), 1.66-1.62 (m, 2H, CH2), 1.28-1.22 (m, 6H, 3×CH2), 0.84(t, 3H, J=7 Hz, CH3).
By replacing methyl-8-benzyloxy-6-(3-benzyloxy-prop-1-ynyl)-4-hydroxyquinoline-2-carboxylate 20d in example 17 by methyl-4-benzyloxy-8-phenylethynyl-quinoline-2-carboxylate 111a and proceeding in the same manner, the abovenamed product is obtained. Yield: 72%. 1H-NMR (200 MHz, CDCl3): δ 8.75 (broad s, 1H, OH), 8.24 (d, 1H, J=8 Hz, 1H arom.), 7.51 (d, 1H, J=8 Hz, 1H arom.), 7.31-7.15 (m, 6H arom.), 6.92 (s, 1H arom.), 4.09 (s, 3H, OCH3), 3.16-3.04 (m, 4H, 2×CH2).
Prepare a suspension of methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate 2a (350 mg, 1.13 mmol) in 1,2-dichloroethane (15 ml). At room temperature, add tosyl isocyanate (0.2 ml, 1.35 mmol), then heat under reflux for 12 hours. Evaporate the solvent and triturate the residue in petroleum ether. Filter the solid obtained. Yield: 73%. 1H-NMR (300 MHz, CDCl3): δ 9.97 (s, 1H, NH), 8.19 (s, 1H arom.), 8.05 (m, 3H arom.), 7.99-7.16 (m, 9H arom.), 5.30 (s, 2H, OCH2), 4.06 (s, 3H, OCH3), 2.41 (s, 3H, CH3).
By replacing methyl-4-hydroxy-8-benzyloxy-quinoline-2-carboxylate 2a in example 18 by methyl-4-hydroxy-8-nitro-quinoline-2-carboxylate 2r and proceeding in the same manner, the abovenamed product is obtained. Yield: 60%. 1H-NMR (200 MHz, CDCl3): δ 12.21 (s, 1H, NH), 8.92-8.73 (m, 2H arom.), 8.28 (s, 1H arom.), 7.89 (m, 3H arom.), 7.41 (d, 2H, J=8 Hz, 2H arom.), 3.98 (s, 3H, OCH3), 2.36 (s, 3H, CH3).
Cool concentrated sulfuric acid (3 ml) to 0° C. Add methyl-8-hydroxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15b (100 mg, 0.27 mmol). Allow to react at 0° C. for 2 hours, then dilute with water (20 ml). Basify this solution to pH 6-7 with saturated sodium bicarbonate solution. Extract the aqueous phase with ethyl acetate. Dry on sodium sulfate and evaporate the organic phase. Yield: 100%. 1H-NMR (200 MHz, MeOD): δ 7.70 (d, 1H, J=9 Hz, 1H arom.), 7.60-7.52 (m, 2H arom.), 7.26 (d, 1H, J=9 Hz, 1H arom.), 4.20 (s, 3H, OCH3).
By replacing methyl-8-hydroxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15b in example 19 by methyl-8-amino-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylate 15d and proceeding in the same manner, the abovenamed product is obtained. Yield: 79%. 1H-NMR (200 MHz, CDCl3): δ 7.36 (s, 1H arom.), 7.30 (m, 1H arom.), 7.02 (d, 1H, J=9 Hz, 1H arom.), 6.89 (d, 1H, J=9 Hz, 1H arom.), 5.17 (broad s, 2H, NH2), 4.85 (broad s, 2H, NH2), 4.00 (s, 3H, CH3).
By replacing 8-hydroxy-4-(toluene-4-sulfonylamino)-quinoline-2-carboxylic 15b in example 19 by methyl-4-(N-methyl-toluene-4-sulfonylamino)-8-nitro-quinoline-2-carboxylate 38a, the abovenamed product is obtained. Yield: 86%. 1H NMR (300 MHz, CDCl3): δ 7.96 (d, 1H, J=9 Hz, H arom.), 7.94 (d, 1H, J=8 Hz, H arom.), 7.52 (dd, 1H, J=8 and 9 Hz, H 6), 7.32 (s, 1H, H3), 5.50 (s, 1H, NH), 4.00 (s, 3H, OCH3), 3.15 (s, 3H, CH3).
Prepare a suspension of methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 2u (200 mg, 0.92 mmol) in acetonitrile (10 ml). At room temperature and under argon add triethylamine (0.13 ml, 0.93 mmol), then acetyl chloride (0.065 ml, 0.91 mmol). Stir for 3 hours, then evaporate the solvent. Take up the residue in water and wash with ethyl acetate. Dry the organic phase on Na2SO4, filter and evaporate the solvents. Purify the crude reaction product by silica gel column chromatography, eluent: EtOAc. Dissolve the O,N-diacetylated product (100 mg, 0.33 mmol) so obtained in a 1:1 mixture of THF/water (10 ml). Add 1 N sodium hydroxide (1 ml). Stir at room temperature overnight. Cool the solution to 0° C., then acidify to pH 3 with 2 N HCl. Filter the resulting precipitate. Yield: 50%. 1H-NMR (300 MHz, MeOD): δ 8.25 (broad s, 1H arom.), 8.06 (d, 1H, J=8 Hz, 1H arom.), 7.50 (m, 1H arom.), 7.30 (s, 1H arom.), 5.36 (broad s, 1H, NH), 2.31 (s, 3H, CH3).
By replacing acetyl chloride in example 20 by pivaloyl chloride and proceeding in the same manner, the abovenamed product is obtained. Yield: 20%. 1H-NMR (200 MHz, DMSO-d6): δ 12.72 and 12.24 (2 broad s, 2H, COOH and OH), 10.24 (broad s, 1H, NH), 8.52 (s, 1H arom.), 7.85 (d, 1H, J=9 Hz, 1H arom.), 7.60-7.47 (m, 2H arom.), 1.35 (s, 9H, C(CH3)3),
By replacing acetyl chloride in example 20 by benzoyl chloride and proceeding in the same manner, the abovenamed product is obtained. Yield: 65%. 1H-NMR (200 MHz, DMSO-d6): δ 13.01 and 12.10 (2 broad s, 2H, COOH and OH), 10.84 (broad s, 1H, NH), 8.72 (s, 1H arom.), 8.00 (m, 3H arom.), 7.53 (m, 5H arom.).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 2u in example 20 by methyl-4-(3-aminoprop-1-yl)-8-benzyloxy-quinoline-2-carboxylate 85b and acetyl chloride by benzoyl chloride and proceeding in the same manner, the abovenamed product is obtained. Yield: 93%. 1H-NMR (200 MHz, CDCl3): δ 8.08 (s, 1H arom.), 7.78-7.28 (m, 12H arom.), 7.10 (d, 1H, J=8 Hz, 1H arom.), 6.27 (broad s, 1H, NH), 5.44 (s, 2H, OCH2), 4.04 (s, 3H, OCH3), 3.67-3.57 (m, 2H, CH2), 3.22 (t, 2H, J=7.8 Hz, CH2), 2.19-2.11 (m, 2H, CH2).
Dissolve methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 2u (200 mg, 0.92 mmol) in methanol (5 ml). At room temperature and under argon, add benzaldehyde (0.1 ml, 0.98 mmol). Heat under reflux overnight then cool the reaction mixture to 0° C. Add NaBH4 (87 mg, 2.30 mmol) and react in the cold for 1 hour. Evaporate the methanol, take up the residue in cold water and extract with ethyl acetate. Adjust the aqueous phase to pH 5 with a saturated NH4Cl solution. Re-extract this aqueous phase with ethyl acetate. Dry the organic phase on Na2SO4, filter and evaporate. The crude reaction product is purified by silica gel column chromatography, eluent: Hex/EtOAc: 1/1. Yield: 85%. 1H-NMR (200 MHz, CDCl3): δ 9.50 (very broad s, 1H, OH), 7.79 (broad s, 1H, NH), 7.37 (m, 8H arom.), 7.00 (s, 1H arom.), 4.47 (s, 2H, CH2), 4.01 (s, 3H, OCH3).
By replacing methyl-4-hydroxy-8-amino-quinoline-2-carboxylate 2u in example 21 by methyl-4-hydroxy-6-formyl-8-methoxy-quinoline-2-carboxylate 2o and benzaldehyde by benzylamine and proceeding in the same manner, the abovenamed product is obtained. Yield: 42%. 1H-NMR (200 MHz, CDCl3): δ 7.80 (m, 1H arom.), 7.36-7.30 (m, 5H arom.), 7.23 (m, 1H arom.), 6.97 (m, 1H arom.), 4.05 (s, 3H, OCH3), 4.04 (s, 3H, OCH3), 3.91 (s, 2H, NCH2), 3.83 (s, 2H, NCH2).
Dissolve methyl-8-benzyloxy-4-hydroxy-6-(furo-2-yl)-quinoline-2-carboxylate 44a (143 mg, 0.381 mmol) in a mixture of HCl 37%/acetic acid (4 ml/2 ml). Heat at 110° C. overnight. Evaporate to dryness and take up in 2 M HCl then filter the precipitate formed. Yield: 80%. 1H-NMR (200 MHz, DMSO-d6): δ 7.87-7.82 (m, 2H arom.), 7.51 (m, 1H arom.), 7.09 (m, 2H arom.), 6.64 (m, 1H arom.).
By replacing methyl-8-benzyloxy-4-hydroxy-6-(furo-2-yl)-quinoline-2-carboxylate 44a in example 22 by methyl-4-hydroxy-6-(4-chloro-phenyl)-8-benzyloxy-quinoline-2-carboxylate 18k and proceeding in the same manner, the abovenamed product is obtained. Yield: 70%. 1H-NMR (200 MHz, DMSO-d6): δ 7.79 (m, 1H arom.), 7.76-7.72 (m, 2H arom.), 7.58-7.54 (m, 2H arom.), 7.48 (m, 1H arom.), 6.92 (broad s, 1H arom.).
By replacing methyl-8-benzyloxy-4-hydroxy-6-(furo-2-yl)-quinoline-2-carboxylate 44a in example 22 by methyl-8-benzyloxy-6-(3,4-dichloro-phenyl)-4-hydroxy-quinoline-2-carboxylate 18m and proceeding in the same manner, the abovenamed product is obtained. Yield: 80%. 1H-NMR (200 MHz, DMSO-d6): δ 7.97 (m, 1H arom.), 7.82 (m, 1H arom.), 7.74 (m, 2H arom.), 7.47 (m, 1H arom.), 7.06 (broad s, 1H arom.).
By replacing methyl-8-benzyloxy-4-hydroxy-6-(furo-2-yl)-quinoline-2-carboxylate 44a in example 22 by methyl-8-benzyloxy-4-hydroxy-6-(pyridin-3-yl)-quinoline-2-carboxylate 18o and proceeding in the same manner, the abovenamed product is obtained. Yield: 70%. 1H-NMR (300 MHz, DMSO-d6): δ 8.37 (s, 1H arom.), 8.16-8.14 (m, 1H arom.), 8.07-8.05 (m, 1H arom.), 7.43 (m, 2H arom.), 7.03 (s, 1H arom.), 6.99 (m, 1H arom.).
By replacing methyl-8-benzyloxy-4-hydroxy-6-(furo-2-yl)-quinoline-2-carboxylate 44a in example 22 by benzyl-4-benzyloxy-8-phenylquinoline-2-carboxylate 45b and proceeding in the same manner, the abovenamed product is obtained. Yield: 82%. 1H-NMR (200 MHz, DMSO-d6): δ 10.00 (broad s, 1H, OH), 8.20-8.17 (d, 1H arom.), 7.74-7.71 (d, 1H arom.), 7.70-7.52 (m, 6H arom.), 6.78 (s, 1H arom.).
By replacing methyl-8-benzyloxy-4-hydroxy-6-(furo-2-yl)-quinoline-2-carboxylate 44a in example 22 by benzyl-4,8-dibenzyloxy-6-(2-chlorophenyl)-quinoline-2-carboxylate 46c and proceeding in the same manner, the abovenamed product is obtained. Yield: 87%. 1H-NMR (300 MHz, DMSO-d6): δ 7.62-7.57 (m, 5H arom.), 7.23 (d, 1H arom.), 7.00 (broad s, 1H arom.).
By replacing methyl-8-benzyloxy-4-hydroxy-6-(furo-2-yl)-quinoline-2-carboxylate 44a in example 22 by benzyl-4,8-dibenzyloxy-6-(3-chlorophenyl)-quinoline-2-carboxylate 48a and proceeding in the same manner, the abovenamed product is obtained. Yield: 76%. 1H-NMR (300 MHz, DMSO-d6): δ 10.76 (broad s, 1H, COOH), 7.82-7.69 (m, 3H arom.), 7.59-7.46 (m, 3H arom.), 7.04 (broad s, 1H arom.).
By replacing methyl-8-benzyloxy-4-hydroxy-6-(furo-2-yl)-quinoline-2-carboxylate 44a in example 22 by benzyl-4,8-dibenzyloxy-7-phenyl-quinoline-2-carboxylate 50e and proceeding in the same manner, the abovenamed product is obtained. Yield: 69%. 1H-NMR (200 MHz, DMSO-d6): δ 10.18 (broad s, 1H, COOH), 7.78-7.63 (m, 3H arom.), 7.59-7.38 (m, 4H arom.), 7.19 (broad s, 1H arom.).
By replacing methyl-8-benzyloxy-4-hydroxy-6-(furo-2-yl)-quinoline-2-carboxylate 44a in example 22 by benzyl-4,8-dibenzyloxy-6-(2-methoxyphenyl)-quinoline-2-carboxylate 51a and proceeding in the same manner, the abovenamed product is obtained. Yield: 31%. 1H-NMR (200 MHz, DMSO-d6): δ 7.63 (d, J=1.7 Hz, 1H arom.), 7.43-7.35 (m, 2H arom.), 7.32 (d, J=1.7 Hz, 1H arom.), 7.18-7.04 (m, 2H arom.), 6.97 (broad s, 1H arom.), 3.80 (s, 3H, OCH3).
By replacing methyl-8-benzyloxy-4-hydroxy-6-(furo-2-yl)-quinoline-2-carboxylate 44a in example 22 by benzyl-4,8-dibenzyloxy-3-phenyl-quinoline-2-carboxylate 53c and proceeding in the same manner, the abovenamed product is obtained. Yield: 75%. 1H-NMR (300 MHz, DMSO-d6): δ 10.87 (broad s, 1H, COOH), 7.58-7.56 (m, 1H arom.), 7.37-7.14 (m, 7H arom.).
By replacing methyl-8-benzyloxy-4-hydroxy-6-(furo-2-yl)-quinoline-2-carboxylate 44a in example 22 by benzyl-4,8-dibenzyloxy-6-pipeeridin-2yl-quinoline-2-carboxylate 61a and proceeding in the same manner, the abovenamed product is obtained. Yield: 75%. 1H-NMR (300 MHz, DMSO-d6): δ 11.17 (broad s, 1H, N+H), 7.60-7.47 (m, 2H arom.), 7.18 (m, 1H arom.), 3.50 (s, 4H, CH2—N—CH2), 1.87-1.67 (m, 6H, CH2—CH2—CH2).
By replacing methyl-8-benzyloxy-4-hydroxy-6-(furo-2-yl)-quinoline-2-carboxylate 44a in example 22 by methyl-7-bromo-8-benzyloxy-4-hydroxy-quinoline-2-carboxylate 50b, the abovenamed product is obtained as a green solid. Yield: 36%. 1H NMR (200 MHz, D2O): δ 7.51 (d, 1H, J=7 Hz, H arom.), 7.09 (d, 1H, J=7 Hz, H arom.), 6.48 (s, 1H, H3).
By replacing methyl-8-benzyloxy-6-(3-benzyloxyprop-1-ynyl)-4-hydroxyquinoline-2-carboxylate 20d in example 17 by benzyl-4-benzyloxy-8-(hex-1-ynyl)-quinoline-2-carboxylate 47a and proceeding in the same manner, the abovenamed product is obtained. Yield: 70%. 1H-NMR (300 MHz, DMSO-d6): δ 8.03-8.01 (m, 1H arom.), 7.66-7.62 (m, 1H arom.), 7.46-7.44 (m, 1H arom.), 7.05 (s, 1H arom.), 3.11-3.09 (t, 2H, Ph-CH2), 1.69 (m, 2H, CH2), 1.34 (m, 6H, 3CH2), 0.88 (m, 3H, CH3).
By replacing methyl-8-benzyloxy-6-(3-benzyloxyprop-1-ynyl)-4-hydroxyquinoline-2-carboxylate 20d in example 17 by benzyl-4,8-dibenzyloxy-6-(3-benzyloxy-prop-1-ynyl)-quinoline-2-carboxylate 49a and proceeding in the same manner, the abovenamed product is obtained. Yield: 71%. 1H-NMR (200 MHz, DMSO-d6): δ 7.38 (s, 1H arom.), 7.02 (s, 1H arom.), 6.86 (s, 1H arom.), 3.45-3.39 (t, 2H, CH2), 2.69 (t, 2H, CH2), 1.76 (t, 2H, CH2).
By replacing methyl-8-benzyloxy-6-(3-benzyloxyprop-1-ynyl)-4-hydroxyquinoline-2-carboxylate 20d in example 17 by benzyl-4,8-dibenzyloxy-7-(3-benzyloxy-prop-1-ynyl)-quinoline-2-carboxylate 54a and proceeding in the same manner, the abovenamed product is obtained. Yield: 50%. 1H-NMR (200 MHz, DMSO-d6): δ 7.55 (d, 1H arom.), 7.12-7.09 (d, 1H arom.), 6.58 (s, 1H arom.), 3.50-3.42 (t, 2H, CH2), 2.78-2.74 (t, 2H, CH2), 1.77-1.72 (t, 2H, CH2).
By replacing methyl-8-benzyloxy-6-(3-benzyloxyprop-1-ynyl)-4-hydroxyquinoline-2-carboxylate 20d in example 17 by benzyl-4,8-dibenzyloxy-7-phenylethynyl-quinoline-2-carboxylate 55a and proceeding in the same manner, the abovenamed product is obtained. Yield: 87%. 1H-NMR (300 MHz, DMSO-d6): δ 9.95 (broad s, CO2H), 7.55-7.52 (d, 1H arom.), 7.38-7.19 (m, 7H arom.), 3.11-2.94 (m, 4H, Ph-CH2—CH2).
By replacing methyl-8-benzyloxy-4-hydroxy-6-(furo-2-yl)-quinoline-2-carboxylate 44a in example 22 by methyl-8-benzyloxy-4-(3-tert-butoxycarbonylaminoprop-1-ynyl)-quinoline-2-carboxylate 12b
and proceeding in the same manner, the abovenamed product is obtained. Yield: 78%. 1H-NMR (300 MHz, DMSO-d6): δ 10.34 (broad s, CO2H), 8.82 (broad s, 2H, —NH2), 8.26 (s, 1H arom.), 7.76-7.70 (m, 2H arom.), 7.29-7.27 (m, 1H arom.), 4.10 (s, 2H, —CH2—).
By replacing methyl-8-benzyloxy-4-hydroxy-6-(furo-2-yl)-quinoline-2-carboxylate 44a in example 22 by methyl-8-benzyloxy-4-(hex-1-yl)-quinoline-2-carboxylate 83c and proceeding in the same manner, the abovenamed product is obtained. Yield: 70%. 1H-NMR (200 MHz, DMSO-d6): δ 7.96 (s, 1H arom.), 7.47-7.36 (m, 2H arom.), 7.08-7.05 (m, 1H arom.), 3.03 (m, 2H, CH2—), 1.77 (m, 2H, CH2—), 1.34-1.26 (m, 6H, CH2—CH2—CH2), 0.88 (m, 3H, CH3).
By replacing methyl-8-benzyloxy-4-hydroxy-6-(furo-2-yl)-quinoline-2-carboxylate 44a in example 22 by methyl-8-benzyloxy-4-(5-hydroxy-pent-1-yl)-quinoline-2-carboxylate 84c and proceeding in the sane manner, the abovenamed product is obtained. Yield: 80%. 1H-NMR (200 MHz, DMSO-d6): δ 8.03 (s, 1H arom.), 7.68-7.66 (m, 2H arom.), 7.24-7.22 (m, 1H arom.), 3.37 (m, 2H, CH2—), 1.16 (m, 2H, CH2—), 1.72-1.44 (m, 6H, 3×CH2).
By replacing methyl-8-benzyloxy-4-hydroxy-6-(furo-2-yl)-quinoline-2-carboxylate 44a in example 22 by methyl-8-hydroxy-4-(piperazin-1-yl)-quinoline-2-carboxylate 87b and proceeding in the same manner, the abovenamed product is obtained. Yield: 74%. 1H-NMR (200 MHz, DMSO-d6): δ 9.93 (broad s, 1H, OH), 9.71 (broad s, 1H, NH), 7.68-7.66 (m, 2H arom.), 7.24-7.22 (m, 1H arom.), 3.58-3.55 (m, 4H, CH2—N—CH2), 3.36-3.34 (m, 4H, CH2—N—CH2).
By replacing methyl-8-benzyloxy-4-hydroxy-6-(furo-2-yl)-quinoline-2-carboxylate 44a in example 22 by benzyl-4,8-dibenzyloxy-6-(3,5-dichlorophenyl)-quinoline-2-carboxylate 88a and proceeding in the same manner, the abovenamed product is obtained. Yield: 90%. 1H-NMR (200 MHz, DMSO-d6): δ 10.93 (broad s, 1H, OH), 7.82 (s, 1H arom.), 7.76 (s, 2H arom.), 7.65 (s, 1H arom.), 7.48 (s, 1H arom.), 7.08 (s, 1H arom.).
By replacing methyl-8-benzyloxy-4-hydroxy-6-(furo-2-yl)-quinoline-2-carboxylate 44a in example 22 by benzyl-4,8-dibenzyloxy-6-(4-fluorophenyl)-quinoline-2-carboxylate 89a and proceeding in the same manner, the abovenamed product is obtained. Yield: 95%. 1H-NMR (200 MHz, DMSO-d6): δ 10.94 (broad s, 1H, OH), 7.78-7.71 (m, 3H arom.), 7.45 (s, 1H arom.), 7.35-7.26 (m, 2H arom.), 7.02 (s, 1H arom.).
By replacing methyl-8-benzyloxy-4-hydroxy-6-(furo-2-yl)-quinoline-2-carboxylate 44a in example 22 by methyl-4,8-dihydroxy-7-(3-tert-butoxycarbonylaminoprop-1-yl)-quinoline-2-carboxylate 90b and proceeding in the same manner, the abovenamed product is obtained. Yield: 95%. 1H-NMR (300 MHz, DMSO-d6): δ 10.14 (broad s, 1H, OH), 8.02 (broad s, 3H, N+H3), 7.60 (d, 1H, J=8 Hz, 1H arom.), 7.43-7.38 (m, 2H arom), 2.88-2.83 (m, 4H, 2×CH2), 1.97-1.92 (m, 2H, CH2).
By replacing methyl-8-benzyloxy-4-hydroxy-6-(furo-2-yl)-quinoline-2-carboxylate 44a in example 22 by methyl-8-benzyloxy-4-hydroxy-5-trifluoromethyl-quinoline-2-carboxylate 98b and proceeding in the same manner, the abovenamed product is obtained. Yield: 88%. 1H-NMR (300 MHz, DMSO-d6): δ 11.73 (broad s, 1H, COOH), 10.01 (broad s, 1H, OH), 7.78 (d, 1H, J=8 Hz, 1H arom.), 7.22 (d, 1H, J=8 Hz, 1H arom.), 7.05 (s, 1H arom.).
By replacing methyl-8-benzyloxy-4-hydroxy-6-(furo-2-yl)-quinoline-2-carboxylate 44a in example 22 by benzyl-4-benzyloxy-8-(piperidin-1-yl)-quinoline-2-carboxylate 102a and proceeding in the same manner, the abovenamed product is obtained. Yield: 86%. 1H-NMR (300 MHz, DMSO-d6): δ 8.12 (d, 1H, J=8 Hz, 1H arom.), 8.01 (d, 1H, J=8 Hz, 1H arom.), 7.62 (t, 1H, J=8 Hz, 1H arom.), 7.25 (s, 1H arom.), 3.43-3.39 (m, 4H, CH2—N—CH2), 2.01-1.71 (m, 6H, 3×CH2).
By replacing methyl-8-benzyloxy-4-hydroxy-6-(furo-2-yl)-quinoline-2-carboxylate 44a in example 22 by benzyl-4-benzyloxy-8-[benzyl(methyl)amino]-quinoline-2-carboxylate 103a and proceeding in the same manner, the abovenamed product is obtained. Yield: 91%. 1H-NMR (300 MHz, DMSO-d6): δ 7.47-7.32 (m, 3H arom), 6.77 (d, 1H, J=8 Hz, 1H arom.), 2.92 (s, 3H, NCH3).
By replacing methyl-8-benzyloxy-4-hydroxy-6-(furo-2-yl)-quinoline-2-carboxylate 44a in example 22 by methyl-4-benzyloxy-8-(morpholin-1-yl)-quinoline-2-carboxylate 104a and proceeding in the same manner, the abovenamed product is obtained. Yield: 68%. 1H-NMR (300 MHz, DMSO-d6): δ 7.94 (d, 1H, J=8 Hz, 1H arom.), 7.72 (d, 1H, J=8 Hz, 1H arom.), 7.49 (t, 1H, J=8 Hz, 1H arom.), 6.89 (s, 1H arom.), 3.92-3.90 (m, 4H, CH2—O—CH2), 3.13-3.11 (m, 4H, CH2—N—CH2).
By replacing methyl-8-benzyloxy-4-hydroxy-6-(furo-2-yl)-quinoline-2-carboxylate 44a in example 22 by methyl-4-benzyloxy-8-(4-benzyl-pipeerazin-1-yl)-quinoline-2-carboxylate 105a and proceeding in the same manner, the abovenamed product is obtained. Yield: 96%. 1H-NMR (300 MHz, DMSO-d6): δ 7.91 (d, 1H, J=7.6 Hz, 1H arom.), 7.68-7.43 (m, 7H arom.), 6.91 (s, 1H arom.), 4.48 (s, 2H, NCH2), 3.48-3.39 (m, 8H, 4×CH2).
By replacing methyl-8-benzyloxy-4-hydroxy-6-(furo-2-yl)-quinoline-2-carboxylate 44a in example 22 by methyl-4-benzyloxy-8-[phenyl(methyl)amino]-quinoline-2-carboxylate 106a and proceeding in the same manner, the abovenamed product is obtained. Yield: 95%. 1H-NMR (200 MHz, DMSO-d6): δ 8.06 (d, 1H, J=8 Hz, 1H arom.), 7.67 (d, 1H, J=8 Hz, 1H arom.), 7.50 (t, 1H, J=8 Hz, H arom.), 7.22 (t, 2H, J=8 Hz, H arom.), 6.84 (t, 1H, J=8 Hz, 1H arom.), 6.74-6.67 (m, 3H arom.), 3.34 (s, 3H, NCH3).
By replacing methyl-8-benzyloxy-4-hydroxy-6-(furo-2-yl)-quinoline-2-carboxylate 44a in example 22 by methyl-4-benzyloxy-8-(4-methyl-piperazin-1-yl)-4-hydroxy-quinoline-2-carboxylate 107a and proceeding in the same manner, the abovenamed product is obtained. Yield: 91%. 1H-NMR (200 MHz, DMSO-d6): δ 11.13 (broad s, 1H, CO2H), 7.90 (d, 1H, J=8 Hz, 1H arom.), 7.57-7.40 (m, 2H arom.), 6.89 (s, 1H arom.), 3.60-3.40 (m, 4H, CH2—N—CH2), 3.39-3.27 (m, 4H, CH2—N—CH2), 2.92 (s, 3H, NCH3).
By replacing methyl-8-benzyloxy-4-hydroxy-6-(furo-2-yl)-quinoline-2-carboxylate 44a in example 22 by methyl-4-benzyloxy-8-(pyridin-2-yl-amino)-quinoline-2-carboxylate 109a and proceeding in the same manner, the abovenamed product is obtained. Yield: 97%. 1H-NMR (200 MHz, DMSO-d6): δ 11.01 (broad s, 1H, COOH), 10.01 (broad s, 2H, NH+OH), 8.20-8.01 (m, 4H arom.), 7.69-7.60 (m, 2H arom.), 7.55 (s, 1H arom.), 7.13 (t, 1H, J=8 Hz, 1H arom.).
By replacing methyl-8-benzyloxy-4-hydroxy-6-(furo-2-yl)-quinoline-2-carboxylate 44a in example 22 by methyl-8-benzyloxy-4-[2-(1-piperazinyl)pyrimidinyl]-quinoline-2-carboxylate 128a and proceeding in the same manner, the abovenamed product is obtained. Yield: 72%. 1H-NMR (200 MHz, DMSO-d6): δ 9.56 (broad s, 1H, COOH), 8.50-8.44 (m, 2H arom.), 7.69-7.59 (m, 2H arom.), 7.55 (s, 1H arom.), 7.38-7.34 (m, 1H arom.), 6.80-6.75 (m, 1H arom.), 4.07-3.97 (m, 4H, 2×CH2), 3.82-3.78 (m, 2H, CH2), 3.17-3.13 (m, 2H, CH2).
Place 4-hydroxy-8-hexyl-quinoline-2-carboxylic acid 47c (31 mg, 0.113 mmol) in 2 ml of water, then add 0.111 ml of 1 M sodium hydroxide. Stir for 1 hour then extract once with ethyl acetate. Evaporate the aqueous phase to dryness to obtain the abovenamed product. Yield: 45%. 1H-NMR (300 MHz, D2O): δ 8.03-8.01 (m, 1H arom.), 7.66-7.62 (m, 1H arom.), 7.47-7.44 (m, 1H arom.), 7.05 (s, 1H arom.), 3.11-3.09 (t, 2H, Ph-CH2), 1.69 (m, 2H, CH2), 1.34 (m, 6H, 3CH2), 0.88 (m, 3H, CH3).
By replacing 4-hydroxy-8-hexyl-quinoline-2-carboxylic acid 47c in example 23 by 4,8-dihydroxy-7-phenyl-quinoline-2-carboxylic acid 50f and proceeding in the same manner, the abovenamed product is obtained. Yield: 87%. 1H-NMR (300 MHz, D2O): δ 7.59-7.56 (m, 2H arom.), 7.41-7.27 (m, 5H arom.), 6.85 (s, 1H arom.).
By replacing 4-hydroxy-8-hexyl-quinoline-2-carboxylic acid 47c in example 23 by 4,8-dihydroxy-3-phenyl-quinoline-2-carboxylic acid 53d and proceeding in the same manner, the abovenamed product is obtained. Yield: 94%. 1H-NMR (300 MHz, D2O): δ 7.67-7.64 (m, 1H arom.), 7.41-7.17 (m, 5H arom.).
By replacing 4-hydroxy-8-phenyl-quinoline-2-carboxylic acid 47c in example 23 by 4-(hex-1-yl)-8-hydroxy-quinoline-2-carboxylic acid 83c and proceeding in the same manner, the abovenamed product is obtained. Yield: 93%. 1H-NMR (200 MHz, DMSO-d6): δ 7.94 (s, 1H arom.), 7.47-7.43 (m, 2H arom.), 7.06-7.03 (m, 1H arom.), 3.02 (t, 2H, J=7.3 Hz, CH2.), 1.66 (m, 2H, CH2), 1.35-1.22 (m, 6H, CH2—CH2—CH2), 0.87 (t, 3H, J=6.6 Hz, CH3).
By replacing 4-hydroxy-8-phenyl-quinoline-2-carboxylic acid 47c in example 23 by 8-amino-4-hydroxy-6-phenyl-quinoline-2-carboxylic acid 86d and proceeding in the same manner, the abovenamed product is obtained. Yield: 96%. 1H-NMR (200 MHz, DMSO-d6): δ 10.31 (broad s, 1H, OH), 7.66-7.25 (m, 7H arom.), 6.49 (s, 1H arom.), 5.96 (broad s, 2H, NH2).
Dissolve methyl-8-benzyloxy-4-hydroxy-quinoline-2-carboxylate 2a (1.323 g, 4.227 mmol) in 50 ml of dichloromethane, cool to −5° C. then add diisopropylamine (0.603 ml, 4.279 mmol). Stir for 5 minutes and add N-bromosuccinimide (0.762 g, 4.281 mmol). Stir for 1 hour then wash the organic phase with 2 M HCl, dry on Na2SO4 filter and evaporate to dryness to obtain the abovenamed product. Yield: 93%. 1H-NMR (300 MHz, CDCl3): δ 11.08 (broad s, 1H, OH), 7.71-7.69 (d, 1H, J=7.9 Hz, 1H arom.), 7.57-7.54 (d, 1H, J=7.53 Hz, 1H arom.), 7.45-7.35 (m, 6H arom.), 5.43 (s, 2H, OCH2), 3.95 (s, 3H, OCH3).
By replacing methyl-8-benzyloxy-4-hydroxy-quinoline-2-carboxylate 2a in example 24 by methyl-8-benzyloxy-7-bromo-4-hydroxy-quinoline-2-carboxylate 50b and proceeding in the same manner, the abovenamed product is obtained. Yield: 53%. 1H-NMR (300 MHz, CDCl3): δ 9.21 (broad s, 1H, OH), 8.00-7.97 (d, 1H, J=8 Hz, 1H arom.), 7.57-7.54 (d, 1H, J=8 Hz, 1H arom.), 7.40-7.37 (m, 5H arom.), 5.24 (s, 2H, OCH2), 4.01 (s, 3H, OCH3).
By replacing methyl-8-benzyloxy-4-hydroxy-quinoline-2-carboxylate 2a in example 24 by methyl-8-cyano-4-hydroxy-quinoline-2-carboxylate 35b and proceeding in the same manner, the abovenamed product is obtained. Yield: 81%. 1H-NMR (300 MHz, CDCl3): δ 9.64 (broad s, 1H, OH), 8.62-8.59 (d, 1H, J=8 Hz, 1H arom.), 8.04-8.01 (d, 1H, J=8 Hz, 1H arom.), 7.52-7.47 (t, 1H, J=8 Hz, 1H arom.), 4.14 (s, 3H, OCH3).
To 8-hydroxyquinoline-2-carbonitrile (100 mg, 0.587 mmol) in solution in 2 ml of dimethylformamide, add sodium nitride (50 mg, 0.769 mmol), ammonium chloride (40 mg, 0.748 mmol), then stir at 120° C. for 24 hours. Dilute the reaction mixture in 1 M HCl (30 ml), then filter the precipitate, wash with water and dry to obtain the abovenamed product. Yield: 69%. 1H-NMR (200 MHz, DMSO-d6): δ 9.70 (broad s, 1H, OH), 8.65-8.61 (d, 1H, J=8.5 Hz, 1H arom.), 8.31-8.27 (d, 1H, J=8.5 Hz, 1H arom.), 7.66-7.54 (m, 2H arom.), 7.28-7.23 (dd, 1H, J=2 Hz and 7 Hz, 1H arom.).
By replacing methyl-8-hydroxyquinoline-2-carbonitrile in example 25 by 8-cyano-4-hydroxy-quinoline-2-carboxylate 35b, without adding ammonium chloride and substituting acetic acid for the dimethylformamide, and proceeding in the same manner, the abovenamed product is obtained. Yield: 69%. 1H-NMR (200 MHz, DMSO-d6): δ 11.75 and 7.49 (2 broad s, 2H, NH and OH), 8.36-8.27 (m, 2H arom.), 7.24-7.16 (m, 1H arom.), 6.67 (s, 1H arom.), 3.85 (s, 3H, OCH3).
To 3-(benzyloxy)benzene-1,2-diamine (300 mg, 1.4 mmol) in solution in 2 ml of ethanol, add ethyl ketomalonate (244 mg, 1.4 mmol) and acetic acid (20 μl), then stir under reflux for 1 hour. Evaporate to dryness and chromatograph to obtain the abovenamed product. Yield: 34%. 1H-NMR (200 MHz, DMSO-d6): δ 11.70 (broad s, 1H, NH), 7.51-7.31 (m, 6H arom.), 6.96-6.92 (d, 1H, J=8 Hz, 1H arom.), 6.84-6.79 (d, 1H, J=8 Hz, 1H arom.), 5.38 (s, 1H, OCH2-Ph), 4.56-4.46 (q, 2H, J=7 Hz, OCH2—CH3), 1.50-1.42 (t, 3H, J=7 Hz, OCH2CH3).
To 3-(benzyloxy)benzene-1,2-diamine (300 mg, 1.4 mmol) in solution in 2 ml of acetic acid, add diethyloxalacetate sodium salt (295 mg, 1.4 mmol) and stir under reflux for 2 hours. Evaporate to dryness and chromatograph to obtain the abovenamed product. Yield: 20%. 1H-NMR (200 MHz, DMSO-d6): δ 11.39 (broad s, 1H, NH), 8.70 (broad s, 1H, NH), 7.53-7.37 (m, 5H arom.), 6.93-6.84 (t, 1H, J=8 Hz, 1H arom.), 6.71-6.67 (d, 1H, J=8 Hz, 1H arom.), 6.57-6.53 (d, 1H, J=8 Hz, 1H arom.), 5.84 (s, 1H, C═CH), 5.29 (s, 1H, OCH2-Ph), 4.30-4.20 (q, 2H, J=7 Hz, OCH2—CH3), 1.35-1.28 (t, 3H, J=7 Hz, OCH2CH3).
In a degassed solution of anhydrous toluene (3 ml) containing cesium carbonate (220 mg, 0.672 mmol, 1.4 eq.), add methyl-6-bromo-8-nitro-4-benzyloxy-quinoline-2-carboxylate 31e (200 mg, 0.48 mmol), N-methylpiperazine (58 mg, 64 μl, 0.58 mmol, 1.2 eq.), bispalladium (0) dibenzylidene acetone (8.8 mg, 0.0096 mmol, 0.02 eq.) and rac-BINAP (18 mg, 0.0289 mmol, 0.06 eq.). Heat at 100° C. for 18 hours. Cool the solution and evaporate to dryness. Take up in dichloromethane (10 ml), wash with water (5 ml) and with a saturated sodium chloride solution (5 ml), dry on Na2SO4, filter and evaporate. Purify the residue by silic gel column chromatography (eluent: CH2Cl2/MeOH: 95/5). The abovenamed product is isolated as an orange solid. Yield: 64%. 1H NMR (300 MHz, CDCl3): δ 7.86 (d, 1H, J=2 Hz, H arom.), 7.68 (s, 1H3), 7.57 (d, 1H, J=2 Hz, H arom.), 7.46 (m, 5H arom.), 5.38 (s, 2H benz.), 4.01 (s, 3H, OCH3), 3.40 (m, 4H, 2 NCH2), 2.61 (m, 4H, 2 CH2), 2.38 (s, 3H, NCH3).
By replacing N-methylpiperazine in example 28 by N-benzylpiperazine, the abovenamed product is obtained as an orange solid. Yield: 73%. 1H NMR (300 MHz, CDCl3): δ 7.89 (d, 1H, J=2 Hz, H arom.), 7.71 (s, 1H3), 7.59 (d, 1H, J=2 Hz, H arom.), 7.40 (m, 10H arom.), 5.40 (s, 2H benz.), 4.05 (s, 3H, OCH3), 3.63 (s, 2H benz.), 3.42 (m, 4H, 2 NCH2), 2.68 (m, 4H, 2 CH2).
By replacing N-methylpiperazine in example 28 by piperidine, the abovenamed product is obtained as an orange solid. Yield: 59%. 1H NMR (200 MHz, CDCl3): δ 7.86 (d, 1H, J=2 Hz, H arom.), 7.66 (s, 1H3), 7.53 (d, 1H, J=2 Hz, H arom.), 7.47 (m, 10H arom.), 5.38 (s, 2H benz.), 4.01 (s, 3H, OCH3), 3.38 (m, 4H, 2 NCH2), 1.70 (m, 6H, 3 CH2).
By replacing N-methylpiperazine in example 28 by diphenylimine, the abovenamed product is obtained as an orange solid. Yield: 82%. 1H NMR (200 MHz, CDCl3): δ 7.77 (m, 2H, 2H arom.), 7.67 (s, 1H 3), 7.53-7.12 (m, 16H, 16H arom.), 5.31 (s, 2H benz.), 4.01 (s, 3H, OCH3).
By replacing N-methylpiperazine in example 28 by aniline, the abovenamed product is obtained as an orange solid. Yield: 84%. 1H NMR (200 MHz, CDCl3): δ 7.87 (m, 2H, 2H arom.), 7.68 (s, 1H3), 7.40 (m, 9H, 9H arom.), 6.24 (s, 1H, 1NH), 7.20 (m, 2H, 2H arom.), 5.36 (s, 2H benz.), 4.02 (s, 3H, OCH3).
By replacing in example 28 N-methylpiperazine by piperidine and methyl-6-bromo-8-nitro-4-benzyloxy-quinoline-2-carboxylate by methyl-5-bromo-8-nitro-4-benzyloxy-quinoline-2-carboxylate 72c, the abovenamed product is obtained as an orange solid. Yield: 61%. 1H NMR (200 MHz, CDCl3): δ 8.10 (d, 1H, J=8 Hz, H arom.), 7.70 (s, 1H3), 7.49 (m, 2H, 2H arom.), 7.47 (m, 3H arom.), 6.94 (d, 1H, J=8 Hz, H arom.), 5.37 (s, 2H benz.), 4.03 (s, 3H, OCH3), 3.29 (m, 2H, NCH2), 2.83 (m, 2H, NCH2), 1.48 (m, 6H, 3 CH2).
By replacing in example 28 N-methylpiperazine by N-benzylpiperazine and methyl-6-bromo-8-nitro-4-benzyloxy-quinoline-2-carboxylate by methyl-5-bromo-8-nitro-4-benzyloxy-quinoline-2-carboxylate 72c, the abovenamed product is obtained as an orange solid. Yield: 58%. 1H NMR (300 MHz, CDCl3): δ 8.07 (d, 1H, J=8 Hz, H arom.), 7.75 (s, 1H3), 7.52 (m, 5H, 5H arom.), 7.21 (m, 5H arom.), 7.96 (d, 1H, J=8 Hz, H arom.), 5.33 (s, 2H benz.), 4.04 (s, 3H, OCH3), 3.20 (m, 2H, 2 NCH), 3.18 (s, 2H benz.), 2.93 (m, 2H, 2 NCH), 2.54 (m, 2H, 2 NCH), 1.96 (m, 2H, 2 NCH).
By replacing in example 28 N-methylpiperazine by piperidine and methyl-6-bromo-8-nitro-4-benzyloxy-quinoline-2-carboxylate 72c by benzyl-4,8-dibenzyloxy-6-bromoquinoline-2-carboxylate 46b and proceeding in the same manner, the abovenamed product is obtained. Yield: 45%. 1H-NMR (200 MHz, CDCl3): δ 7.61-7.32 (m, 16H arom.), 7.06 (m, 1H arom.), 6.92 (m, 1H arom.), 5.46 (s, 2H, OCH2), 5.37 (s, 2H, OCH2), 5.34 (s, 2H, OCH2), 3.28 (m, 4H, CH2—N—CH2), 1.72 (m, 6H, CH2—CH2—CH2).
Starting with methyl-8-benzyloxy-4-trifluoromethanesulfonyloxy-quinoline-2-carboxylate 11 and by replacing in example 28 N-methylpiperazine by N-benzylylpiperazine and proceeding in the same manner, the abovenamed product is obtained. Yield: 62%. 1H-NMR (200 MHz, CDCl3): δ 7.70 (s, 1H arom.), 7.61-7.28 (m, 12H arom.), 7.04 (d, 1H, J=8 Hz, 1H arom.), 5.43 (s, 2H, OCH2), 4.03 (s, 3H, OCH3), 3.65 (s, 2H, NCH2), 3.35-3.31 (m, 4H, CH2—N—CH2), 2.78-2.75 (m, 4H, CH2—N—CH2).
Starting with methyl-8-benzyloxy-4-trifluoromethanesulfonyloxy-quinoline-2-carboxylate 11 and by replacing in example 28 N-methylpiperazine by morpholine and proceeding in the same manner, the abovenamed product is obtained. Yield: 96%. 1H-NMR (300 MHz, CDCl3): δ 7.73 (s, 1H arom.), 7.57-7.28 (m, 7H arom.), 7.06 (d, 1H, J=8 Hz, 1H arom.), 5.44 (s, 2H, OCH2), 4.04 (s, 3H, OCH3), 4.01-3.98 (m, 4H, CH2—O—CH2), 3.31-3.28 (m, 4H, CH2—N—CH2).
Starting with methyl-8-benzyloxy-4-trifluoromethanesulfonyloxy-quinoline-2-carboxylate 11 and by replacing in example 28 N-methylpiperazine by piperidine and proceeding in the same manner, the abovenamed product is obtained. Yield: 62%. 1H-NMR (300 MHz, CDCl3): δ 7.69 (s, 1H arom.), 7.57-7.28 (m, 7H arom.), 7.04 (d, 1H, J=8 Hz, 1H arom.), 5.43 (s, 2H, OCH2), 4.03 (s, 3H, OCH3), 3.27-3.23 (m, 4H, CH2—N—CH2), 1.86-1.71 (m, 6H, 3×CH2).
Starting with methyl-8-nitro-4-trifluoromethanesulfonyloxy-quinoline-2-carboxylate 92a and by replacing in example 28 N-methylpiperazine by piperidine and proceeding in the same manner, the abovenamed product is obtained. Yield: 76%. 1H-NMR (300 MHz, CDCl3): δ 8.22 (d, 1H, J=8 Hz, 1H arom.), 8.20 (d, 1H, J=8 Hz, 1H arom.), 7.72 (s, 1H arom.), 7.58 (t, 1H, J=8 Hz, 1H arom.), 4.03 (s, 3H, OCH3), 3.31-3.28 (m, 4H, CH2—N—CH2), 1.92-1.57 (m, 6H, 3×CH2).
Starting with benzyl-4-benzyloxy-8-bromo-quinoline-2-carboxylate 45a and by replacing in example 28 N-methylpiperazine by piperidine and proceeding in the same manner, the abovenamed product is obtained. Yield: 67%. 1H-NMR (300 MHz, CDCl3): δ 7.72-7.69 (dd, 1H arom.), 7.63 (s, 1H arom.), 7.58-7.35 (m, 11H arom.), 7.16-7.14 (dd, 1H arom.), 5.44 (s, 2H, OCH2), 5.40 (s, 2H, OCH2) 3.31-3.28 (m, 4H, CH2—N—CH2), 1.67-1.55 (m, 6H, 3×CH2).
Starting with methyl-4-benzyloxy-8-bromo-quinoline-2-carboxylate 45a′ and by replacing in example 28 N-methylpiperazine by N-benzylmethylamine and proceeding in the same manner, the abovenamed product is obtained. Yield: 75%. 1H-NMR (300 MHz, CDCl3): δ 7.87-7.83 (dd, 1H arom.), 7.68 (s, 1H arom.), 7.58-7.27 (m, 11H arom.), 7.09-7.06 (dd, 1H arom.), 5.37 (s, 2H, OCH2), 4.90 (s, 2H, NCH2), 3.97 (s, 3H, OCH3), 2.91 (s, 3H, NCH3).
Starting with methyl-4-benzyloxy-8-bromo-quinoline-2-carboxylate 45a′ and by replacing in example 28 N-methylpiperazine by mopholine and proceeding in the same manner, the abovenamed product is obtained. Yield: 96%. 1H-NMR (300 MHz, CDCl3): δ 7.89 (d, 1H, J=8 Hz, 1H arom.), 7.67 (s, 1H arom.), 7.53-7.26 (m, 6H arom.), 7.15 (d, 1H, J=8 Hz, 1H arom.), 5.5 (s, 2H, OCH2), 4.09-4.02 (m, 4H, CH2—O—CH2), 4.02 (s, 3H, OCH3), 3.49-3.46 (m, 4H, CH2—N—CH2).
Starting with methyl-4-benzyloxy-8-bromo-quinoline-2-carboxylate 45a′ and by replacing in example 28 N-methylpiperazine by N-benzylpiperazine and proceeding in the same manner, the abovenamed product is obtained. Yield: 68%. 1H-NMR (200 MHz, CDCl3): δ 7.87 (d, 1H, J=7.5 Hz, 1H arom.), 7.51 (s, 1H arom.), 7.44-7.28 (m, 11H arom.), 7.14 (d, 1H, J=7.6 Hz, 1H arom.), 5.34 (s, 2H, OCH2), 4.02 (s, 3H, OCH3), 3.67 (s, 2H, NCH2), 3.49-3.47 (m, 4H, CH2—N—CH2), 2.86-2.83 (m, 4H, CH2—N—CH2).
Starting with methyl-4-benzyloxy-8-bromo-quinoline-2-carboxylate 45a′ and by replacing in example 28 N-methylpiperazine by N-phenyl,N-methylamine and proceeding in the same manner, the abovenamed product is obtained. Yield: 65%. 1H-NMR (300 MHz, CDCl3): δ 8.08 (d, 1H, J=8 Hz, 1H arom.), 7.67-7.44 (m, 8H arom.), 7.20-7.18 (m, 2H arom.), 6.93-6.081 (m, 3H arom.), 5.36 (s, 2H, OCH2), 3.92 (s, 3H, OCH3), 3.56 (s, 3H, NCH3).
By replacing methyl-4-benzyloxy-6-bromo-8-nitro-quinoline-2-carboxylate 31e in example 28 by benzyl-4-benzyloxy-8-bromo-quinoline-2-carboxylate 45a and proceeding in the same manner, the abovenamed product is obtained. Yield: 68%. 1H-NMR (200 MHz, CDCl3): δ 7.87 (d, 1H, J=7.5 Hz, 1H arom.), 7.54 (s, 1H arom.), 7.51-7.15 (m, 6H arom.), 7.16 (d, 1H, J=8 Hz, 1H arom.), 5.35 (s, 2H, OCH2), 4.02 (s, 3H, OCH3), 3.52-3.49 (m, 4H, CH2—N—CH2), 2.83-2.81 (m, 4H, CH2—N—CH2), 2.45 (s, 3H, NCH3).
Starting with methyl-4-benzyloxy-8-bromo-quinoline-2-carboxylate 45a′ and by replacing in example 28 N-methylpiperazine by 2-aminopyridine and proceeding in the same manner, the abovenamed product is obtained. Yield: 80%. 1H-NMR (300 MHz, CDCl3): δ 9.22 (s, 1H, NH), 8.88 (d, 1H, J=8 Hz, 1H arom.), 8.38-8.35 (m, 1H arom.), 7.79-7.42 (m, 9H arom.), 7.06 (d, 1H, J=8 Hz, 1H arom.), 6.87-6.80 (m, 1H arom.), 5.38 (s, 2H, OCH2), 4.08 (s, 3H, OCH3).
By replacing methyl-4-benzyloxy-6-bromo-8-nitro-quinoline-2 carboxylate 31e in example 28 by methyl-8-benzyloxy-4-trifluoromethanesulfonyloxy-quinoline-2-carboxylate 11 and proceeding in the same manner, the abovenamed product is obtained. Yield: 68%. 1H-NMR (200 MHz, CDCl3): δ 7.72 (s, 1H arom.), 7.60-7.54 (m, 3H arom.), 7.43-7.30 (m, 4H arom.), 7.04 (d, 1H, J=8 Hz, 1H arom.), 5.43 (s, 2H, OCH2), 4.03 (s, 3H, OCH3), 3.37-3.32 (m, 4H, CH2—N—CH2), 2.74-2.71 (m, 4H, CH2—N—CH2), 2.42 (s, 3H, NCH3).
Starting with methyl-8-benzyloxy-4-trifluoromethanesulfonyloxy-quinoline-2-carboxylate 11 and by replacing in example 28 N-methylpiperazine by 2-(1-piperazinyl)pyrimidine and proceeding in the same manner, the abovenamed product is obtained. Yield: 46%. 1H-NMR (200 MHz, CDCl3): δ 8.36 (d, 2H, J=5 Hz, 1H arom.), 7.75 (s, 1H arom.), 7.70-7.35 (m, 7H arom.), 7.07 (d, 1H, J=8 Hz, 1H arom.), 6.58 (d, 1H, J=5 Hz, 1H arom.), 5.44 (s, 2H, OCH2), 3.35-3.31 (m, 4H, 2×CH2), 4.05 (s, 3H, OCH3), 3.38-3.34 (m, 4H, 2×CH2).
To a solution of methyl-3-bromo-8-nitro-4-hydroxy-quinoline-2-carboxylate 45a (100 mg, 0.3 mmol) in THF (2.5 ml), add a Na2S2O4 solution (264 mg, 1.52 mmol, 5 eq.) in water (2 ml). Stir at room temperature for 3 hours, then add ethyl acetate (20 ml) and water (10 ml) and extract the organic phase, which is washed successively with water (10 ml) and saturated NaCl (10 ml). Dry the organic phase on Na2SO4, filter, evaporate to dryness and purify by silica gel chromatography (eluent: CH2Cl2/EtOAc: 55/45) to give the abovenamed product in the form of a yellow solid. Yield: 83%. 1H NMR (200 MHz, d6-DMSO): δ 11.31 (s, 1 HO), 7.41 (dd, 1H, J=1 and 8 Hz, H arom.), 7.23 (t, 1H, J=8 Hz, H arom.), 6.97 (dd, 1H, J=2 and 8 Hz, H arom.), 6.45 (s, 2 HN), 4.03 (s, 3H, OCH3).
By replacing methyl-3-bromo-8-nitro-4-hydroxy-quinoline-2-carboxylate 45a in example 21 by methyl-6-bromo-8-nitro-4-hydroxy-quinoline-2-carboxylate 31b, the abovenamed product is obtained as a white solid. Yield: 51%. 1H NMR (200 MHz, d6-DMSO): δ 11.80 (s, 1 HO), 7.47 (s, 1H3), 7.35 (d, 1H, J=2 Hz, H5), 6.97 (d, 1H, J=2 Hz, H7), 6.28 (s, 2 HN), 3.93 (s, 3H, OCH3).
By replacing methyl-3-bromo-8-nitro-4-hydroxy-quinoline-2-carboxylate 45a in example 21 by methyl-6-chloro-8-nitro-4-hydroxy-quinoline-2-carboxylate 117b, the abovenamed product is obtained as an orange solid. Yield: 59%. 1H NMR (200 MHz, d6-DMSO): δ 11.60 (s, 1 HO), 7.45 (s, 1H3), 7.17 (d, 1H, J=2 Hz, H5), 6.85 (d, 1H, J=2 Hz, H7), 6.27 (s, 2 HN), 3.90 (s, 3H, OCH3).
By replacing methyl-3-bromo-8-nitro-4-hydroxy-quinoline-2-carboxylate 45a in example 21 by benzyl-8-nitro-4-benzyloxy-quinoline-2-carboxylate 34a, the abovenamed product is obtained as a yellow solid. Yield: 80%. 1H NMR (200 MHz, CDCl3): δ 7.41 (m, 13H, 13H arom.), 6.94 (d, 1H, J=8 Hz, 1H6), 5.48 (s, 2H, CH2benz.), 5.33 (s, 2H, CH2benz.), 5.12 (s, 2H, NH2).
To a solution of benzyl-8-amino-4-benzyloxy-quinoline-2-carboxylate 34b (100 mg, 0.32 mmol) in absolute ethanol (10 ml), add iodine (82 mg, 0.32 mmol, 1 eq.) and silver sulfate (101 mg, 0/32 mmol, 1 eq.) and stir at room temperature for 6 hours. Add sodium thiosulfate solution (10 ml) and evaporate the ethanol. Take up in dichloromethane (50 ml), wash the organic phase with water (10 ml) and dry on sodium sulfate, filter and evaporate to dryness. Purify the residue by silica gel column chromatography (eluent: CH2Cl2/MeOH: 98/2) to isolate the abovenamed product as a yellow product. Yield: 36%. 1H NMR (200 MHz, CDCl3): δ 7.73 (d, 1H, J=8 Hz, H7), 7.65 (s, 1H3), 7.43 (m, 10H arom.), 7.32 (d, 1H, J=8 Hz, H6), 5.62 (s, 2H, 2 NH), 5.35 (s, 2H benz.), 5.27 (s, 2H benz.).
A solution of methyl-6-bromo-8-nitro-4-hydroxy-quinoline-2-carboxylate 31e (400 mg, 0.96 mmol), zinc cyanide (67.5 mg, 0.27 mmol, 0.6 eq.), diphenylphosphineferrocene (DPPF, 21.2 mg, 0.038 mg, 0.04 eq.), bispalladium(0)dibenzylideneacetone (Pd2(dba)3, (17.6 mg, 0.019 mmol, 0.02 eq.) and zinc powder (7.5 mg, 0.115 mmol, 0.12 eq.) in degassed N,N-dimethylacetamide (6 ml) is heated at 120° C. for 16 hours. Transfer the solution into 50 ml of ethyl acetate. Wash the organic phase with 2 M NH4OH (50 ml). Extract the aqueous phase three times with ethyl acetate (3×10 ml). Combine the organic phases and wash with saturated NaCl solution, dry on Na2SO4, filter and evaporate to dryness. Purify the residue by silica gel chromatography (eluent: CH2Cl2/EtOAc: 99/1) to isolate the abovenamed product as a white solid. Yield: 66%. 1H NMR (200 MHz, CDCl3): δ 8.82 (d, 1H, J=2 Hz, H7), 8.21 (d, 1H, J=2 Hz, H5), 7.88 (s, 1H3), 7.49 (m, 5H arom.), 5.44 (s, 2H benz.), 4.06 (s, 3H, OCH3).
To a solution of methyl-4-hydroxy-8-nitro-2-quinoline-2-carboxylate 2s (0.5 g, 2 mmol) in CCl4 (35 ml), add N-bromosuccinimide (0.39 g, 2.2 mmol, 1.1 eq.) and react under reflux for 2 hours. Evaporate the solvent and purify the residue by silica gel chromatography (eluent: EtOAc/CH2Cl2/Hexane: 1/1.6/2.4) to obtain the abovenamed product as a yellow solid. Yield=80%. 1H NMR (300 MHz, CDCl3): δ 12.15 (s, 1 HO), 8.80 (dd, 1H, J=2 and 8 Hz, H arom.), 8.76 (dd, 1H, J=2 and 8 Hz, H arom.), 7.56 (dt, 1H, J=2 and 8 Hz, H arom.), 4.19 (s, 3H, OCH3).
To a solution of methyl-6-diphenylmethylenamino-8-nitro-4-benzyloxy-quinoline-2-carboxylate 32a (210 mg, 0.386 mmol) in THF (10 ml), add at room temperature 2 M hydrochloric acid (4 ml) and stir for 2 hours. Filter the purple precipitate which forms and wash with water, then with ethyl acetate (2×2 ml). Dissolve the solid in dichloromethane (10 ml) and wash with a saturated sodium carbonate solution (2 ml), water (2 ml), then dry on sodium sulfate, filter and evaporate. The abovenamed product is isolated as an orange solid. Yield: 82%. 1H NMR (300 MHz, CDCl3): δ 7.67 (s, 1H3), 7.50 (m, 6H arom.), 7.59 (s, 1H, 1H arom.), 5.34 (s, 2H benz.), 4.30 (s, 2H, NH2), 4.05 (s, 3H, OCH3).
To methyl-3-trimethylsilylethynyl-8-nitro-4-hydroxy-quinoline-2-carboxylate ester 57a (101 mg, 0.29 mmol) in a mixture of THF/MeOH (1:1.4 ml), add KOH solution (0.04 g, 0.71 mmol, 2.5 eq.) in water (1 ml). Stir the solution at room temperature for 4 hours and neutralize by adding 1 M HCl. Evaporate the THF and take up the residual solution in CH2Cl2. Extract the organic phase, wash with water, then with saturated NaCl. Dry on sodium sulfate, filter and evaporate. The abovenamed product is obtained as a beige solid. Yield: 63%. 1H NMR (200 MHz, CDCl3): δ 8.64 (d, 1H, J=8 Hz, H arom.), 8.25 (d, 1H, J=8 Hz, H arom.), 8.02 (s, 1H, OH), 7.90 (t, 1H, J=8 Hz, H arom.), 5.30 (s, 1H, CH), 4.14 (s, 3H, CH3).
By replacing methyl-3-trimethylsilylethynyl-8-nitro-4-hydroxy-quinoline-2-carboxylate 57a in example 34 by methyl-8-cyano-4-hydroxy-6-[(trimethylsilyl)ethynyl]-quinoline-2-carboxylate 69a and proceeding in the same manner, the abovenamed product is obtained. Yield: 91%. 1H-NMR (300 MHz, CDCl3+MeOD): δ 8.49 (m, 1H arom.), 7.99 (m, 1H arom.), 7.04 (m, 1H arom.), 3.99 (s, 3H, OCH3), 6.67 (s, 1H, CCH).
To a solution of methyl-8-nitro-4-hydroxy-quinoline-2-carboxylate 2u (500 mg, 2 mmol) in MeOH (10 ml) add an aqueous 10% sodium hydroxide solution (2 ml) and stir at room temperature for 3 hours. Acidify to pH 3 by adding 1 M HCl and filter the yellow precipitate formed. Dry the solid and isolate 8-nitro-4-hydroxy-quinoline-2-carboxylic acid as a yellow solid. Yield: 78%. 1H NMR (200 MHz, d6-DMSO): δ 11.66 (s, 1H, OH), 8.74 (d, 1H, J=8 Hz, 1H arom.), 8.74 (d, 1H, J=8 Hz, 1H arom.), 7.61 (t, 1H, J=8 Hz, H6), 6.84 (s, 1H, H3). Dissolve the previous solid in DMF (10 ml) and add potassium carbonate (1.0 g, 7.22 mmol, 2.8 eq.) then benzyl bromide (0.96 g, 7.22 mmol, 2.8 eq.) and heat at 60° C. for 4 hours. Pour the reaction mixture into iced water (80 ml) and filter the solid formed, redissolve in CH2Cl2, wash with H2O then with saturated NaCl and dry on Na2SO4, filter and evaporate to dryness. Crystallize by addition of Et2O/Hexane 1/3. The abovenamed product is isolated as a white solid. Yield: 86%. 1H NMR (200 MHz, CDCl3): δ 8.52 (d, 1H, J=8 Hz, 1H arom.), 8.14 (d, 1H, J=8 Hz, 1H arom.), 7.79 (s, 1H, 1H3), 7.68 (t, 1H, J=8 Hz, 1H6), 7.55 (m, 10H, 10H arom.), 5.53 (s, 2H, CH2benz.), 5.53 (s, 2H, CH2benz.).
To a solution of methyl-8-benzyloxy-4-hydroxy-quinoline-2-carboxylate 2a (300 mg, 0.97 mmol) in ethanol (20 ml), add at room temperature morpholine (0.25 mL, 2.87 mmol, 2.9 eq.) then formol (0.15 of a 37% solution in water, 1.62 mmol, 1.6 eq.) and heat under reflux for 24 hours. Evaporate the solvents and add shaved ice. Filter the precipitate formed. The abovenamed product is isolated as a pink solid. Yield: 55%. 1H NMR (200 MHz, d6-DMSO): δ 11.85 (s, 1H, OH), 10.37 (s, 1H, OH), 7.69 (d, 1H, J=8 Hz, 1H arom.), 7.46 (m, 7H, 7H arom.), 5.39 (s, 2H, CH2benz.), 4.53 (s, 2H, CH2N), 3.80 (m, 4H, 2 CH2), 3.42 (m, 2H, 2 CH2).
By replacing morpholine in example 36 by pyrolidine, the abovenamed product is obtained as a beige solid. Yield: 32%. 1H NMR (200 MHz, d6-DMSO): δ 10.60 (s, 1H, OH), 10.48 (s, 1H, OH), 7.69 (d, 1H, J=8 Hz, 1H arom.), 7.45 (m, 7H, 7H arom.), 5.40 (s, 2H, CH2benz.), 4.57 (s, 2H, CH2N), 3.28 (m, 4H, 2 CH2), 1.98 (m, 4H, 2 CH2).
Dissolve 200 mg (0.444 mmol) of methyl-8-benzyloxy-4-(3-tert-butoxycarbonylaminoprop-1-yl)-quinoline-2-carboxylate 85a in 2 ml of dichloromethane and add 1 ml of trifluoroacetic acid. Stir at room temperature for 1 hour, evaporate to dryness and dry to obtain the abovenamed product. Yield: 93%. 1H-NMR (300 MHz, DMSO-d6): δ 8.05 (s, 1H arom.), 7.81-7.36 (m, 8H arom.), 5.43 (s, 2H, OCH2), 3.96 (s, 3H, CH3), 3.22 (t, 2H, J=7.5 Hz, CH2), 2.95 (m, 2H, CH2), 1.99 (m, 2H, CH2).
Screening Protocol
Screening comprises testing the synthetic compounds at a fairly low concentration (10 μM) for their ability to displace the binding of 200 nM [3H]-XA (using non-radiolabelled xanthurenic acid as control). If this concentration produces the same or greater displacement than the same concentration of non-radiolabelled XA, then an IC50 is determined.
Binding is carried out in 50 mM Pipes buffer pH 7.4 at 0° C. (in ice) in the presence of synaptic membranes (from 0.1 to 0.3 mg of protein per tube), tritium-labelled xanthurenic acid ([3H]-XA) at 200 nM final concentration and
The incubation time is 25 min. The filtration by which unbound [3H]-XA is separated from [3H]-XA bound to its binding site(s) is carried out by rapid aspiration of the incubation medium through Whatmann (GF/B) fiberglass filters which are then successively washed twice with cold 50 mM Pipes buffer pH 7.4 (3×3 ml altogether). The filters are placed in scintillation vials to which 5 ml of Rotiszint® (Roth) are added and the vials are counted in a Beckman LS6000sc liquid scintillation counter.
Specific binding is given as the difference between total binding and nonspecific binding. The percentage inhibition of binding that the synthetic compounds produce is calculated for each compound in relation to its positive control.
Competition Protocol—IC50 Determination (50% Inhibitory Concentration)
Binding is carried out in 50 mM Pipes buffer pH 7.4 at 0° C. (in ice) in the presence of synaptic membranes (from 0.1 to 0.3 mg of protein per tube), tritium-labelled xanthurenic acid ([3H]-XA) at 200 nM final concentration and either buffer (to determine total binding), or non-radiolabelled xanthurenic acid at 2 mM concentration (to determine nonspecific binding) or different concentrations of a non-radiolabelled synthetic compound. If the compound reversibly binds to the binding site of [3H]-XA, the two ligands will compete with each other and a binding displacement curve for [3H]-XA can be plotted against the concentration of the competitor molecule. The incubation time is 25 minutes, followed by filtration.
Graphpad Prism software is used to compute the IC50 which is the concentration of the compound that produces 50% inhibition of binding of xanthurenic acid. In a competition experiment between [3H]-XA and non-radiolabelled XA, a binding displacement curve is obtained which, after analysis by Graphpad Prism software, gives a two site binding model, one IC50 at 300 nM and one IC50 at 57 μM.
Results
The results obtained are shown in the following tables and in FIG. 1.
These results demonstrate the properties of the inventive compounds to modulate the activity of xanthurenic acid, and thereby to modulate dopaminergic neurotransmission in particular.
The determinations at 50 μM or 10 μM were set arbitrarily to 100% inhibition of binding. Thus, compounds with values ≧100 are as potent as xanthurenic acid. For example, compound 19f is about 10 times more potent than xanthurenic acid (IC50=5.2 and 57 μM, respectively).
Compounds which increase the binding of xanthurenic acid are potential allosteric modulators of the xanthurenic acid receptor. Examples include kynurenic acid and compounds 3x and 22c
Compound 3u is a quite potent inhibitor of xanthurenic acid binding (IC50=14.6 μM). In in vitro (electrophysiology) experiments and in vivo (stereotypic behaviors) studies, this compound blocks the effects of xanthurenic acid without displaying an intrinsic effect. It is thus the first competitive antagonist acting on the xanthurenic acid receptor.
The dichlorinated derivative 3i was used as precursor to prepare the tritiated radioligand, which allowed development of the method to determine specific binding of xanthurenic acid, and represents an important tool in the search for better xanthurenic acid ligands.
The tritiated derivative was prepared by catalytic hydrogenation (palladium/charcoal) of the dichlorinated precursor 3i in the presence of tritium gas under 15 psi of pressure for 24 hours.
| Number | Date | Country | Kind |
|---|---|---|---|
| 0109730 | Jul 2001 | FR | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/FR02/02594 | 7/19/2002 | WO | 3/1/2005 |
