US2017267648A1PendingUtilityA1
Substituted uracils as chymase inhibitors
Est. expiryNov 8, 2033(~7.3 yrs left)· nominal 20-yr term from priority
Inventors:Chantal FürstnerJens AckerstaffAlexander StraubHeinrich MeierHanna TinelKatja ZimmermannDmitry ZubovJens Schamberger
A61P 9/04A61P 9/12A61P 43/00A61P 9/00A61P 11/00C07D 417/14C07D 239/557A61P 13/12C07D 417/12A61P 17/00A61K 9/08C07D 413/10C07D 403/12C07D 239/54C07D 403/14C07D 413/14A61K 31/513C07D 403/04C07D 413/04A61P 11/06A61K 9/20A61K 45/06C07D 403/10C07D 417/04A61K 9/0053C07D 413/12
48
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Claims
Abstract
The present application relates to novel substituted uracil derivatives, to a method for the production thereof, to the use thereof either alone or in combination for treating and/or preventing diseases, and to the use thereof for producing pharmaceuticals for the treatment and/or prevention of diseases.
Claims
exact text as granted — not AI-modified1 . A compound of the formula (I)
in which
R 1 represents cyano, 5- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl,
where 5- to 7-membered heterocyclyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of oxo, (C 1 -C 4 )-alkyl and halogen,
and
where 5- or 6-membered heteroaryl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of (C 1 -C 4 )-alkyl, hydroxy and halogen,
or
R 1 represents a group of the formula
where
* represents the point of attachment to the uracil group,
m represents 0 or 1,
L 1A represents a bond or (C 1 -C 4 )-alkanediyl,
in which (C 1 -C 4 )-alkanediyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl, hydroxy and (C 1 -C 4 )-alkoxy,
R 5 represents hydrogen or (C 1 -C 4 )-alkyl,
R 6 represents hydrogen or (C 1 -C 4 )-alkyl,
in which (C 1 -C 4 )-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (C 1 -C 4 )-alkyl, hydroxy and (C 1 -C 4 )-alkoxy,
or
R 5 and R 6 together with the carbon atoms to which they are attached form a 3- to 7-membered carbocycle,
R 7 represents hydrogen, cyano, (C 3 -C 7 )-cycloalkyl, hydroxycarbonyl or (C 1 -C 4 )-alkoxycarbonyl,
or
R 1 represents a group of the formula
where
*** represents the point of attachment to the uracil group,
R 2 represents a group of the formula
where
** represents the point of attachment to the uracil nitrogen atom,
A represents —CH 2 —, —CH 2 —CH 2 —, —O—CH 2 -## or oxygen,
in which ## represents the point of attachment to the phenyl ring,
n represents a number 0, 1 or 2,
R 10 represents hydrogen, halogen, difluoromethyl, trifluoromethyl, (C 1 -C 4 )-alkyl, difluoromethoxy, trifluoromethoxy or (C 1 -C 4 )-alkoxy,
R 11A represents hydrogen or deuterium,
R 11B represents hydrogen, deuterium or (C 1 -C 4 )-alkyl,
R 12 represents hydrogen, halogen, (C 1 -C 4 )-alkyl, difluoromethyl or trifluoromethyl,
R 13 represents halogen, (C 1 -C 4 )-alkyl, difluoromethyl or trifluoromethyl,
R 14 represents hydrogen or halogen,
R 15 represents hydrogen or halogen,
R 3 represents
where
# represents the point of attachment to the uracil nitrogen atom,
R 16 represents hydrogen,
R 17 represents hydrogen, halogen, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkoxy,
R 18 represents (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-alkylsulfinyl, (C 1 -C 4 )-alkylsulfonyl or —N(R 21 R 22 ),
in which (C 1 -C 4 )-alkoxy may be substituted by a substituent independently of one another selected from the group consisting of hydroxy, (C 1 -C 4 )-alkoxycarbonyl, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl and di-(C 1 -C 4 )-alkylaminocarbonyl,
where
R 21 represents (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxycarbonyl or (C 1 -C 4 )-alkylaminocarbonyl,
in which (C 1 -C 4 )-alkylaminocarbonyl may be substituted by hydroxy or (C 1 -C 4 )-alkoxy,
R 22 represents hydrogen or (C 1 -C 4 )-alkyl,
or
R 18 represents 4- to 7-membered heterocyclyl or 5- to 6-membered heteroaryl,
in which 4- to 7-membered heterocyclyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, trifluoromethyl, (C 1 -C 4 )-alkyl, hydroxy, oxo, amino and (C 1 -C 4 )-alkoxycarbonyl,
in which (C 1 -C 4 )-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of halogen, hydroxy and —N(R 23 R 24 ),
in which R 23 represents hydrogen, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkylcarbonyl,
in which R 24 represents hydrogen or (C 1 -C 4 )-alkyl,
in which 5- to 6-membered heteroaryl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of halogen, trifluoromethyl, (C 1 -C 4 )-alkyl, hydroxy, amino and (C 1 -C 4 )-alkoxycarbonyl,
in which (C 1 -C 4 )-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of halogen, hydroxy and —N(R 23 R 24 ),
in which R 23 represents hydrogen, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkylcarbonyl,
in which R 24 represents hydrogen or (C 1 -C 4 )-alkyl,
R 19 represents hydrogen, halogen, cyano, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkoxy,
R 20 represents hydrogen, halogen, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkoxy,
or
R 3 represents
in which
# represents the point of attachment to the uracil nitrogen atom,
the ring Q represents 5- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl,
in which 5- to 7-membered heterocyclyl may be substituted by 1 to 4 substituents independently selected from the group of halogen, difluoromethyl, trifluoromethyl, trideuteromethyl, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, oxo, hydroxyl, (C 1 -C 4 )-alkylcarbonyl, (C 1 -C 4 )-alkoxycarbonyl, aminocarbonyl and (C 1 -C 4 )-alkylsulfonyl,
in which 5- or 6-membered heteroaryl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, hydroxy, (C 1 -C 4 )-alkylcarbonyl, (C 1 -C 4 )-alkoxycarbonyl, aminocarbonyl and (C 1 -C 4 )-alkylsulfonyl,
and
in which two (C 1 -C 6 )-alkyl radicals attached to a carbon atom of 5- to 7-membered heterocyclyl together with the carbon atom to which they are attached may form a 3- to 6-membered carbocycle,
R 25 represents halogen, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkoxy,
p represents a number 0, 1, 2 or 3,
R 4 represents hydrogen or (C 1 -C 4 )-alkyl,
and the salts, solvates and solvates of the salts thereof.
2 . The compound of the formula (I) as claimed in claim 1 , in which
R 1 represents cyano, 5-membered heterocyclyl or 5-membered heteroaryl, where 5-membered heterocyclyl may be substituted by oxo, and
where 5-membered heteroaryl may be substituted by hydroxy,
or R 1 represents a group of the formula
where
* represents the point of attachment to the uracil group,
m represents 0 or 1,
L 1A represents a bond or (C 1 -C 4 )-alkanediyl,
R 5 represents hydrogen or (C 1 -C 4 )-alkyl,
R 6 represents hydrogen or (C 1 -C 4 )-alkyl,
in which (C 1 -C 4 )-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (C 1 -C 4 )-alkyl, hydroxy and (C 1 -C 4 )-alkoxy,
or
R 5 and R 6 together with the carbon atoms to which they are attached form a 3- to 6-membered carbocycle,
R 7 represents hydrogen, (C 1 -C 4 )-alkyl, cyano, (C 3 -C 6 )-cycloalkyl, hydroxycarbonyl or (C 1 -C 4 )-alkoxycarbonyl,
or
R 1 represents a group of the formula
where
*** represents the point of attachment to the uracil group,
R 2 represents a group of the formula
where
** represents the point of attachment to the uracil nitrogen atom,
A represents —CH 2 — or —CH 2 —CH 2 —,
n represents a number 0, 1 or 2,
R 10 represents hydrogen, fluorine, chlorine, difluoromethyl, trifluoromethyl or methyl,
R 11A represents hydrogen or deuterium,
R 11B represents hydrogen or deuterium,
R 12 represents fluorine, chlorine, methyl or trifluoromethyl,
R 13 represents fluorine, chlorine, methyl or trifluoromethyl,
R 14 represents hydrogen,
R 15 represents hydrogen,
R 3 represents
in which
# represents the point of attachment to the uracil nitrogen atom,
R 16 represents hydrogen,
R 17 represents hydrogen, halogen, methoxy or ethoxy,
R 18 represents (C 1 -C 4 )-alkyl, methoxy or ethoxy,
or
R 18 represents 5- or 6-membered heterocyclyl,
where 5- or 6-membered heterocyclyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of trifluoromethyl, methyl and oxo,
R 19 represents hydrogen,
R 20 represents hydrogen,
or
R 3 represents a group of the formula
where
# represents the point of attachment to the uracil nitrogen atom,
G 1 represents C═O or SO 2 ,
G 2 represents CR 27A R 27B , NR 28 , O or S,
where
R 27A represents hydrogen, fluorine, (C 1 -C 4 )-alkyl or hydroxy,
R 27B represents hydrogen, fluorine, chlorine, (C 1 -C 4 )-alkyl or trifluoromethyl,
or
R 27A and R 27B together with the carbon atom to which they are attached form a 3- to 6-membered carbocycle,
R 28 represents hydrogen, (C 1 -C 6 )-alkyl or (C 3 -C 7 )-cycloalkyl,
R 25 represents fluorine or methyl,
p represents a number 0 or 1,
R 26 represents hydrogen, (C 1 -C 6 )-alkyl or (C 3 -C 6 )-cycloalkyl,
R 4 represents hydrogen or methyl,
and the salts, solvates and solvates of the salts thereof.
3 . The compound of the formula (I) as claimed in claim 1 or 2 in which
R 1 represents cyano,
or
R 1 represents a group of the formula
in which
* represents the point of attachment to the uracil carbon atom,
or
R 1 represents a group of the formula
where
* represents the point of attachment to the uracil group,
m represents 0 or 1,
L 1A represents a bond, methanediyl or ethanediyl,
R 5 represents hydrogen,
R 6 represents hydrogen or methyl,
in which methyl may be substituted by hydroxy,
or
R 5 and R 6 together with the carbon atom to which they are attached form a 3- to 5-membered carbocycle,
R 7 represents hydrogen, cyano, hydroxycarbonyl, methoxycarbonyl or ethoxycarbonyl,
R 2 represents a group of the formula
where
** represents the point of attachment to the uracil nitrogen atom,
A represents —CH 2 — or —CH 2 —CH 2 —,
R 10 represents chlorine or trifluoromethyl,
R 11A represents hydrogen,
R 11B represents hydrogen,
R 12 represents chlorine or methyl,
R 13 represents chlorine or trifluoromethyl,
R 14 represents hydrogen,
R 15 represents hydrogen,
R 3 represents
in which
# represents the point of attachment to the uracil nitrogen atom,
R 16 represents hydrogen,
R 17 represents hydrogen or methoxy,
R 18 represents methoxy or ethoxy,
or
R 18 represents a group of the formula
in which
### represents the point of attachment to the phenyl ring,
R 19 represents hydrogen,
R 20 represents hydrogen,
or
R 3 represents a group of the formula
where
# represents the point of attachment to the uracil nitrogen atom,
R 4 represents hydrogen,
and the salts, solvates and solvates of the salts thereof.
4 . A process for preparing compounds of the formula (I), in which
[A] a compound of the formula (II)
in which
T 1A represents (C 1 -C 4 )-alkyl,
T 2 represents (C 1 -C 4 )-alkyl,
T 3 represents (C 1 -C 4 )-alkyl,
is reacted in an inert solvent, optionally in the presence of a suitable base, with a compound of the formula (III)
R 3 —NH 2 (III),
in which R 3 has the meaning given above
to give a compound of the formula (IV)
in which T 1A and R 3 each have the meanings given above,
this is then reacted in an inert solvent, in the presence of a suitable base, with a compound of the formula (V)
X 1 —R 2 (V)
in which R 2 has the meaning given above
and
X 1 represents hydroxy or a suitable leaving group, in particular chlorine, bromine or iodine,
to give a compound of the formula (VI)
in which T 1A , R 2 and R 3 each have the meanings given above,
the compound of the formula (VI) is then hydrolyzed in an inert solvent in the presence of a suitable acid or base to give a compound of the formula (VII)
in which T 1B represents hydrogen and
in which R 2 and R 3 each have the meanings given above,
and then in an inert solvent with a compound of the formula (VIII)
converted into a compound of the formula (I-1)
in which R 2 , R 3 , R 5 , R 6 , R 7 , L 1A and m each have the meanings given above,
or
[B] a compound of the formula (IX)
in which T 1A , T 2 and T 3 each have the meanings mentioned above,
is converted in an inert solvent or else without solvent with a compound of the formula (III) into a compound of the formula (X)
in which R 3 , T 1A and T 3 each have the meanings given above,
this is subsequently reacted in an inert solvent with chlorosulfonyl isocyanate to give a compound of the formula (IV) and this is subsequently converted analogously to process [A] into a compound of the formula (I-1),
or
[C] a compound of the formula (XI)
in which
T 2 represents (C 1 -C 4 )-alkyl,
T 3 represents (C 1 -C 4 )-alkyl and
R 4 has the meaning given above,
is reacted in an inert solvent, optionally in the presence of a suitable base, with a compound of the formula (III) to give a compound of the formula (XII)
in which R 3 and R 4 each have the meanings given above,
and this is then, by reaction with a compound of the formula (V) in an inert solvent, if appropriate in the presence of a suitable base,
converted into a compound of the formula (I-2)
in which R 2 , R 3 and R 4 each have the meanings given above,
or
[D] a compound of the formula (I-2) is converted with an azide source in the presence of a catalyst in an inert solvent into a compound of the formula (I-3)
in which R 2 , R 3 and R 4 each have the meanings given above,
or
[E] a compound of the formula (I-2) is converted with hydroxylamine into a compound of the formula (XIII)
in which R 2 and R 3 each have the meanings given above,
and then in an inert solvent with a carbonyl donor or a thiocarbonyl donor, if appropriate in the presence of a base, to give a compound of the formula (I-4)
in which R 2 and R 3 each have the meanings given above and in which
Q* represents oxygen or sulfur,
any protecting groups are detached and/or the compounds of the formulae (I-1), (I-2), (I-3) and (I-4) are, where appropriate, converted with the appropriate (i) solvents and/or (ii) bases or acids to the solvates, salts and/or solvates of the salts thereof.
5 . The compound as defined in any of claims 1 to 3 for treatment and/or prophylaxis of diseases.
6 . The compound as defined in any of claims 1 to 3 for use in a method for treatment and/or prophylaxis of heart failure, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, kidney failure, nephropathy, fibrotic disorders of the internal organs and dermatological fibroses.
7 . The use of a compound as defined in any of claims 1 to 3 for preparing a medicament for the treatment and/or prophylaxis of heart failure, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, kidney failure, nephropathy, fibrotic disorders of the internal organs and dermatological fibroses.
8 . A medicament comprising a compound as defined in any of claims 1 to 3 in combination with one or more inert, nontoxic, pharmaceutically suitable excipients.
9 . A medicament comprising a compound as defined in any of claims 1 to 3 in combination with one or more further active ingredients selected from the group consisting of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, rho-kinase inhibitors, diuretics, kinase inhibitors, matrix metalloprotease inhibitors, stimulators and activators of soluble guanylate cyclase and phosphodiesterase inhibitors.
10 . The medicament as claimed in claim 8 or 9 for treatment and/or prophylaxis of heart failure, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, kidney failure, nephropathy, fibrotic disorders of the internal organs and dermatological fibroses.
11 . A method for treatment and/or prophylaxis of heart failure, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, kidney failure, nephropathy, fibrotic disorders of the internal organs and dermatological fibroses in humans and animals using an effective amount of at least one compound as defined in any of claims 1 to 3 , or of a medicament as defined in any of claims 8 to 10 .Join the waitlist — get patent alerts
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