1-pyrimidinylacetamide human leukocyte elastate inhibitors

• US 5,441,960 A
• Filed: 04/08/1993
• Issued: 08/15/1995
• Est. Priority Date: 04/16/1992
• Status: Expired due to Fees

• Current Assignee: Astrazeneca UK Limited (Astrazeneca PLC)
• Original Assignee: Zeneca Incorporated (Astrazeneca PLC)
• Inventors: Warner, Peter, Shaw, Andrew, Wolanin, Donald J., Bernstein, Peter R., Veale, Chris A., Thomas, Royston M., Edwards, Philip D.
• Primary Examiner(s): Gupta, Yogendra N.
• Application Number:
  US08/044,866
• Time in Patent Office: 859 Days
• Field of Search: 514/235.8, 514/269, 544/123, 544/243, 544/295, 544/319, 544/322, 544/296, 544/333
• US Class Current: 514/269
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07K 5/0205 containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
• CPC Class Codes: C07K 5/06191 containing heteroatoms different from O, S, or N

Abstract

The present invention relates to certain novel substituted ketones which are 1-pyrimidinylacetamide derivatives of formula I, ##STR1## set out herein, which are inhibitors of human leukocyte elastase (HLE), also known as human neutrophil elastase (HNE), making them useful whenever such inhibition is desired, such as for research tools in pharmacological, diagnostic and related studies and in the treatment of diseases in mammals in which HLE is implicated. The invention also includes intermediates ##STR2## useful in the synthesis of these substituted ketones processes for preparing the substituted ketones pharmaceutical compositions containing such substituted ketones and methods for their use.

Claims

1. A compound of formula I (formula set out hereinbelow) wherein:

R⁰ is (1-5C)alkyl;

R is hydrogen;

or

R is an acyl group of formula A.X.CO- in which A.X-, taken together, is hydrogen, trifluoromethyl, 2,2,2-trifluoroethoxy, amino, methoxyamino, 2,2,2-trifluoroethylamino, RbRcN.O-, RaOCONH-, R¹ SO₂ NH-, RaOCO-, RbRcNCO- or RaCO-;

or

R is an acyl group of formula A.X.CJ- in which

J is oxygen or sulfur;

X is a direct bond, imino, oxy or thio; and

A is as defined below or

A is tetrahydropyran-4-yl, 1-methylpiperid-4-yl, or 5-methyl-1,3-dioxacyclohex-5-ylmethyl;

or

R is a sulfonyl group of formula D.W.SO₂ - in which D.W-, taken together, is hydroxy, amino, di(lower alkyl)amino, 2,2,2-trifluoroethylamino, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl or trifluoromethyl;

or

W is a direct bond, imino, carbonylimino, oxycarbonylimino or iminocarbonylimino; and

D is as defined below;

or

R is a group G as defined below;

The group A, D or G is (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-3C)alkyl, aryl, aryl(1-3C)alkyl, heteroaryl or heteroaryl(1-3C)-alkyl wherein an aryl or heteroaryl moiety may bear one or more halogeno, nitro, methyl or trifluoromethyl groups and further wherein the group A, D or G may bear one or more substituents selected from a group consisting of hydroxy, lower alkoxy, lower acyloxy, COORa, CH₂ COORa, CONRbRc, CH₂ CONRbRc, COO(CH₂)₂ NReRf, cyano, SO₂ R¹, CONRdSO₂ R¹, NReRf, NRgCHO, NRgCOR², NRgCOOR², NRhCQNRiRj, NRkSO₂ R³, SO₂ NRlRm, SO₂ NRnCOR⁴ and P(O)(ORa)₂ in which

Q is oxygen or sulfur;

Ra-Rn are independently hydrogen, benzyl or lower alkyl;

or, independently, a group NRbRc, NReRf, NRiRj or NRlRm is a cyclic radical selected from a group consisting of 1-pyrrolidinyl, piperidino, morpholino or 1-piperazinyl which may bear a lower alkyl substituent at the 4-position;

or independently, a group NReRf is a cyclic radical selected from a group consisting of 2-pyrrolidinon-1-yl, succinimido, oxazolidin-2-on-3-yl, 2-benzoxazolinon-3-yl, phthalimido and cis-hexahydrophthalimido; and

R¹ -R⁴ are independently trifluoromethyl, (1-6C)alkyl, (3-6C)cycloalkyl, aryl or heteroaryl in which the aryl or heteroaryl may bear one or more substituents selected from a group consisting of lower alkyl, hydroxy, lower alkoxy, halogeno or trifluoromethyl;

R⁶ is (1-5C)alkyl which has no tertiary carbon, (3-7C)cycloalkyl, aryl or heteroaryl, which aryl or heteroaryl independently may bear one or more of the substituents defined for the group A or an aryl or heteroaryl moiety thereof;

R^A is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloakyl(1-3C)alkyl, aryl(1-3C)alkyl, or heteroaryl(1-3C)alkyl, wherein an aryl or heteroaryl may bear one or more halogeno, methyl or trifluoromethyl group and further wherein the group R^A may bear one or more substituents selected from a group consisting of hydroxy, lower alkoxy, COORs, CONRtRu, SO₂ Rv, CONHSO₂ Rv, NRtRu, NRsCHO, NRsCORv, NRsCOORv, NRsCONRtRu, NRsSO₂ Rv, SO₂ NRtRu, SO₂ NRsCORv, and P(O)(ORv)₂ in which Rs-Ru are independently hydrogen, benzyl or lower alkyl, or, independently, a group NRtRu is a cyclic radical selected from a group consisting of 1-pyrrolidinyl, piperidino, morpholino or 1-piperazinyl which may bear a lower alkyl group at the 4-position; and

Rv is trifluoromethyl, (1-6C)alkyl, (3-6C)cycloalkyl, aryl or heteroaryl in which the aryl or heteroaryl may bear one or more substituents selected from a group consisting of lower alkyl, hydroxy, lower alkoxy, halogeno or trifluoromethyl; and

provided that no sp³ carbon is bonded to more than one nitrogen or oxygen, except as part of a cyclic ketal or where the nitrogen bears a carbonyl group;

or,

for a compound of formula I which is acidic or basic, a pharmaceutically acceptable salt thereof.

2. A compound as claimed in claim 1 wherein R⁰ is methyl, ethyl, propyl, isopropyl or isobutyl;

W is a direct bond or imino;

G is (1-3C)alkyl, aryl(1-C)alkyl or heteroaryl(1-2C)alkyl which may bear one or more substituents as defined in claim 1 for G or a part thereof;

(1-6C)alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, 3-methylbutyl, 1-ethylpropyl, hexyl or 4-methylpentyl;

(3-6C)cycloalkyl is cyclopropyl, cyclopentyl or cyclohexyl;

the (1-3C)alkyl portion of (3-6C)cycloalkyl(1-3C)alkyl, aryl(1-3C)alkyl or heteroaryl(1-3C)alkyl is methylene, ethylene or trimethylene;

aryl is phenyl, indenyl or naphthyl;

heteroaryl is furyl, imidazolyl, tetrazolyl, pyridyl (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl or quinolinyl (or its N-oxide);

lower alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl;

lower acyloxy is acetoxy;

lower alkoxy is methoxy, ethoxy, propoxy, isoproxy or t-butoxy;

halogeno is bromo, chloro or fluoro;

COORa is carboxy or methoxycarbonyl;

CONRbRc is carbamoyl or N,N-dimethylcarbamoyl;

NRgCOR² is trifluoroacetylamino;

CONRdSO₂ R¹ is N-phenylsulfonylcarbamoyl or N-(4-chlorophenylsulfonyl)carbamoyl;

A.X-, taken together, is tris(hydroxymethyl)methylamino, tris(acetoxymethyl)methylamino or 2,2-bis(hydroxymethyl)propoxy;

R⁶ is, isopropyl, cyclopentyl, cyclohexyl, phenyl, furyl, thienyl or pyridyl in which a phenyl or heteroaryl may bear one or two substitutes as defined in claim 1 for R⁶ ; and

R^A is hydrogen, methyl, ethyl, propyl, 2-(3-6C)cycloalkylethyl, phenethyl, 2-(pyridyl)ethyl, (wherein the phenyl or pyridyl group may bear one or two halogeno or methyl groups and further wherein the group R^A may bear a substituent selected from hydroxy, methoxy, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylsulfonyl, N-methsulfonylcarbamoyl, N-phenylsulfonylcarbamoyl, amino, and dimethylamino) or 2-(dimethylamino)ethyl, 2-morpholinoethyl, 2-piperidinoethyl or 2-(4-methylpiperazin-1-yl)ethyl.

3. A compound as claimed in claim 2 wherein R⁰ is isopropyl;

J is oxygen;

X is a direct bond, imino or oxy;

A is methyl, ethyl, phenyl, benzyl, phenethyl, pyridyl, thienyl, 5-tetrazolyl, thiazolyl, pyridylmethyl, thenyl, 5-tetrazolylmethyl, 2-(pyridyl) ethyl, 2-(thienyl)ethyl or 2-(thiazolyl)ethyl wherein the phenyl or heteroaryl group may bear one or two halogeno or methyl groups and further wherein the group A may bear a substituent selected from hydroxy, methoxy, t-butoxy, acetoxy, pivaloyloxy, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, dimethylcarbamoyl, 2-(dimethylamino)ethoxycarbonyl, cyano, methylsulfonyl, phenylsulfonyl, N-methylsulfonylcarbamoyl, N-phenylsulfonylcarbamoyl, amino, dimethylamino, oxazolidin-2-on-3-yl, acetylamino, trifluoroacetylamino, ureido, methylsulfonyl, sulfamoyl, dimethylphosphoryl or diethylphosphoryl;

D is methyl, ethyl, isopropyl, tert-butyl, cyclohexyl, phenyl, benzyl, phenethyl, pyridyl, thienyl, 5-tetrazolyl, thiazolyl, quinolinyl, pyridylmethyl, thenyl, 5-tetrazolylmethyl, 2-(pyridyl)ethyl, 2-(thienyl)ethyl or 2-(thiazolyl)ethyl wherein the phenyl or heteroaryl group may bear one or two halogeno or methyl groups and further wherein the group D may bear a substituent selected from hydroxy, methoxy, t-butoxy, acetoxy, pivaloyloxy, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, dimethylcarbamoyl, 2-(dimethylamino)ethoxycarbonyl, cyano, methylsulfonyl, phenylsulfonyl, N-methylsulfonylcarbamoyl, N-phenylsulfonylcarbamoyl, N-(4-chlorophenylsulfonyl)carbamoyl, methylsulfonylamino, amino, dimethylamino, oxazolidin-2-on-3-yl, acetylamino, trifluoroacetylamino, ureido, methylsulfonyl, sulfamoyl, dimethylphosphoryl or diethylphosphoryl; and

G is methyl, ethyl, benzyl, phenethyl, pyridyl, pyridylmethyl, thenyl, 5-tetrazolylmethyl, or 2-(pyridyl)ethyl, wherein the phenyl or heteroaryl group may bear one or two halogeno or methyl groups and further wherein the group G may bear a substituent selected from hydroxy, methoxy, acetoxy, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, dimethylcarbamoyl, phenylcarbamoyl, pyridylcarbamoyl, methylsulfonylamino, amino, dimethylamino, acetylamino, nicotinoylamino, or trifluoroacetylamino.

4. A compound as claimed in claim 1, 2 or 3 wherein R is hydrogen, trifluoroacetyl, hydroxyoxalyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, 4-fluorophenoxycarbonyl, 4-bromophenoxycarbonyl, 4-methoxyphenoxycarbonyl, benzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-pyridylmethoxycarbonyl, 3-methylpyrid-4-ylmethoxycarbonyl, 2,6-dimethylpyrid-4-ylmethoxycarbonyl, 2-pyridylmethoxycarbonyl, 6-methylpyrid-2-ylmethoxycarbonyl, 2-dimethylaminoethoxycarbonyl, acetyl, carbamoylmethylaminocarbonyl, 4-(N-phenylsulfonylcarbamoyl)phenylacetyl, sulfo, aminosulfonyl, dimethylaminosulfonyl, trifluoromethylsulfonyl, methylsulfonyl (which may bear a methoxycarbonyl, carboxy or ethylsulfonyl substituent), methylaminosulfonyl, isopropylaminosulfonyl, butylsulfonyl, butylaminosulfonyl, tert-butylaminosulfonyl, cyclohexylaminosulfonyl, phenylsulfonyl (in which the phenyl may bear a chloro, nitro, amino, acetylamino, trifluoroacetylamino, methoxy, carboxy, N-(4-chlorophenylsulfonyl)carbamoyl, or methylsulfonylamino substituent at the 3- or 4-position), anilino, pyridylsulfonyl, quinolinylsulfonyl, benzylsulfonyl (in which the phenyl ring may bear a nitro or amino substituent at the 3- or 4-position), pyridylmethylsulfonyl, 2-(pyridyl)ethylsulfonyl, benzylaminosulfonyl, methyl, ethyl, benzyl, phenethyl or pyridylmethyl.

5. A compound as claimed in any one of claims 1-3 in which R⁶ is 2-furyl, 2-thienyl, 3-pyridyl or phenyl in which the phenyl may bear one or two halogeno, trifluoromethyl, methyl, hydroxy, methoxy, tert-butoxy, methoxycarbonyl or carboxy substituents.

6. A compound as claimed in claim 5 wherein R⁶ is phenyl, 4-fluorophenyl or 2-thienyl.

7. A compound as claimed in claim 1 selected from 2-(5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-[3,3-difluoro-1-isopropyl-2-oxo-3-(N-phenethylcarbamoyl)propyl]acetamide, 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-[3,3-difluoro-1-isopropyl-2-oxo-3-(N-propylcarbamoyl)propyl]acetamide, 2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-[3,3-difluoro-1-isopropyl-2-oxo-3-(N-phenethylcarbamoyl)propyl]acetamide and 2-[6-oxo-2-phenyl-5-(4-pyridylmethoxycarbonylamino)-1,6-dihydropyrimidin-1-yl]-N-[3,3-difluoro-1-isopropyl-2-oxo-3-(N-phenethylcarbamoyl)propyl]acetamide.

8. A salt as claimed in claim 1 selected from

(a) for an acidic compound of formula I, an alkalai metal salt, an alkaline earth metal salt, an aluminum salt, an ammonium salt, or a salt made from an organic base which affords a pharmaceutically acceptable cation;

and

(b) for a basic compound of formula I, an acid-addition salt made with an acid which provides a pharmaceutically acceptable anion.

10. A pharmaceutical composition comprising a compound as defined in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

11. A method of administering a compound of claim 1, or a pharmaceutically acceptable salt thereof, to a human is need thereof for treatment of a disease or condition in which human leukocyte elastase is implicated.

9. A compound of formula Vb, set out hereinbelow, or a salt thereof ##STR4## wherein:

R is (1-6C) alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-3C)alkyl, aryl, aryl(1-3C)alkyl, heteroaryl or heteroaryl(1-3C)-alkyl wherein an aryl or heteroaryl moiety may bear one or more halogeno, nitro, methyl or trifluoromethyl groups and further wherein the group A, D or G may bear one or more substituents selected from a group consisting of hydroxy, lower alkoxy, lower acyloxy, COORa, CH₂ COORa, CONRbRc, CH₂ CONRbRc, COO(CH₂)₂ NReRf, cyano, SO₂ R¹, CONRdSO₂ R¹, NReRf, NRgCHO, NRgCOR², NRgCOOR², NRhCQNRiRj, NRkSO₂ R³, SO₂ NRlRm, SO₂ NRnCOR⁴ and P(O)(ORa)₂ in which

Q is oxygen or sulfur;

Ra-Rn are independently hydrogen, benzyl or lower alkyl;

or, independently, a group NRbRc, NReRf, NRiRj or NRlRm is a cyclic radical selected from a group consisting of 1-pyrrolidinyl, piperidino, morpholino or 1-piperazinyl which may bear a lower alkyl substituent at the 4-position;

or, independently, a group NReRf is a cyclic radical selected from a group consisting of 2-pyrrolidinon-1-yl, succinimido, oxazolidin-2-on-3-yl, 2-benzoxazolinon-3-yl, phthalimido and cis-hexahydrophthalimido; and

R⁴ -R⁴ are independently trifluoromethyl, (1-6C)alkyl, (3-6C)cycloalkyl, aryl or heteroaryl in which the aryl or heteroaryl may bear one or more substituents selected from a group consisting of lower alkyl, hydroxy, lower alkoxy, halogeno or trifluoromethyl;

R^A is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloakyl(1-3C)alkyl, aryl(1-3C)alkyl, or heteroaryl(1-3C)alkyl, wherein an aryl or heteroaryl may bear one or more halogeno, methyl or trifluoromethyl group and further wherein the group R^A may bear one or more substituents selected from a group consisting of hydroxy, lower alkoxy, COORs, CONRtRu, SO₂ Rv, CONHSO₂ Rv, NRtRu, NRsCHO, NRsCORv, NRsCOORv, NRsCONRtRu, NRsSO₂ Rv, SO₂ NRtRu, SO₂ NRsCORv, and P(O)(ORv)₂ in which Rs-Ru are independently hydrogen, benzyl or lower alkyl, or, independently, a group NRtRu is a cyclic radical selected from a group consisting of 1-pyrrolidinyl, piperidino, morpholino or 1-piperazinyl which may bear a lower alkyl group at the 4-position; and

Rv is trifluoromethyl, (1-6C)alkyl, (3-6C)cycloalkyl, aryl or heteroaryl in which the aryl or heteroaryl may bear one or more substituents selected from a group consisting of lower alkyl, hydroxy, lower alkoxy, halogeno or trifluoromethyl; and

R⁰ is (1-5C)alkyl;

R⁶ is (1-5C)alkyl which has no tertiary carbon, (3-7C)cycloalkyl, aryl or heteroaryl, which aryl or heteroaryl independently may bear one or more of the substituents defined for the group A or an aryl or heteroaryl moiety thereof;

and Rx is a group which protects and activates a primary amino group for substitution.