1-pyrimidinylacetamide compounds which are inhibitors of human leukocyte elastase

• US 5,736,535 A
• Filed: 01/19/1995
• Issued: 04/07/1998
• Est. Priority Date: 04/16/1992
• Status: Expired due to Fees

• Current Assignee: Zeneca Incorporated (Astrazeneca PLC), Zeneca Limited
• Original Assignee: Zeneca Incorporated (Astrazeneca PLC)
• Inventors: Edwards, Philip Duke, Shaw, Andrew, Shenvi, Ashokkumar Bhikkappa, Warner, Peter, Veale, Chris Allan, Bernstein, Peter Robert, Wolanin, Donald John, Thomas, Royston Martin
• Primary Examiner(s): BERNHARDT, EMILY A
• Application Number:
  US08/375,136
• Time in Patent Office: 1,174 Days
• Field of Search: 544/69, 544/229, 514/64
• US Class Current: 514/64
• 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 5/06191 containing heteroatoms different from O, S, or N

Abstract

The present invention relates to certain novel substituted derivatives which are 1-pyrimidinylacetamide derivatives of formula I, ##STR1## 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 useful in the synthesis of these substituted derivatives, processes for preparing the substituted derivatives, pharmaceutical compositions containing such substituted derivatives and methods for their use.

Claims

1. A compound of Formula I wherein

R⁰ is (1-5C)alkyl;

R⁶ is (a) phenyl which may optionally bear one or more substituents selected from halogeno, (1-6C)alkyl, lower alkoxy, and amino;

(b)(1-5C)alkyl which has no tertiary carbon;

or

(c) thienyl;

R is (a) hydrogen;

(b) an acyl group of the formula A. X. CJ where J is oxygen;

X is oxy or a direct bond; and

A is (1-6C)alkyl, benzyl, phenyl or pyridyl(1-3C)alkyl which may optionally bear one or more methyl groups;

or

(c) a sulfonyl group of the formula D. W. SO₂ wherein D is (1-6C) alkyl or (3-6C)cycloalkyl and W is a direct bond or imino;

Q¹ and Q², which may be the same or different, is each hydroxy or OR⁷, or when taken together form a moiety derived from a physiologically acceptable dihydroxy compound wherein said moiety is the residue derived from 2,3-butanediol, 2,3-dimethyl-2,3-butanediol, 1,3-propanediol, diethanolamine, catechol, (1R,2R,3S,5R)-(-)-pinanediol, (1S,2S,3R,5S-(+)-pinanediol, or 2,5-dimethylhexan-3,4-diol, wherein R⁷ is (1-10C)alkyl, (3-10C)cycloalkyl, benzyl or phenyl in which benzyl or phenyl the ring may bear one or more halogeno, lower alkyl or lower alkoxy substituents;

or pharmaceutically acceptable salt thereof.

2. A compound as claimed in claim 5 wherein R⁰ is methyl, ethyl, propyl, isopropyl or isobutyl;

R is a sulfonyl group of the formula D. W. SO₂ ;

W is a direct bond or imino;

D is (1-3C)alkyl, (3-6C)cycloalkyl;

R⁶ is isopropyl, thienyl or phenyl which may optionally bear one or two substituents selected from halogeno, (1-6C)alkyl, lower alkoxy, and amino;

Q¹ and Q² are each hydroxy, methoxy, ethoxy or isopropoxy;

or Q¹ and Q², taken together, are the residue derived from 2,3-butanediol, 2,3-dimethyl-2,3-butanediol, 1,3-propanediol, diethanolamine, catechol, (1R,2R,3S,5R)-(-)-pinanediol, (1S,2S,3R, 5S)-(+)-pinanediol, or 2,5-dimethylhexan-3,4-diol.

3. A compound as claimed in claim 1 wherein R⁰ is isopropyl;

A is an acyl group of the formula A. X. CJ where J is oxygen;

X is a direct bond or oxy;

A is methyl, ethyl, phenyl, benzyl, or pyridylmethyl which may optionally bear one or more methyl groups.

4. A compound as claimed in claim 1, 2, or 3 wherein R is hydrogen, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, benzyloxycarbonyl, 4-pyridylmethoxycarbonyl, 2,6-dimethylpyrid-4-ylmethoxycarbonyl, 2-pyridylmethoxycarbonyl, methylsulfonyl, acetyl, or cyclohexylaminosulfonyl.

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

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

9. 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 treating emphysema comprising administering to a human patient in need of treatment therefor an effective amount of a compound of claim 1.

6. A compound of formula Vb:

##STR3## wherein R is (a) hydrogen;

(b) an acyl group of the formula A. X. CJ where J is oxygen;

X is oxy or a direct bond; and

A is (1-6C)alkyl, benzyl, phenyl or pyridyl(1-3C)alkyl which may optionally bear one or more methyl groups;

or

(c) a sulfonyl group of the formula D. W. SO₂ wherein D is (1-6C) alkyl or (3-6C)cycloalkyl; and

W is a direct bond or imino;

Q¹ and Q², which may be the same or different, is each hydroxy or OR⁷, or when taken together form a moiety derived from a physiologically acceptable dihydroxy compound wherein said moiety is the residue derived from 2,3-butanediol, 2,3-dimethyl-2,3-butanediol, 1,3-propanediol, diethanolamine, catechol, (1R,2R,3S,5R)-(-)-pinanediol, (1S,2S,3R,5S-(+)-pinanediol, or 2,5-dimethylhexan-3,4-diol, wherein R⁷ is (1-10C)alkyl, (3-10C)cycloalkyl, benzyl or phenyl in which benzyl or phenyl the ring may bear one or more halogeno, lower alkyl or lower alkoxy substituents;

R⁰ is (1-5C)alkyl;

R⁶ is (a) phenyl which may optionally bear one or more substituents selected from halogeno, (1-6C)alky, lower alkoxy and amino;

(b) (1-5C)alkyl which has no tertiary carbon;

or

(c) thienyl; and

Rx is benzoyloxycarbonyl or trifluoroacetyl.

8. A compound selected from 2-(5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N- 2-methyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolidin-2-yl)propyl!acetamide, 2- 5-cyclohexylaminosulfonylamino-2-(4-fluorophenyl)-6-oxo-1,6-dihydro-1-pyrimidinyl!-N- 2-methyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolidin-2-yl)propyl!acetamide, 2-(5-cyclohexylaminosulfonylamino-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl)-N- 2-methyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolidin-2-yl)propyl!acetamide, and 2- 2-(4-aminophenyl)-5-cyclohexylaminosulfonylamino-6-oxo-1,6-dihydro-1-pyrimidinyl!-N- 2-methyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolidin-2-yl)propyl!acetamide, or a pharmaceutically acceptable salt thereof.