Diphenylmethyl compounds useful as muscarinic receptor antagonists Number:7,071,224 from the United States Patent and Trademark Office (PTO) owispatent This invention provides compounds of formula I: ##STR00001## wherein a, b, c, e, m, R.sup.1, R.sup.2, R.sup.3, R.sup.4a, R.sup.4b, R.sup.5, R.sup.6, R.sup.7 and R.sup.8are as defined in the specification. The compounds of formula I are muscarinic receptor antagonists. The invention also provides pharmaceutical compositions containing such compounds, processes and intermediates for preparing such compounds and methods of using such compounds to treat pulmonary disorders.<H Diphenylmethyl, antagonists, Diphenylmethyl, , 7071224.html, Patent, pto, 7071224

Title: Diphenylmethyl compounds useful as muscarinic receptor antagonists

Abstract: This invention provides compounds of formula I: ##STR00001## wherein a, b, c, e, m, R.sup.1, R.sup.2, R.sup.3, R.sup.4a, R.sup.4b, R.sup.5, R.sup.6, R.sup.7 and R.sup.8are as defined in the specification. The compounds of formula I are muscarinic receptor antagonists. The invention also provides pharmaceutical compositions containing such compounds, processes and intermediates for preparing such compounds and methods of using such compounds to treat pulmonary disorders.

Patent Number: 7,071,224 Issued on 07/04/2006 to Mammen, et al.

Inventors: Mammen; Mathai (Redwood Shores, CA); Ji; Yu-Hua (Redwood City, CA); Dunham; Sarah (South Yarra, AU); Li; Li (Sunnyvale, CA)
Assignee: Theravance, Inc. (South San Francisco, CA)

Appl. No.: 076658

Filed: March 10, 2005

Current U.S. Class: 514/408 ; 548/568

Current International Class: A61K 31/40 (20060101); C07D 207/04 (20060101)

Field of Search: 548/568,542 514/424,428,408

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Primary Examiner: Saeed; Kamal A.
Assistant Examiner: Barker; Michael P.
Attorney, Agent or Firm: Hagenah; Jeffrey A. Eberle; Shelley

Parent Case Text

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 60/552,368, filed on Mar. 11, 2004; the entire disclosure of which is incorporated herein by reference in its entirety.

Claims

What is claimed is:

1. A compound of formula I: ##STR00027## wherein: each R.sup.1 and R.sup.2 are independently selected from (1 4C)alkyl, (2 4C)alkenyl, (2 4C)alkynyl, (3 6C)cycloalkyl, cyano, halo, --OR.sup.a, --SR.sup.a, --NR.sup.aR.sup.b, --S(O)R.sup.c and --S(O).sub.2R.sup.c; where each R.sup.a and R.sup.b independently represents hydrogen, (1 4C)alkyl, (2 4C)alkenyl, (2 4C)alkynyl or (3 6C)cycloalkyl; each R.sup.c independently represents (1 4C)alkyl,(2 4C)alkenyl, (2 4C)alkynyl or (3 6C)cycloalkyl; or two adjacent R.sup.1 groups or two adjacent R.sup.2 groups are joined together to form (3 6C)alkylene, (2 4C)alkylene-O-- or --O-(2 4C)alkylene-O--; a and b each independently are 0 or an integer of from 1 to 5; each R.sup.3 independently is fluoro or (1 4C)alkyl; c is 0 or an integer of from 1 to 3; R.sup.4a and R.sup.4b are independently selected from hydrogen, (1 4C)alkyl, and phenyl-(1 4C)alkyl; or R.sup.4a and R.sup.4b together with the nitrogen atom to which they are attached form a (3 6C)heterocyclic ring optionally containing one additional heteroatom selected from nitrogen, oxygen or sulfur and wherein the heterocyclic ring is unsubstituted or substituted with 1 or 2 substituents selected independently from (1 4C)alkyl and fluoro; e is 1 or2; m is 4, 5 or 6; R.sup.5 is selected from hydrogen, (1 4C)alkyl, and (3 4C)cycloalkyl; R.sup.6 is hydrogen or an unbranched (1 4C)alkyl; or R.sup.6 and R.sup.8 are joined, together with the atoms to which they are attached, to form a pyrrolidin-2-yl group; R.sup.7 is selected from hydrogen, (1 6C)alkyl, (3 6C)cycloalkyl, --CH.sub.2Ar.sup.1, --CH.sub.2CH.sub.2----CH.sub.2CH.sub.2--O-(1 4C)alkyl; wherein Ar.sup.1 represents phenyl or (3 5C)heteroaryl, wherein the phenyl or heteroaryl group is unsubstituted or substituted with from 1 to 3 substituents selected independently from halo, (1 4C)alkyl and (1 4C)alkoxy; wherein each alkyl and alkoxy is optionally substituted with from 1 to 3 fluoro substituents; and R.sup.8 is hydrogen or (1 6C)alkyl; or R.sup.7 and R.sub.8 together with the nitrogen atom to which they are attached form a pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl or thiomorpholin-1-yl group; wherein each alkyl group in R.sup.1, R.sup.2, R.sup.3, R.sup.4a, R.sup.4b, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.a-c is optionally substituted with from 1 to 5 fluoro substituents; or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.

2. The compound of claim 1, wherein a, b and c each represents 0.

3. The compound of claim 1, wherein R.sup.4a and R.sup.4b are hydrogen.

4. The compound of claim 1, wherein e is 1.

5. The compound of claim 1, wherein m is 5.

6. The compound of claim 1, wherein R.sup.5 is hydrogen.

7. The compound of claim 1, wherein R.sup.6 is hydrogen or an unbranched (1 4C)alkyl.

8. The compound of claim 1, wherein a, b, and c are 0; R.sup.4a and R.sup.4b are hydrogen; e is 1; m is 5; and R.sup.5 is hydrogen.

9. The compound of claim 1, wherein a, b, and c are 0; R.sup.4a and R.sup.4b are hydrogen; e is 1; m is 5; R.sup.5 is hydrogen; and R.sup.6 is hydrogen.

10. The compound of any one of claims 1 to 9, wherein R.sup.7 is selected from hydrogen, (1 4C)alkyl, (3 5C)cycloalkyl, --CH.sub.2Ar.sup.1, and --CH.sub.2CH.sub.2--O-(1 3C)alkyl, where Ar.sup.1 represents phenyl.

11. The compound of any one of claims 1 to 9, wherein R.sup.8 is hydrogen or (1 4C)alkyl.

12. A compound selected from: 2-{(S)-1-[5-(2-methylamino)acetylamino)pentyl]pyrrolidin-3-yl}-2,2-diphen- ylacetamide; 2-{(S)-1-[5-(2-aminoacetylamino)pentyl]pyrrolidin-3-yl}-2,2-diphenylaceta- mide; 2-amino-N-{5-[(S)-3-(carbamoyldiphenylmethyl)pyrrolidin-1-yl]pentyl}- propionamide; pyrrolidine-2-carboxylic acid {5-[(S)-3-(carbamoyldiphenylmethyl)pyrrolidin-1-yl]pentyl}amide; N-{5-[(S)-3-(carbamoyldiphenylmethyl)pyrrolidin-1-yl]pentyl}-2-methylamin- opropionamide; 2-{(S)-1-[5-(2-ethylaminoacetylamino)pentyl]pyrrolidin-3-yl}-2,2-diphenyl- acetamide; 2,2-diphenyl-2-{(S)-1-[5-(2-propylaminoacetylamino)pentyl]pyrro- lidin-3-yl}acetamide; 2-((S)-1-{5-[2-(2-methoxyethylamino)acetylamino]pentyl}pyrrolidin-3-yl)-2- ,2-diphenylacetamide; 2-{(S)-1-[5-(2-benzylaminoacetylamino)pentyl]pyrrolidin-3-yl}-2,2-dipheny- lacetamide; 2-{(S)-1-[5-(2-dimethylaminoacetylamino)pentyl]pyrrolidin-3-yl}-2,2-diphe- nylacetamide; 2-{(S)-1-[5-(2-cyclopropylaminoacetylamino)pentyl]pyrrolidin-3-yl}-2,2-di- phenylacetamide; 2-{(S)-1-[5-(2-cyclobutylaminoacetylamino)pentyl]pyrrolidin-3-yl}-2,2-dip- henylacetamide; and 2-{(S)-1-[5-(2-cyclopentylaminoacetylamino)pentyl]pyrrolidin-3-yl}-2,2-di- phenylacetamide; or a pharmaceutically acceptable salt or solvate thereof.

13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1 or 12.

14. The pharmaceutical composition of claim 13, wherein the composition further comprises a therapeutically effective amount of an agent selected from .beta..sub.2 adrenergic receptor agonists, steroidal anti-inflammatory agents, phosphodiesterase-4 inhibitors, and combinations thereof.

15. The pharmaceutical composition of claim 14, wherein the composition comprises a therapeutically effective amount of a .beta..sub.2 adrenergic receptor agonist and a steroidal anti-inflammatory agent.

16. A process for preparing a compound of claim 1 or 12, the process comprising: (a) reacting a compound of formula II: ##STR00028## with a compound of formula III: X.sup.1--(CH.sub.2).sub.m--NR.sup.5CO--CHR.sup.6--NR.sup.7R.sup.8 III wherein X.sup.1 represents a leaving group; (b) coupling a compound of formula IV: ##STR00029## with a compound of formula V: HOOC--CHR.sup.6--NR.sup.7R.sup.8 V or a reactive derivative thereof; (c) reacting a compound of formula II with a compound of formula VI: OHC--(CH.sub.2).sub.m-1--NR.sup.5CO--CHR.sup.6--NR.sup.7R.sup.8 VI in the presence of a reducing agent; or (d) for a compound of formula (I) in which R.sup.6 represents a hydrogen atom or an unbranched (1 4C)alkyl group, reacting a compound of formula VII: ##STR00030## wherein X.sup.2 represents a leaving group, with a compound of formula VIII: HNR.sup.7R.sup.8 VIII to provide a compound of formula I.

17. The process of claim 16, wherein the process further comprises forming a pharmaceutically acceptable salt of the compound of formula I.

18. The product prepared by the process of claim 16.

19. The product prepared by the process of claim 17.

20. A method for antagonizing a muscarinic receptor for treating a pulmonary disorder, chronic pulmonary disease, or asthma in a mammal which comprises administering to the mammal, a therapeutically effective amount of a compound of claim 1 or 12.

21. A method of producing bronchodilation in a patient, the method comprising administering to a patient a bronchodilation-producing amount of a compound of claim 1 or 12.

Description

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel diphenylmethyl compounds having muscarinic receptor antagonist or anticholinergic activity. This invention also relates to pharmaceutical compositions comprising such diphenylmethyl compounds, processes and intermediates for preparing such diphenylmethyl compounds and methods of using such diphenylmethyl compounds to treat pulmonary disorders.

2. State of the Art

Pulmonary or respiratory disorders, such as chronic obstructive pulmonary disease (COPD) and asthma, afflict many millions of people worldwide and such disorders are a leading cause of morbidity and mortality.

Muscarinic receptor antagonists are known to provide bronchoprotective effects and therefore, such compounds are useful for treating respiratory disorders, such as COPD and asthma. When used to treat such disorders, muscarinic receptor antagonists are typically administered by inhalation. However, even when administered by inhalation, a significant amount of the muscarinic receptor antagonist is often absorbed into the systemic circulation resulting in systemic side effects, such as dry mouth, mydriasis and cardiovascular side effects.

Additionally, many inhaled muscarinic receptor antagonists have a relatively short duration of action requiring that they be administered several times per day. Such a multiple-daily dosing regime is not only inconvenient but also creates a significant risk of inadequate treatment due to patient non-compliance with the required frequent dosing schedule.

Accordingly, a need exists for new muscarinic receptor antagonists. In particular, a need exists for new muscarinic receptor antagonists that having high potency and reduced systemic side effects when administered by inhalation. Additionally, a need exists for inhaled muscarinic receptor antagonists having a long duration of action thereby allowing for once-daily or even once-weekly dosing. Such compounds are expected to be particularly effective for treating pulmonary disorders, such as COPD and asthma, while reducing or eliminating side effects, such as dry-mouth and constipation.

SUMMARY OF THE INVENTION

The present invention provides novel diphenylmethyl derivatives having muscarinic receptor antagonist or anticholinergic activity. Among other properties, compounds of the invention are expected to possess high potency and reduced systemic side effects when administered by inhalation and to have a long duration of action.

Accordingly, in one of its composition aspects, the present invention provides a compound of formula I:

##STR00002## wherein:

each R.sup.1 and R.sup.2 are independently selected from (1 4C)alkyl, (2 4C)alkenyl, (2 4C)alkynyl, (3 6C)cycloalkyl, cyano, halo, --OR.sup.a, --SR.sup.a, --NR.sup.aR.sup.b, --S(O)R.sup.c and --S(O).sub.2R.sup.c; where each R.sup.a and R.sup.b independently represents hydrogen, (1 4C)alkyl, (2 4C)alkenyl, (2 4C)alkynyl or (3 6C)cycloalkyl; each R.sup.c independently represents (1 4C)alkyl, (2 4C)alkenyl, (2 4C)alkynyl or (3 6C)cycloalkyl; or two adjacent R.sup.1 groups or two adjacent R.sup.2 groups are joined together to form (3 6C)alkylene, (2 4C)alkylene-O-- or --O-- (2 4C)alkylene-O--;

a and b each independently are 0 or an integer of from 1 to 5;

each R.sup.3 independently is fluoro or (1 4C)alkyl;

c is 0 or an integer of from 1 to 3;

R.sup.4a and R.sup.4b are independently selected from hydrogen, (1 4C)alkyl, and phenyl-(1 4C)alkyl; or R.sup.4a and R.sup.4b together with the nitrogen atom to which they are attached form a (3 6C)heterocyclic ring optionally containing one additional heteroatom selected from nitrogen, oxygen or sulfur and wherein the heterocyclic ring is unsubstituted or substituted with 1 or 2 substituents selected independently from (1 4C)alkyl and fluoro;

e is 1 or 2;

m is 4, 5 or 6;

R.sup.5 is selected from hydrogen, (1 4C)alkyl, and (3 4C)cycloalkyl;

R.sup.6 is hydrogen or an unbranched (1 4C)alkyl; or R.sup.6 and R.sup.8 are joined, together with the atoms to which they are attached, to form a pyrrolidin-2-yl group;

R.sup.7 is selected from hydrogen, (1 6C)alkyl, (3 6C)cycloalkyl, --CH.sub.2Ar.sup.1, --CH.sub.2CH.sub.2--OH and --CH.sub.2CH.sub.2--O-(1 4C)alkyl; wherein Ar.sup.1 represents phenyl or (3 5C)heteroaryl, wherein the phenyl or heteroaryl group is unsubstituted or substituted with from 1 to 3 substituents selected independently from halo, (1 4C)alkyl and (1 4C)alkoxy; wherein each alkyl and alkoxy is optionally substituted with from 1 to 3 fluoro substituents; and

R.sup.8 is hydrogen or (1 6C)alkyl; or R.sup.7 and R.sup.8 together with the nitrogen atom to which they are attached form a pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl or thiomorpholin-1-yl group;

wherein each alkyl group in R.sup.1, R.sup.2, R.sup.3, R.sup.4a, R.sup.4b, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.a-c is optionally substituted with from 1 to 5 fluoro substituents;

or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.

In another of its composition aspects, this invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. Such pharmaceutical compositions may optionally contain other therapeutic agents. Accordingly, in one embodiment, this invention is directed to such a pharmaceutical composition wherein the composition further comprises a therapeutically effective amount of a steroidal anti-inflammatory agent, such as a corticosteroid; a .beta..sub.2 adrenergic receptor agonist; a phosphodiesterase-4 inhibitor; or a combination thereof.

Compounds of this invention possess muscarinic receptor antagonist activity. Accordingly, compounds of formula I are expected to be useful for treating pulmonary disorders, such as chronic obstructive pulmonary disease and asthma.

Accordingly, in one of its method aspects, this invention is directed to a method for treating a pulmonary disorder, the method comprising administering to a patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.

Additionally, in another of its method aspects, this invention is directed to a method of producing bronchodilation in a patient, the method comprising administering to a patient a bronchodilation-producing amount of a compound of formula I or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.

This invention is also directed to a method of treating chronic obstructive pulmonary disease or asthma, the method comprising administering to a patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.

In another one of its method aspects, this invention is directed to a method for antagonizing a muscarinic receptor in a mammal comprising administering to the mammal, a therapeutically effective amount of the compound of formula I.

Since compounds of this invention possess muscarinic receptor antagonist activity, such compounds are also useful as research tools. Accordingly, in yet another of its method aspects, this invention is directed to a method for using a compound of formula I or a pharmaceutically acceptable salt or solvate or stereoisomer thereof as a research tool for studying a biological system or sample, or for discovering new chemical compounds having muscarinic receptor antagonist activity.

This invention is also directed to processes and novel intermediates useful for preparing compounds of formula I or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. Accordingly, in another of its method aspects, this invention is directed to a process of preparing a compound of formula I, the process comprising: (a) reacting a compound of formula II with a compound of formula III; (b) reacting a compound of formula IV with a compound of formula V; (c) reacting a compound of formula II with a compound of formula VI; or (d) for a compound of formula I in which R.sup.6 represents hydrogen or an unbranched (1 4C)alkyl group, reacting a compound of formula VII with a compound of formula VIII; to provide a compound of formula I; wherein compounds of formula II-VIII are as defined herein.

In one embodiment, the above process further comprises the step of forming a pharmaceutically acceptable salt of a compound of formula I. In other embodiments, this invention is directed to the other processes described herein; and to the product prepared by any of the processes described herein.

This invention is also directed to a compound of formula I or a pharmaceutically acceptable salt or solvate or stereoisomer thereof, for use in therapy or as a medicament.

Additionally, this invention is directed to the use of a compound of formula I or a pharmaceutically acceptable salt or solvate or stereoisomer thereof, for the manufacture of a medicament; especially for the manufacture of a medicament for the treatment of a pulmonary disorder or for antagonizing a muscarinic receptor in a mammal.

DETAILED DESCRIPTION OF THE INVENTION

In one of its composition aspects, this invention is directed to novel diphenylmethyl compounds of formula I or pharmaceutically acceptable salts or solvates or stereoisomers thereof. These compounds may contain one or more chiral centers and therefore, this invention is directed to racemic mixtures; pure stereoisomers (i.e., enantiomers or diastereomers); stereoisomer-enriched mixtures and the like unless otherwise indicated. When a particular stereoisomer is shown or named herein, it will be understood by those skilled in the art that minor amounts of other stereoisomers may be present in the compositions of this invention unless otherwise indicated, provided that the desired utility of the composition as a whole is not eliminated by the presence of such other isomers.

In particular, when e is 1, the compounds of formula I contain a chiral center at the carbon atom indicated by the symbol * in the following partial formula (shown without optional substituents for clarity):

##STR00003##

In one embodiment of this invention, the carbon atom identified by the symbol * has the (R) configuration. In this embodiment, it is preferred for compounds of formula I to have the (R) configuration at the carbon atom identified by the symbol * or to be enriched in a stereoisomeric form having the (R) configuration at this carbon atom. In another embodiment of this invention, the carbon atom identified by the symbol * has the (S) configuration. In this embodiment, it is preferred for compounds of formula I to have the (S) configuration at the carbon atom identified by the symbol * or to be enriched in a stereoisomeric form having the (S) configuration at this carbon atom.

The compounds of formula I also contain several basic groups (e.g., amino groups) and therefore, the compounds of formula I can exist as the free base or in various salt forms. All such salt forms are included within the scope of this invention. Furthermore, solvates of compounds of formula I or salts thereof are included within the scope of this invention.

Additionally, where applicable, all cis-trans or E/Z isomers (geometric isomers), tautomeric forms and topoisomeric forms of the compounds of formula I are included within the scope of this invention unless otherwise specified.

The compounds of formula I, as well as those compounds used in its synthesis, may also include isotopically-labeled compounds, i.e., where one or more atoms have been enriched with atoms having an atomic mass different from the atomic mass predominately found in nature. Examples of isotopes that may be incorporated into the compounds of Formula (I) include, but are not limited to, .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N, .sup.18O and .sup.17O.

The nomenclature used herein to name the compounds of this invention is illustrated in the Examples herein. This nomenclature has generally been derived using the commercially-available AutoNom software (MDL, San Leandro, Calif.).

Representative Embodiments

The following substituents and values are intended to provide representative examples of various aspects and embodiments of this invention. These representative values are intended to further define and illustrate such aspects and embodiments and are not intended to exclude other embodiments or to limit the scope of this invention. In this regard, the representation that a particular value or substituent is preferred is not intended in any way to exclude other values or substituents from this invention unless specifically indicated.

The values for a and b are independently 0, 1, 2, 3, 4 or 5; particularly independently 0, 1 or 2, and even more particularly 0 or 1. In one embodiment, both a and b are 0.

When present, each R.sup.1 and R.sup.2 may be at the 2, 3, 4, 5 or 6-position of the phenyl ring to which it is attached. Each R.sup.1 and R.sup.2 are independently selected from (1 4C)alkyl, (2 4C)alkenyl, (2 4C)alkynyl, (3 6C)cycloalkyl, cyano, halo, --OR.sup.a, --SR.sup.a, --NR.sup.aR.sup.b, --S(O)R.sup.c and --S(O).sub.2R.sup.c. Each R.sup.a and R.sup.b independently represents hydrogen, (1 4C)alkyl, (2 4C)alkenyl, (2 4C)alkynyl or (3 6C)cycloalkyl. Each R.sup.c independently represents (1 4C)alkyl, (2 4C)alkenyl, (2 4C)alkynyl or (3 6C)cycloalkyl. Alternatively, two adjacent R.sup.1 groups or two adjacent R.sup.2 groups may be joined together to form (3 6C)alkylene, (2 4C)alkylene-O-- or --O-(2 4C)alkylene-O--. In additions each alkyl group in R.sup.1, R.sup.2, and R.sup.a-c is optionally substituted with from 1 to 5 fluoro substituents, and in one embodiment optionally substituted with 1 to 3 fluoro substituents. In a specific embodiment, R.sup.1 or R.sup.2 are independently selected from (1 4C)alkyl, fluoro, chloro and --OR.sup.a. In another specific embodiment, each R.sup.1 and R.sup.2 is (1 2C)alkyl or fluoro. Representative R.sup.1 and R.sup.2 groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, fluoro, chloro, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy.

The value for c is 0, 1, 2, or 3; particularly 0, 1 or 2; and even more particularly 0 or 1. A particular value for c is 0. Particular mention is made of compounds in which each of a, b and c represents 0.

When present, each R.sup.3 independently is fluoro or (1 4C)alkyl. In addition, each alkyl group in R.sup.3 is optionally substituted with from 1 to 5 fluoro substituents, and in one embodiment optionally substituted with 1 to 3 fluoro substituents. In a specific embodiment, each R.sup.3 is independently selected from (1 2C)alkyl and fluoro. When two R.sup.3 substituents are present (c=2), they can be on the same or different carbon atoms. Representative R.sup.3 groups include, but are not limited to, methyl, ethyl, difluoromethyl, trifluoromethyl and fluoro.

R.sup.4a and R.sup.4b are independently selected from hydrogen, (1 4C)alkyl, and phenyl-(1 4C)alkyl. R.sup.4a and R.sup.4b together with the nitrogen atom to which they are attached may form a (3 6C)heterocyclic ring optionally containing one additional heteroatom selected from nitrogen, oxygen or sulfur. This heterocyclic ring is unsubstituted or substituted with 1 or 2 substituents selected independently from (1 4C)alkyl and fluoro. In addition, each alkyl group in R.sup.4a and R.sup.4b is optionally substituted with from 1 to 5 fluoro substituents, and in one embodiment optionally substituted with 1 to 3 fluoro substituents. In one embodiment, R.sup.4a and R.sup.4b are independently hydrogen or (1 4C)alkyl. In another embodiment R.sup.4a and R.sup.4b are independently hydrogen or (1 2C)alkyl, such as methyl and ethyl. In yet another embodiment, R.sup.4a and R.sup.4b are both hydrogen. Alternatively, in another specific embodiment, R.sup.4a and R.sup.4b are joined together with the nitrogen atom to which they are attached to form a (3 5C)heterocyclic ring optionally containing one additional heteroatom selected from nitrogen, oxygen or sulfur.

Representative heterocyclic rings include, but are not limited to, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-(1 4C)alkylpiperazin-1-yl, morpholin-4-yl and thiomorpholin-4-yl.

The value for e is 1 or 2. In one embodiment, e is 1.

The value for m is 4, 5 or 6. In one embodiment, m is 5.

R.sup.5 represents hydrogen, (1 4C)alkyl, or (3 4C)cycloalkyl. Examples of (1 4C)alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. Examples of (3 4C)cycloalkyl groups include cyclopropyl and cyclobutyl. In addition, each alkyl group in R.sup.5 is optionally substituted with from 1 to 5 fluoro substituents, and in one embodiment optionally substituted with 1 to 3 fluoro substituents. In one embodiment, R.sup.5 is hydrogen or (1 3C)alkyl, such as methyl, ethyl, n-propyl and isopropyl. In a particular embodiment, R.sup.5 is hydrogen or methyl. In another embodiment, R.sup.5 is hydrogen.

R.sup.6 is hydrogen or an unbranched (1 4C)alkyl. In addition, each alkyl group in R.sup.6 is optionally substituted with from 1 to 5 fluoro substituents, and in one embodiment optionally substituted with 1 to 3 fluoro substituents. Particular values for R.sup.6 include hydrogen and methyl. In a particular embodiment, R.sup.6 is hydrogen. Alternatively, R.sup.6 and R.sup.8 may be joined, together with the atoms to which they are attached, to form a pyrrolidin-2-yl group. For example, --CHR.sup.6--NR.sup.7R.sup.8 forms a pyrrolidin-2-yl group.

R.sup.7 is selected from hydrogen, (1 6C)alkyl, (3 6C)cycloalkyl, --CH.sub.2Ar.sup.1, --CH.sub.2CH.sub.2--OH and --CH.sub.2CH.sub.2--O-(1 4C)alkyl. In addition, each alkyl group in R.sup.7 is optionally substituted with from 1 to 5 fluoro substituents, and in one embodiment optionally substituted with 1 to 3 fluoro substituents. In one embodiment, R.sup.7 represents hydrogen. In another embodiment, R.sup.7 represents (1 4C)alkyl, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Particular values for R.sup.7 in this embodiment are methyl, ethyl, n-propyl and isopropyl. In a particular embodiment, R.sup.7 is methyl. In yet another embodiment, R.sup.7 is (3 5C)cycloalkyl, such as cyclopropyl, cyclobutyl and cyclopentyl. In still another embodiment, R.sup.7 is --CH.sub.2Ar.sup.1, including --CH.sub.2-(phenyl), i.e. benzyl. In yet another embodiment, R.sup.7 is --CH.sub.2CH.sub.2--OH or --CH.sub.2CH.sub.2--O(1 3C)alkyl, including --CH.sub.2CH.sub.2--O-CH.sub.3, --CH.sub.2CH.sub.2--O--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2--O--(CH.sub.2).sub.2CH.sub.3 and --CH.sub.2CH.sub.2--O--CH(CH.sub.3).sub.2. Particular values for R.sup.7 in this embodiment are --CH.sub.2CH.sub.2--OH and --CH.sub.2CH.sub.2--O--CH.sub.3. In another particular embodiment, R.sup.7 is hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, benzyl, 2-hydroxyethyl or 2-methoxyethyl.

R.sup.8 is hydrogen or (1 6C)alkyl. In addition, each alkyl group in R.sup.8 is optionally substituted with from 1 to 5 fluoro substituents, and in one embodiment optionally substituted with 1 to 3 fluoro substituents. In one embodiment, R.sup.8 is hydrogen or (1 4C)alkyl, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Particular values for R.sup.8 are hydrogen, methyl, ethyl, n-propyl and isopropyl. In a particular embodiment, R.sup.8 is hydrogen or methyl. A particular value for R.sup.8 is hydrogen. Alternatively, R.sup.7 and R.sup.8 together with the nitrogen atom to which they are attached may form a pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl or thiomorpholin-1-yl group. In one embodiment, R.sup.7 and R.sup.8 are joined, together with the nitrogen atom to which they are attached, to form a pyrrolidin-1-yl or piperidin-1-yl group.

Ar.sup.1 represents phenyl or (3 5C)heteroaryl. The phenyl or heteroaryl group is unsubstituted or substituted with from 1 to 3 substituents selected independently from halo, (1 4C)alkyl and (1 4C)alkoxy, where each alkyl and alkoxy is optionally substituted with from 1 to 3 fluoro substituents;

In one embodiment, Ar.sup.1 is phenyl, wherein the phenyl group is unsubstituted or substituted with 1, 2 or 3 substituents selected independently from halo, (1 4C)alkyl or (1 4C)alkoxy, wherein each alkyl and alkoxy group is optionally substituted with from 1 to 3 fluoro substituents. Representative substituents include fluoro, chloro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, isopropoxy, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and trifluoromethoxy. A particular value for Ar.sup.1 in this embodiment is phenyl.

In another embodiment, Ar.sup.1 is a (3 5C)heteroaryl group containing 1 or 2 heteroatoms selected independently from oxygen, nitrogen or sulfur; wherein the heteroaryl group is unsubstituted or substituted with 1 or 2 substituents selected independently from halo, (1 4C)alkyl or (1 4C)alkoxy; wherein each alkyl and alkoxy group is optionally substituted with from 1 to 3 fluoro substituents. Representative heteroaryl groups include monovalent species of pyrrole, imidazole, thiazole, oxazole, furan, thiophene, pyrazole, isoxazole, isothiazole, pyridine, pyrazine, pyridazine and pyrimidine, where the point of attachment is at any available carbon or nitrogen ring atom. Representative substituents include fluoro, chloro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, isopropoxy, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and trifluoromethoxy. Particular examples of Ar.sup.1 groups in this embodiment include 2-furyl, 2-thienyl and 2-pyridyl.

A particular group of compounds of interest are compound of formula I wherein R.sup.5 is hydrogen or (1 4C)alkyl.

A particular group of compounds of interest are compounds of formula I wherein a and b are 0. Another group of compounds of interest are compounds of formula I wherein a, b and c are 0. A particular group of compounds of interest are compounds of formula I wherein a, b and c are 0; and R.sup.4a and R.sup.4b are hydrogen.

Another particular group of compounds of interest are compounds of formula I wherein a, b and c are 0; R.sup.4a and R.sup.4b are hydrogen; and R.sup.5 is hydrogen.

Another particular group of compounds of interest are compounds of formula I wherein a, b and c are 0; R.sup.4a and R.sup.4b are hydrogen; R.sup.5 is hydrogen; and R.sup.6 is hydrogen or an unbranched (1 4C)alkyl such as methyl.

Another particular group of compounds of interest are compounds of formula I, where a, b, and c are 0; R.sup.4a and R.sup.4b are hydrogen; e is 1; m is 5; and R.sup.5 is hydrogen. These compounds have the formula Ia:

##STR00004## where R.sup.6, R.sup.7 and R.sup.8 are as defined herein; or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.

Another particular group of compounds of interest are compounds of formula I, where a, b, and c are 0; R.sup.4a and R.sup.4b are hydrogen; e is 1; m is 5; R.sup.5 is hydrogen; and R.sup.6 is hydrogen. These compounds have the formula Ib:

##STR00005## where R.sup.7 and R.sup.8 are as defined herein; or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.

Particular compounds of interest include:

2-{(S)-1-[5-(2-methylamino)acetylamino)pentyl]pyrrolidin-3-yl}-2,2-dipheny- lacetamide;

2-{(S)-1-[5-(2-aminoacetylamino)pentyl]pyrrolidin-3-yl}-2,2-diphenylacetam- ide;

2-amino-N-{5-[(S)-3-(carbamoyldiphenylmethyl)pyrrolidin-1-yl]pentyl}propio- namide;

pyrrolidine-2-carboxylic acid {5-[(S)-3-(carbamoyldiphenylmethyl)pyrrolidin-1-yl]pentyl}amide;

N-{5-[(S)-3-(carbamoyldiphenylmethyl)pyrrolidin-1-yl]pentyl}-2-methylamino- propionamide;

2-{(S)-1-[5-(2-ethylaminoacetylamino)pentyl]pyrrolidin-3-yl}-2,2-diphenyla- cetamide;

2,2-diphenyl-2-{(S)-1-[5-(2-propylaminoacetylamino)pentyl]pyrrolidin-3-yl}- acetamide;

2-((S)-1-{5-[2-(2-methoxyethylamino)acetylamino]pentyl}pyrrolidin-3-yl)-2,- 2-diphenylacetamide;

2-{(S)-1-[5-(2-benzylaminoacetylamino)pentyl]pyrrolidin-3-yl}-2,2-diphenyl- acetamide;

2-{(S)-1-[5-(2-dimethylaminoacetylamino)pentyl]pyrrolidin-3-yl}-2,2-diphen- ylacetamide;

2-{(S)-1-[5-(2-cyclopropylaminoacetylamino)pentyl]pyrrolidin-3-yl}-2,2-dip- henylacetamide;

2-{(S)-1-[5-(2-cyclobutylaminoacetylamino)pentyl]pyrrolidin-3-yl}-2,2-diph- enylacetamide; and

2-{(S)-1-[5-(2-cyclopentylaminoacetylamino)pentyl]pyrrolidin-3-yl}-2,2-dip- henylacetamide;

or a pharmaceutically acceptable salt or solvate thereof.

Definitions

When describing the compounds, compositions, methods and processes of this invention, the following terms have the following meanings unless otherwise indicated.

The term "alkyl" means a monovalent saturated hydrocarbon group which may be linear or branched. Unless otherwise defined, such alkyl groups typically contain from 1 to 10 carbon atoms. Representative alkyl groups include, by way of example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.

The term "alkylene" means a divalent saturated hydrocarbon group which may be linear or branched. Unless otherwise defined, such alkylene groups typically contain from 1 to 10 carbon atoms. Representative alkylene groups include, by way of example, methylene, ethane-1,2-diyl ("ethylene"), propane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl and the like.

The term "alkoxy" means a monovalent group of the formula (alkyl)-O--, where alkyl is as defined herein. Representative alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy and the like.

The term "alkenyl" means a monovalent unsaturated hydrocarbon group which may be linear or branched and which has at least one, and typically 1, 2 or 3, carbon-carbon double bonds. Unless otherwise defined, such alkenyl groups typically contain from 2 to 10 carbon atoms. Representative alkenyl groups include, by way of example, ethenyl, n-propenyl, isopropenyl, n-but-2-enyl, n-hex-3-enyl and the like. The term "alkenylene" means a divalent alkenyl group.

The term "alkynyl" means a monovalent unsaturated hydrocarbon group which may be linear or branched and which has at least one, and typically 1, 2 or 3, carbon-carbon triple bonds. Unless otherwise defined, such alkynyl groups typically contain from 2 to 10 carbon atoms. Representative alkynyl groups include, by way of example, ethynyl, n-propynyl, n-but-2-ynyl, n-hex-3-ynyl and the like. The term "alkynylene" means a divalent alkynyl group.

The term "aryl" means a monovalent aromatic hydrocarbon having a single ring (i.e., phenyl) or fused rings (i.e., naphthalene). Unless otherwise defined, such aryl groups typically contain from 6 to 10 carbon ring atoms. Representative aryl groups include, by way of example, phenyl and naphthalene-1-yl, naphthalene-2-yl, and the like. The term "arylene" means a divalent aryl group.

The term "azacycloalkyl" means a monovalent heterocyclic ring containing one nitrogen atom, i.e., a cycloalkyl group in which one carbon atom has been replaced with a nitrogen atom. Unless otherwise defined, such azacycloalkyl groups typically contain from 2 to 9 carbon atoms. Representative examples of an azacycloalkyl group are pyrrolidinyl and piperidinyl groups. The term "azacycloalkylene" means a divalent azacycloakyl group. Representative examples of an azacycloalkylene group are pyrrolidinylene and piperidinylene groups.

The term "cycloalkyl" means a monovalent saturated carbocyclic hydrocarbon group. Unless otherwise defined, such cycloalkyl groups typically contain from 3 to 10 carbon atoms. Representative cycloalkyl groups include, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The term "cycloalkylene" means a divalent cycloalkyl group.

The term "halo" means fluoro, chloro, bromo and iodo. Examples of particular values for halo are fluoro, chloro and bromo.

The term "heteroaryl" means a monovalent aromatic group having a single ring or two fused rings and containing in the ring at least one heteroatom (typically 1 to 3 heteroatoms) selected from nitrogen, oxygen or sulfur. Unless otherwise defined, such heteroaryl groups typically contain from 5 to 10 total ring atoms. Representative heteroaryl groups include, by way of example, monovalent species of pyrrole, imidazole, thiazole, oxazole, furan, thiophene, triazole, pyrazole, isoxazole, isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine, indole, benzofuran, benzothiophene, benzimidazole, benzthiazole, quinoline, isoquinoline, quinazoline, quinoxaline and the like, where the point of attachment is at any available carbon or nitrogen ring atom. The term "heteroarylene" means a divalent heteroaryl group.

The term "heterocyclyl" or "heterocyclic" means a monovalent saturated or unsaturated (non-aromatic) group having a single ring or multiple condensed rings and containing in the ring at least one heteroatom (typically 1 to 3 heteroatoms) selected from nitrogen, oxygen or sulfur. Unless otherwise defined, such heterocyclic groups typically contain from 2 to 9 total ring carbon atoms. Representative heterocyclic groups include, by way of example, monovalent species of pyrrolidine, imidazolidine, pyrazolidine, piperidine, 1,4-dioxane, morpholine, thiomorpholine, piperazine, 3-pyrroline and the like, where the point of attachment is at any available carbon or nitrogen ring atom. The term "heterocyclene" means a divalent heterocyclyl or heterocyclic group.

When a specific number of carbon atoms is intended for a particular term used herein, the number of carbon atoms is shown in parentheses preceding the term. For example, the term "(1 4C)alkyl" means an alkyl group having from 1 to 4 carbon atoms.

The term "pharmaceutically acceptable salt" means a salt which is acceptable for administration to a patient, such as a mammal (e.g., salts having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids. Salts derived from pharmaceutically acceptable inorganic bases include ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. Salts derived from pharmaceutically acceptable acids include acetic, ascorbic, benzenesulfonic, benzoic, camphosulfonic, citric, ethanesulfonic, edisylic, fumaric, gentisic, gluconic, glucoronic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, lactobionic, maleic, malic, mandelic, methanesulfonic, mucic, naphthalenesulfonic, naphthalene-1,5-disulfonic, naphthalene-2,6-disulfonic, nicotinic, nitric, orotic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, xinafoic and the like. Particularly preferred are citric, hydrobromic, hydrochloric, isethionic, maleic, naphthalene-1,5-disulfonic, phosphoric, sulfuric and tartaric acids.

The term "salt thereof" means a compound formed when the hydrogen of an acid is replaced by a cation, such as a metal cation or an organic cation and the like. Preferably, the salt is a pharmaceutically acceptable salt, although this is not required for salts of intermediate compounds that are not intended for administration to a patient.

The term "solvate" as used herein refers to a complex or aggregate formed by one or more molecules of a solute, i.e. a compound of the invention or a pharmaceutically-acceptable salt thereof, and one or more molecules of a solvent. Such solvates are typically crystalline solids having a substantially fixed molar ratio of solute and solvent. Representative solvents include by way of example, water, methanol, ethanol, isopropanol, acetic acid, and the like. When the solvent is water, the solvate formed is a hydrate.

It will be appreciated that the term "or a pharmaceutically-acceptable salt or solvate or stereoisomer thereof" is intended to include all permutations of salts, solvates and stereoisomers, such as a solvate of a pharmaceutically acceptable salt of a stereoisomer of a compound of formula (I).

The term "therapeutically effective amount" means an amount sufficient to effect treatment when administered to a patient in need of treatment.

The term "treating" or "treatment" as used herein means the treating or treatment of a disease or medical condition (such as COPD) in a patient, such as a mammal (particularly a human) that includes: (a) preventing the disease or medical condition from occurring, i.e., prophylactic treatment of a patient; (b) ameliorating the disease or medical condition, i.e., eliminating or causing regression of the disease or medical condition in a patient; (c) suppressing the disease or medical condition, i.e., slowing or arresting the development of the disease or medical condition in a patient; or (d) alleviating the symptoms of the disease or medical condition in a patient.

The term "leaving group" means a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. By way of example, representative leaving groups include chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.

The term "protected derivatives thereof" means a derivative of the specified compound in which one or more functional groups of the compound are protected from undesired reactions with a protecting or blocking group. Functional groups which may be protected include, by way of example, carboxylic acid groups, amino groups, hydroxyl groups, thiol groups, carbonyl groups and the like. Representative protecting groups for carboxylic acids include esters (such as a p-methoxybenzyl ester), amides and hydrazides; for amino groups, carbamates (such as tert-butoxycarbonyl) and amides; for hydroxyl groups, ethers and esters; for thiol groups, thioethers and thioesters; for carbonyl groups, acetals and ketals; and the like. Such protecting groups are well-known to those skilled in the art and are described, for example, in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, N.Y., 1999, and references cited therein.

The term "amino-protecting group" means a protecting group suitable for preventing undesired reactions at an amino group. Representative amino-protecting groups include, but are not limited to, 1,1-di-(4'-methoxyphenyl)methyl; tert-butoxycarbonyl (BOC), benzyl (Bn), trityl (Tr), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), formyl, trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), and the like.

The term "carboxy-protecting group" means a protecting group suitable for preventing undesired reactions at a carboxy group. Representative carboxy-protecting groups include, but are not limited to, esters, such as methyl, ethyl, tert-butyl, benzyl (Bn), p-methoxybenzyl (PMB), 9-fluroenylmethyl (Fm), trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), diphenylmethyl (benzhydryl, DPM) and the like.

The term "hydroxyl-protecting group" means a protecting group suitable for preventing undesirable reactions at a hydroxyl group. Representative hydroxyl-protecting groups include, but are not limited to, silyl groups including tri(1 6C)alkylsilyl groups, such as trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS) and the like; esters (acyl groups) including (1 6C)alkanoyl groups, such as formyl, acetyl and the like; arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), diphenylmethyl (benzhydryl, DPM) and the like. Additionally, two hydroxyl groups can also be protected as an alkylidene group, such as prop-2-ylidine, formed, for example, by reaction with a ketone, such as acetone.

General Synthetic Procedures

The diphenylmethyl compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures or by using other information readily available to those of ordinary skill in the art. Although a particular embodiment of the present invention may be shown or described herein, those skilled in the art will recognize that all embodiments or aspects of the present invention can be prepared using the methods described herein or by using other methods, reagents and starting materials known to those skilled in the art. It will also be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. While the optimum reaction conditions may vary depending on the particular reactants or solvent used, such conditions can be readily determined by one skilled in the art by routine optimization procedures.

Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary or desired to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection of such functional groups are well-known in the art. Protecting groups other than those illustrated in the procedures described herein may be used, if desired. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, N.Y., 1999, and references cited therein.

By way of illustration, the compounds of formula I can be prepared by a process comprising:

(a) reacting a compound of formula II:

##STR00006## with a compound of formula III: X.sup.1--(CH.sub.2).sub.m--NR.sup.5CO--CHR.sup.6--NR.sup.7R.sup.8 III wherein X.sup.1 represents a leaving group;

(b) coupling a compound of formula IV:

##STR00007## with a compound of formula V: HOOC--CHR.sup.6--NR.sup.7R.sup.8 V or a reactive derivative thereof;

(c) reacting a compound of formula II with a compound of formula VI: OHC--(CH.sub.2).sub.m-1--NR.sup.5CO--CHR.sup.6--NR.sup.7R.sup.8 VI in the presence of a reducing agent; or

(d) for a compound of formula (I) in which R.sup.6 represents a hydrogen atom or an unbranched (1 4C)alkyl group, reacting a compound of formula VII:

##STR00008## wherein X.sup.2 represents a leaving group, with a compound of formula VIII: HNR.sup.7R.sup.8 VIII to provide a compound of formula I; and optionally, forming a pharmaceutically acceptable salt thereof.

In these reactions, depending upon the particular substituents present, one or more protecting group may be employed. If such protecting groups are used, they are removed using conventional procedures to provide the compound of formula I.

Generally, if a salt of one of the starting materials is used in the processes described above, such as an acid addition salt, the salt is typically neutralized before or during the reaction process. This neutralization reaction is typically accomplished by contacting the salt with one molar equivalent of a base for each molar equivalent of acid addition salt.

In process (a), the reaction between the compounds of formula II and III, the leaving group represented by X.sup.1 can be, for example, halo, such as chloro, bromo, or iodo; or a sulfonic acid ester group, such as mesylate or tosylate. The reaction is conveniently performed in the presence of a base, for example a tertiary amine such as diisopropylethylamine. Convenient solvents include nitrites, such as acetonitrile. The reaction is conveniently conducted at a temperature in the range of from 0.degree. C. to 100.degree. C.

Compounds of formula II may be prepared as described in U.S. Pat. No. 5,096,890 to Cross et al., the disclosure of which is incorporated herein by reference in its entirety.

Alternatively, compounds of formula II can be prepared by deprotecting a compound of formula IX:

##STR00009## in which P.sup.1 represents an amino-protecting group, such as a benzyl group. Benzyl groups are conveniently removed by reduction, for example, using a hydrogen or ammonium formate and a Group VIII metal catalyst, such as palladium.

Compounds of formula IX can be prepared by reacting a carboxylic acid of formula X:

##STR00010## with an amine of formula HNR.sup.4aR.sup.4b under amide bond forming conditions.

Compounds of formula X may be prepared by hydrolyzing a compound of formula XI:

##STR00011##

Compounds of formula XI can be prepared as described in U.S Pat. No. 5,096,890 to Cross et al.

Compounds of formula III can be prepared from a compounds of formula XII: HO--(CH.sub.2).sub.m--NR.sup.5CO--CHR.sup.6--NR.sup.7R.sup.8 XII by, for example, reacting compound XII with a halogenating agent, such as thionyl chloride, or with an appropriate sulfonyl chloride, such as p-toluenesulfonyl chloride.

Compounds of formula XII can be prepared from an amino alcohol and an amino acid using conventional coupling reagents and reaction conditions. For example, representative conditions are described in Example 1 herein.

In process (b), the coupling reaction can be conducted using any conventional amide coupling reagents and reaction conditions. For example, a carboxylic acid halide, such as a carboxylic acid chloride, of compound V can be used or a dehydrating agent, such as HATU (O-(7-azabenzo-triazol-1-yl-N,N,N',N'-tetramethyluronium-hexafluorophosph- ate) may be employed in this reaction to activate the carboxylic acid typically in the presence of a tertiary amine, such as diisopropylethylamine. Convenient solvents include amides, such as dimethylformamide. The coupling is conveniently performed at a temperature in the range of from 0.degree. C. to 100.degree. C.

Compounds of formula IV can be prepared by reacting a compound of formula XIII:

##STR00012## with an amine of formula XIV: H.sub.2NR.sup.5 XIV in the presence of a reducing agent as described, for example, in process (c) herein.

Compounds of formula XIII can be prepared by reacting a compound of formula XV:

##STR00013## with a suitable oxidizing agent, such as sulfur trioxide pyridine complex in dimethyl sulfoxide in the presence of a tertiary amine base, such as diisopropylethylamine.

Compounds of formula XV can be prepared by reacting a compound of formula II with a compound of formula XVI: X.sup.