β-alanine derivates Number:6,953,798 from the United States Patent and Trademark Office (PTO) owispatent

Title: β-alanine derivates

Abstract: Alkanoic acid derivatives of formula (1) are described:

Ar¹ is an optionally substituted aromatic or heteroarotic group;

L¹ is a covalent bond or a linker atom or group;

Ar² is an optionally substituted phenylene or nitrogen-containing six-membered heteroarylene group;

R is a carboxylic acid (—CO₂H) or a derivative thereof;
and the salts, solvates, hydrates and N-oxides thereof.

The compounds are able to inhibit the binding of α4 integrins to their ligands and are of use in the prophylaxis and treatment of immune or inflammatory disorders.

Patent Number: 6,953,798 Issued on 10/11/2005 to Porter,   et al.

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Inventors:	Porter; John Robert (Chinnor, GB); Head; John Clifford (Maidenhead, GB); Warrellow; Graham John (Northwood, GB); Archibald; Sarah Catherine (Maidenhead, GB)
Assignee:	Celltech R&D Limited (GB)
Appl. No.:	450999
Filed:	November 29, 1999

Foreign Application Priority Data

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Nov 30, 1998[GB]

9826174

Current U.S. Class:	514/245; 514/255.05; 514/332; 514/335; 514/336; 514/338; 514/341; 514/342; 514/343; 544/212; 544/405; 546/261; 546/267; 546/268.7; 546/269.1; 546/269.7; 546/275.4; 546/282.1; 546/323
Intern'l Class:	C07D 403/12; C07D 401/12; A61K 031/53; A61K 031/44.4; A61P 019/10
Field of Search:	514/25505,332,335,336,338,341,342,343 544/405 546/261,267,268.7,269.1,269.7,275.4,278.4,282.1,323

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References Cited [Referenced By]

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Primary Examiner: McKenzie; Thomas C.
Attorney, Agent or Firm: Woodcock Washburn LLP

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Claims

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1. A compound of formula (1):


wherein

Ar¹ is an aromatic or C_1-9 heteroaromatic group containing one to four heteroatoms selected from oxygen, nitrogen, and sulfur, and is optionally substituted with one or more atoms or groups -L²(Alk)_tL³ (R⁴)_u;

L² and L³, which may be the same or different, is each a covalent bond or a divalent linker atom or group selected from —O—, —S—, —C(O)—, —C(O)O—, —OC(O)—, —C(S)—, —S(O)—, —S(O)₂—, —N(R⁸)—, —CON(R⁸)—, —OC(O)N(R⁸)—, —CSN(R⁸)—, —N(R⁸)CO—, —N(R⁸)C(O)O—, —N(R⁸)CS—, —S(O)₂N(R⁸)—, —N(R⁸)S(O)₂—, —N(R⁸)CON(R⁸)—, —N(R⁸)CSN(R⁸)—, and —N(R⁸)SO₂N(R⁸)—;

R⁸ is a hydrogen atom or a C_1-6alkyl group optionally substituted with one or more halogen atoms, hydroxy groups, or C_1-6alkoxy groups;

t is zero or the integer 1;

u is an integer 1, 2 or 3;

Alk is an aliphatic or heteroaliphatic chain;

R⁴ is a hydrogen or halogen atom or a group selected from C_1-6alkyl, —OR⁵, —SR⁵, —NR⁵R⁶, —NO₂, —CN, —CO₂R⁵, —SO₃H, —SO₃R⁵, —SOR⁵, —SO₂R⁵, —OCO₂R⁵, —CONR⁵R⁶, —OCONR⁵R⁶, —CSNR⁵R⁶, —COR⁵, —OCOR⁵, —N(R⁵)COR⁶, —N(R⁵)CSR⁶, —SO₂N(R⁵)(R⁶), —N(R⁵)SO₂R⁶, —N(R⁵)CON(R⁶)⁷), —N(R⁵)CSN(R⁶)(R⁷), and —N(R⁵)SO₂N(R⁶)(R⁷); and

R⁵, R⁶, and R⁷, which may be the same or different, is each a hydrogen atom or a straight or branched C_1-6alkyl group optionally substituted with one or more halogen atoms, hydroxy groups, or C_1-6alkoxy groups;

provided that when t is zero and each of L² and L³ is a covalent bond, then u is the integer 1 and R⁴ is other than a hydrogen atom;

L¹ is a covalent bond or a linker atom or group selected from —CON(R²)—, —S(O)₂N(R²)—, —N(R²)—, and —O—;

R² is a hydrogen atom or a C_1-3alkyl group;

Ar² is a phenylene group optionally substituted with one or two atoms or groups -L²(Alk)_tL³(R⁴)_u;

R¹ is a group selected from —NHCOR³, —NHSO₂R³, —NHR³, —NHC(O)OR³, —NHCSR³, —NHCON(R³)(R^3a), —NHSO₂N(R³)(R^3a), and —NHCSN(R³)(R^3a);

R³ is an optionally substituted C_3-10 cycloaliphatic group, an optionally substituted C_7-10 polycycloaliphatic group, an optionally substituted C_3-10 heterocycloaliphatic group containing one, two, three or four heteroatoms or heteroatom-containing groups selected from —O—, —S—, —C(O)—, —C(O)O—, OC(O)—, —C(S)—, —S(O)—, —S(O)₂—, —N(R⁸)—, —C(O)NR⁸—, —OC(O)N(R⁸)—, —CSN(R⁸)—, —N(R⁸)CO—, —N(R⁸)C(O)O—, —N(R⁸)CS—, —S(O)₂N(R⁸)—, —N(R⁸)S(O)₂—, —N(R⁸)CON(R⁸)—, —N(R⁸)CSN(R⁸)— and —N(R⁸)SO₂N(R⁸)—; an optionally substituted C_7-10 heteropolycycloaliphatic group containing one, two, three or four heteroatoms or heteroatom-containing groups selected from —O—, —S—, —C(O)—, —C(O)O—, OC(O)—, —C(S)—, —S(O)—, —S(O)₂—, —N(R⁸)—, —C(O)NR⁸—, —OC(O)N(R⁸)—, —CSN(R⁸)—, —N(R⁸)CO—, —N(R⁸)C(O)O—, —N(R⁸)CS—, —S(O)₂N(R⁸)—, —N(R⁸)S(O)₂—, —N(R⁸)CON(R⁸)—, —N(R⁸)CSN(R⁸)— and —N(R⁸)SO₂N(R⁸)—; an optionally substituted aromatic group, or an optionally substituted C_1-9 heteroaromatic group containing one, two, three or four heteroatoms selected from oxygen, nitrogen, and sulfur;

R^3a is a hydrogen atom, an optionally substituted C_1-6 aliphatic group, an optionally substituted C_1-6 heteroaliphatic group containing one, two, three or four heteroatoms or heteroatom-containing groups selected from —O—, —S—, —C(O)—, —C(O)O—, OC(O)—, —C(S)—, —S(O)—, —S(O)₂—, —N(R⁸)—, —C(O)NR⁸—, —OC(O)N(R⁸)—, —CSN(R⁸)—, —N(R⁸)CO—, —N(R⁸)C(O)O—, —N(R⁸)CS—, —S(O)₂N(R⁸)—, —N(R⁸)S(O)₂—, —N(R⁸)CON(R⁸)—, —N(R⁸)CSN(R⁸)— and —N(R⁸)SO₂N(R⁸)—, an optionally substituted C_3-10 cycloaliphatic group, an optionally substituted C_7-10 polycycloaliphatic group, an optionally substituted C_3-10 heterocycloaliphatic group containing one, two, three or four heteroatoms or heteroatom-containing groups selected from —O—, —S—, —C(O)—, —C(O)O—, OC(O)—, —C(S)—, —S(O)—, —S(O)₂—, —N(R⁸)—, —C(O)NR⁸—, —OC(O)N(R⁸)—, —CSN(R⁸)—, —N(R⁸)CO—, —N(R⁸)C(O)O—, —N(R⁸)CS—, —S(O)₂N(R⁸)—, —N(R⁸)S(O)₂—, —N(R⁸)CON(R⁸)—, —N(R⁸)CSN(R⁸)— and —N(R⁸)SO₂N(R⁸)—; an optionally substituted C_7-10 heteropolycycloaliphatic group containing one, two, three or four heteroatoms or heteroatom-containing groups selected from —O—, —S—, —C(O)—, —C(O)O—, OC(O)—, —C(S)—, —S(O)—, —S(O)₂—, —N(R⁸)—, —C(O)NR⁸—, —OC(O)N(R⁸)—, —CSN(R⁸)—, —N(R⁸)CO—, —N(R⁸)C(O)O—, —N(R⁸)CS—, —S(O)₂N(R⁸)—, —N(R⁸)S(O)₂—, —N(R⁸)CON(R⁸)—, —N(R⁸)CSN(R⁸)— and —N(R⁸)SO₂N(R⁸)—; an optionally substituted aromatic group, or an optionally substituted C_1-9 heteroaromatic group containing one, two, three or four heteroatoms selected from oxygen, nitrogen, and sulfur;

wherein the optional substituents for the aromatic groups and the heteroaromatic groups of R³ and R^3a are selected from one or more atoms or groups R¹³ wherein R¹³ is —R^13a or -Alk⁴(R^3a)_m;

R^13a is a halogen atom, or an amino, substituted amino, nitro, cyano, amidino, hydroxyl, substituted hydroxyl, formyl, carboxyl, esterified carboxyl, thiol, substituted thiol, —COR¹⁴; —CSR¹⁴, —SO₃H, —SOR¹⁴, —SO₂R¹⁴, —SO₂NH₂, —SO₂NHR¹⁴, —SON₂(R¹⁴)₂, —CONH₂, —CSNH₂, —CONHR¹⁴, —CSNHR¹⁴, —CON(R¹⁴)₂, —CSN(R¹⁴)₂, —N(R¹¹)SO₂R¹⁴, —N(SO₂R¹⁴)₂, —N(R¹¹)SO₂NH₂, —N(R¹¹)SO₂NHR¹⁴, —N(R¹¹)SO₂N(R¹⁴)₂, —N(R¹¹)COR¹⁴, —N(R¹¹)CONH₂, —N(R¹¹)CONHR¹⁴, —N(R¹¹)CON(R¹⁴)₂, —N(R¹¹)CSNH₂, —N(R¹¹)CSNHR¹⁴, —N(R¹¹)CSN(R¹⁴)₂, —N(R¹¹)CSR¹⁴, —N(R¹¹)C(O)OR¹⁴, —SO₂NHet¹, —CONHet¹, —CSNHet¹, —N(R¹¹)SO₂NHet¹, —N(R¹¹)CONHet¹, —N(R¹¹)CSNHet¹, —SO₂N(R¹¹)Het², -Het², —CON(R¹¹)Het², —CSN(R¹¹)Het², —N(R¹¹)CON(R¹¹)Het², —N(R¹¹)CSN(R¹¹)Het², aryl or heteroaryl group;

R¹⁴ is an -Alk⁴(R^13a)_m, aryl or heteroaryl group;

NHet¹ is a C_5-7cyclicamino group optionally containing one or more —O— or —S— atoms or —N(R¹¹)—, —C(O)— or —C(S)— groups and optionally substituted with one or more substituents as defined for the cycloaliphatic groups of R³ and R^3a;

Het² is a monocyclic C_5-7carbocyclic group optionally containing one or more —O— or —S— atoms or —N(R¹¹)—, —C(O) or —C(S)— groups and optionally substituted with one or more substituents as defined for the cycloaliphatic groups of R³ and R^3a;

Alk⁴ is a straight or branched C_1-6alkylene, C_2-6alkenylene or C_2-6alkynylene chain, optionally interrupted by one, two, or three —O— or —S— atoms or —S(O), or —N(R¹⁵)— groups;

R¹⁵ is a hydrogen atom or C_1-6alkyl group;

m is zero or an integer 1, 2 or 3;

n is an integer 1 or 2;

wherein the optional substituents for the aliphatic groups and the heteroaliphatic groups of R^3a are selected from halogen atoms, hydroxy groups, C_1-6alkoxy groups, thiol groups, C_1-6alkylthio groups, amino groups, and substituted amino groups;

wherein the optional substituents for the cycloaliphatic, polycycloaliphatic, heterocycloaliphatic and heteropolycycloaliphatic groups of R³ and R^3a are selected from halogen atoms, C_1-6alkyl groups, haloC_1-6alkyl groups optionally substituted with hydroxyl groups, hydroxyl groups, C_1-6alkoxy groups, haloC_1-6alkoxy groups, thiol groups, C_1-6alkylthio groups, aromatic groups, heteroaromatic groups, and -(Alk²)_vR¹⁰ groups;

Alk² is a straight or branched C_1-3 alkylene chain;

v is zero or an integer 1;

R¹⁰ is a —OH, —SH, —N(R¹¹)₂, —CN, —CO₂R¹¹, —NO₂, —CON(R¹¹)₂, —CSN(R¹¹)₂, —OC(O)N(R¹¹)₂, —C(O)H, —COR¹¹, —OCO₂R¹¹, —OC(O)R¹¹, —C(S)R¹¹, —CSN(R¹¹)₂, —N(R¹¹)COR¹¹, —N(R¹¹)CSR¹¹, —SO₃H, —SOR¹¹, —SO₂R¹¹, —SO₃R¹¹, —SO₂N(R¹¹)₂, —N(R¹¹)SO₂R¹¹, —N(R¹¹)CON(R¹¹)₂, —N(R¹¹)CSN(R¹¹)₂, or —N(R¹¹)SO₂N(R¹¹)₂ group; and

R¹¹ is an atom or group as defined for R⁸ or an optionally substituted cycloaliphatic or hetercycloaliphatic group as defined for R³;

and when R³ is a heterocycloaliphatic group containing one or more nitrogen atoms each nitrogen atom is optionally substituted with a group -(L⁵)_p(Alk³)_qR¹²;

L⁵ is —C(O)—, —C(O)O—, —C(S)—, —S(O)—, —S(O)₂—, —CON(R¹¹)—, —CSN(R¹¹)—, —SON(R¹¹)— or —SO₂N(R¹¹)—;

p is zero or an integer 1;

Alk³ is an optionally substituted aliphatic or heteroaliphatic chain;

q is zero or an integer 1;

R¹² is a hydrogen atom or an optionally substituted cycloaliphatic, heterocycloaliphatic, polycycloaliphatic, polyheterocycloaliphatic, aromatic or heteroaromatic group;

R^a and R^a′, which may be the same or different, are each independently selected from a hydrogen or halogen atom or an optionally substituted straight or branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, alkylthio or -(Alk^b)_mR^b group (in which Alk^b is a C_1-3 alkylene chain, m is zero or the integer 1, and R^b is —OH, —SH, —NO₂, —CN, —CO₂H, —CO₂R^c (where R^c is an optionally substituted straight or branched C_1-6 alkyl group), —SO₃H, —SOR^c, —SO₂R^c, —SO₃R^c, —OCO₂R^c, —C(O)H, —C(O)R^c, —OC(O)R^c, —C(S)R^c, —NR^dR^e (where R^d and R^e, which may be the same or different, are each a hydrogen atom or an optionally substituted straight or branched C_1-6 alkyl group), —CON(R^d)(R^e), —OC(O)N(R^d)(R^e), —N(R^d)C(O)R^e, —CSN(R^d)(R^e), —N(R^d)C(S)R^e, —S(O)₂N(R^d)(R^e), —N(R^d)SO₂R^e, —N(R^d)CON(R^e)(R^f) (where R^f is a hydrogen atom or an optionally substituted straight or branched C_1-6 alkyl group), —N(R^d)C(S)N(R^e)(R^f) or —N(R^d)SO₂N(R^e)(R^f) group);

Alk^a is an optionally substituted C_1-6 aliphatic or C_1-6 heteroaliphatic chain containing one, two, three or four heteroatoms or heteroatom-containing groups selected from —O—, —S—, —C(O)—, —C(O)O—, OC(O)—, —C(S)—, —S(O)—, —S(O)₂—, —N(R⁸)—, —C(O)NR⁸—, —OC(O)N(R⁸)—, —CSN(R⁸)—, —N(R⁸)CO—, —N(R⁸)C(O)O—, —N(R⁸)CS—, —S(O)₂N(R⁸)—, —N(R⁸)S(O)₂—, —N(R⁸)CON(R⁸—, —N(R⁸)CSN(R⁸)—, and —N(R⁸)SO₂N(R⁸)—;

wherein the optional substituents for the aliphatic and heteroaliphatic groups of Alk^a are selected from halogen atoms, hydroxy groups, C_1-6alkoxy groups, thiol groups, C_1-6alkylthio groups, amino groups, and substituted amino groups;

r is zero or the integer 1;

R is a carboxylic acid (CO₂H), a carboxylic ester group, or carboxylic amide group;

and the salts, hydrates and N-oxides thereof.

2. A compound according to claim 1 in which R is a —CO₂H group.

3. A compound according to claim 1 in which R^a′ is a hydrogen atom.

4. A compound according to claim 1 in which R^a is a hydrogen atom or a hydroxyl group.

5. A compound according to claim 1 in which (Alk^a)_rL¹ is a —CON(R²)— group.

6. A compound according to claim 5 in which (Alk^a)_rL¹ is a —CONH— group.

7. A compound according to claim 1 in which Ar² is a 1,4-phenylene group optionally substituted with one or two atoms or groups -L²(Alk)_tL³(R⁴)_u.

8. A compound according to claim 7 in which Ar² is a 1,4-phenylene group.

9. A compound according to claim 1 in which Ar¹ is a pyrimidinyl, pyridyl or phenyl group optionally substituted with one or more atoms or groups -L²(Alk)_tL³(R⁴)_u.

10. A compound according to claim 9 in which Ar¹ is a pyridyl or phenyl group optionally substituted with one or more atoms or groups -L²(Alk)_tL³(R⁴)_u.

11. A compound according to claim 10 in which Ar¹ is a 3,5-dichloropyridin-4-yl group.

12. A compound according to claim 1 in which R¹ is the group —NHCOR³ or —NHR³.

13. A compound according to claim 12 in which R³ is a pyrrolidinyl or thiazolidinyl group optionally substituted with one or more halogen atoms, C_1-6alkyl groups, haloC_1-6alkyl groups optionally substituted with one or more hydroxyl groups, hydroxyl groups, C_1-6alkoxy groups, haloC_1-6alkoxy groups, thiol groups, C_1-6alkylthio groups, aromatic groups, heteroaromatic groups, or -(Alk²)_vR¹⁰ groups, and each nitrogen atom of the pyrrolidinyl or thiazolidinyl group is optionally substituted with a group -(L⁵)_p(Alk³)_qR¹²;

or R³ is a phenyl, pyrimidinyl or 1,3,5-triazinyl group optionally substituted with one or more atoms or groups —R^13a or -Alk⁴(R^13a)_m.

14. A compound which is:

3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-3-({4-[2-hydroxyethylamino]-6-methoxy-1,3,5-triazin-2-yl}amine)propanoic acid;

3-[(3,5-Dichloroisonicotinoyl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)-amino]phenyl}propanoic acid;

3-{4-(3,5-Dichloroisonicotinoyl)amino]phenyl}-3-[(2,6-dimethoxybenzoyl)amino]propanoic acid;

3-({[(4S)-3-Acetyl-1,3-thiazolinan-4-yl]carbonyl}amino-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoic acid;

3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-3-[({(2S)-1-[(3,5-dichlorophenyl)sulphonyl]tetrahydro-1-H-pyrrol-2-yl}carbonyl)amino]propanoic acid;

(2RS,3RS)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-3-{[((2S)-1-[(3,5-dichlorophenyl)sulphonyl]tetrahydro-1-H-pyrrol-2-yl)carbonyl]amino}-2-hydroxypropanoic acid;

3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-3-[({2-[(2,5-dimethoxyphenyl)thio]-3-pyridinyl}carbonyl)amino]propanoic acid;

and the salts, hydrates and N-oxides thereof.

15. A pharmaceutical composition comprising a compound according to claim 1 together with one or more pharmaceutically acceptable carriers, excipients or diluents.

16. A method for the treatment of a mammal suffering from inflammatory arthritis, multiple sclerosis, allograft rejection, diabetes, inflammatory dermatoses, asthma or inflammatory bowel disease, comprising administering to the mammal a therapeutically effective amount of a compound according to claim 1.

17. A method according to claim 16 wherein said inflammatory arthritis is selected from the group consisting of rheumatoid arthritis vasculitis and polydermatomyositis.

18. A method according to claim 16 wherein said inflammatory dermatoses are selected from the group consisting of psoriasis and dermatitis.

19. A method for inhibiting, in a mammal, the binding of α4 integrins to the ligands thereof, comprising administering to the mammal an effective amount of a compound according to claim 1.

20. A method according to claim 19 wherein the α4 integrins are selected from the group consisting of α4β1 and α4β7 integrins.

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Description

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This invention relates to a series of alkanoic acid derivatives, to processes for their preparation, and to their use in medicine.

Over the last few years it has become increasingly clear that the physical interaction of inflammatory leukocytes with each other and other cells of the body plays an important role in regulating immune and inflammatory responses [Springer, T A. Nature, 346, 425, (1990); Springer, T. A. Cell 76, 301, (1994)]. Many of these interactions are mediated by specific cell surface molecules collectively referred to as cell adhesion molecules.

The adhesion molecules have been sub-divided into different groups on the basis of their structure. One family of adhesion molecules which is believed to play a particularly important role in regulating immune and inflammatory responses is the integrin family. This family of cell surface glycoproteins has a typical non-covalently linked heterodimer structure. At least 14 different integrin alpha chains and 8 different integrin beta chains have been identified [Sonnenberg, A. Current Topics in Microbiology and Immunology, 184, 7, (1993)]. The members of the family are typically named according to their heterodimer composition although trivial nomenclature is widespread in this field. Thus the integrin termed α4β1 consists of the integrin alpha 4 chain associated with the integrin beta 1 chain, but is also widely referred to as Very Late Antigen 4 or VLA4. Not all of the potential pairings of integrin alpha and beta chains have yet been observed in nature and the integrin family has been subdivided into a number of subgroups based on the pairings that have been recognised [Sonnenberg, A