NPY antagonists

• US 6,127,414 A
• Filed: 10/26/1998
• Issued: 10/03/2000
• Est. Priority Date: 09/23/1997
• Status: Expired due to Fees

• Current Assignee: Astra AB (Astrazeneca PLC)
• Original Assignee: Astra AB (Astrazeneca PLC)
• Inventors: D'Ambra, Thomas, Bergman, Nils-.ANG.ke, Pilling, Garry M
• Primary Examiner(s): Richter, Johann
• Assistant Examiner(s): Davis, Brian J.
• Application Number:
  US09/171,779
• Time in Patent Office: 708 Days
• Field of Search: 560/34, 560/25, 560/27, 560/28, 592/439, 594/47, 594/56, 594/147, 594/153, 594/154, 594/157, 514/533, 514/539, 514/586, 514/595, 514/616, 514/618, 514/619, 514/620
• US Class Current: 514/533
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/02 Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• 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: C07B 2200/07 Optical isomers
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2602/08 the other ring being five-membered, e.g. indane
• CPC Class Codes: C07C 279/14 being further substituted by carboxyl groups

Abstract

There is provided pharmaceutically useful compounds of formula I, ##STR1## wherein Ar¹, R¹, R², R³, R⁴, R⁵ and R⁶ have meanings given in the description, which are useful as antagonists of neuropeptide Y and in particular in the treatment of cardiovascular diseases, for example vasoconstriction.

Claims

1. A compound of formula I, ##STR17## wherein Ar¹ represents a structural fragment of the formula ##STR18## or represents 1- or 2-naphthyl, which latter group is optionally substituted by one or more substituents selected from OH, halo or C_1-7 alkoxy;

R¹ represents C(O)NH₂, C_1-4 alkyl (optionally substituted or terminated by one or more substituents selected from hydroxy or amino), or, together with

R⁷ (in Ar¹), forms C_2-3 alkylene;

R⁴ represents H, C_1-7 alkyl or C_1-4 alkylenephenyl (in which latter group, the phenyl group is optionally substituted by one or more substituent selected from OH or C_1-4 alkoxy);

R⁵ and R⁶ independently represent H, OH, C_1-4 alkyl, C_1-4 alkoxy or halo;

R⁷ represents H, OH or, together with R¹, forms C_2-3 alkylene;

R⁸ represents H, halo, OH, C_1-7 alkoxy, phenyl, phenoxy, benzyloxy, --CH₂)_n C(O)N(R¹⁰)R¹¹, --(CH₂)_n N(H)C(O)N(R¹⁰)R¹¹ or --O(CH₂)_n C(O)OR¹⁰ ;

R⁹ represents H, halo, OH or C_1-7 alkoxy;

R², R³, R¹⁰ and R¹¹ independently represent H or C_1-7 alkyl; and

n represents 1, 2, 3 or 4;

or a pharmaceutically acceptable derivative thereof.

2. A compound of formula I as claimed in claim 1, wherein R¹ represents C(O)NH₂, CH₂ OH, ethyl or methyl.

3. A compound of formula I as claimed in claim 2, wherein R¹ represents methyl.

4. A compound of formula I as claimed in claim 1, wherein R² represents H.

5. A compound of formula I as claimed in claim 1, wherein R³ represents H or methyl.

6. A compound of formula I as claimed in claim 1, wherein R⁴ represents H.

7. A compound of formula I as claimed in claim 1, wherein R⁵ represents H, OH, halo, methyl or methoxy.

8. A compound of formula I as claimed in claim 7, wherein R⁵ represents H.

9. A compound of formula I as claimed in claim 1, wherein R⁶ represents H, OH, halo, methyl or methoxy.

10. A compound of formula I as claimed in claim 9, wherein R⁶ represents H.

11. A compound of formula I as claimed in claim 1, wherein R⁷ represents H.

12. A compound of formula I as claimed in claim 1, wherein R⁸ represents OCH₃, bromo, --CH₂ C(O)NH₂, --CH₂ N(H)C(O)NH₂ or OH.

13. A compound of formula I as claimed in claim 12, wherein R⁸ represents OH.

14. A compound of formula I as claimed in claim 1, wherein R⁹ represents H.

15. A compound of formula I as claimed in claim 1, wherein R¹⁰ represents H.

16. A compound of formula I as claimed in claim 1, wherein R¹¹ represents H.

17. A compound of formula I as claimed in claim 1, wherein the carbon atom which is in the α

-position relative to Ar¹ in the fragment ##STR19## is in the R-configuration when R¹ represents C_1-4 alkyl.

18. A compound of formula I as claimed in claim 1, wherein the carbon atom which is in the α

-position relative to Ar¹ in the fragment ##STR20## is in the S-configuration when R¹ represents C(O)NH₂ or CH₂ OH.

19. A compound as claimed in claim 1 which is:

(R)-N² -(diphenylacetyl)-(R)-N-[1-(4-methoxyphenyl)ethyl]arginine amide;

(R)-N² -(diphenylacetyl)-(R,S)-N-(1-phenylpropyl)arginine amide;

(R)-N² -(diphenylacetyl)-(R,S)-N-[1-(4-hydroxyphenyl)ethyl]arginine amide;

(R)-N² -(diphenylacetyl)-(R)-N-[1-(4-hydroxyphenyl)ethyl]arginine amide;

(R)-N² -(diphenylacetyl)-(S)-N-[1-(4-methoxyphenyl)ethyl]arginine amide;

(R)-N² -(diphenylacetyl)-(S)-N-[1-(4-bromophenyl)ethyl]arginine amide;

(R)-N² -(diphenylacetyl)-(R)-N-[1-(4-bromophenyl)ethyl]arginine amide;

(R)-N² -(diphenylacetyl)-(R,S)-N-[1-(3-methoxyphenyl)ethyl]arginine amide;

(R)-N² -(diphenylacetyl)-(R)-N-(1-phenylethyl)arginine amide;

(R)-N² -(diphenylacetyl)-(S)-N-(1-phenylethyl)arginine amide;

(R)-N² -(diphenylacetyl)-(R,S)-N-[1-cyclopropyl-1-(4-methoxyphenyl)methyl]arginine amide;

(R)-N² -(diphenylacetyl)-N-(1-methyl-1-phenylethyl)arginine amide;

(R)-N² -(diphenylacetyl)-(R,S)-N-(1-indanyl)arginine amide;

(R)-N² -(diphenylacetyl)-(S or R)-N-(1-carbamoyl-phenylmethyl)arginine amide;

(R)-N² -(diphenylacetyl)-(R or S)-N-[1-carbamoyl-(4-methoxyphenyl)-methyl]arginine amide;

(R)-N² -(diphenylacetyl)-(S)-N-(2-hydroxy-1-phenylethyl)arginine amide;

(R)-N² -(diphenylacetyl)-(R)-N-(2-hydroxy-1-phenylethyl)arginine amide;

(R)-N² -(diphenylacetyl)-(R)-N-[2-hydroxy-1-(4-methoxyphenyl)ethyl]arginine amide;

(R)-N² -(diphenylacetyl)-(S)-N-[2-hydroxy-1-(4-methoxyphenyl)ethyl]arginine amide;

(R)-N² -(diphenylacetyl)-(S)-N-[1-(4-hydroxyphenyl)ethyl]arginine amide;

(R)-N² -(diphenylacetyl)-(R,S)-N-[1-(4-methoxyphenyl)ethyl]arginine amide;

(R)-N² -(diphenylacetyl)-N-methyl-(R)-N-(1 -phenylethyl)arginine amide;

(R)-N² -(diphenylacetyl)-N-methyl-(S)-N-(1-phenylethyl)arginine amide;

(R)-N² -(diphenylacetyl)-(R,S)-N-[1-(4-cyclopropylmethoxyphenyl)ethyl]-arginine amide;

(R)-N² -(diphenylacetyl)-(R)-N-[1-(4-benzyloxyphenyl)ethyl]arginine amide;

(R)-N² -(diphenylacetyl)-(R,S)-N-[1-(4-phenoxyphenyl)ethyl]arginine amide;

(R)-N² -(diphenylacetyl)-(R,S)-N-[1-(4-phenylphenyl)ethyl]arginine amide;

(R)-N² -(diphenylacetyl)-(R,S)-N-[1-(2-naphthyl)ethyl]arginine amide;

(R)-N² -(diphenylacetyl)-(R)-N-[1-(1-naphthyl)ethyl]arginine amide;

(R)-N² -[(R,S)-2-(4-methoxyphenyl)phenylacetyl]-(R)-N-[1-(4-hydroxyphenyl)ethyl]arginine amide;

(R)-N² -[(R,S)-2-(4-methylphenyl)phenylacetyl]-(R)-N-[1-(4-hydroxyphenyl)ethyl]arginine amide;

(R)-N² -[(R,S)-2-(4-chlorophenyl)phenylacetyl]-(R)-N-[1-(4-hydroxyphenyl)ethyl]arginine amide;

(R)-N² -(4,4'"'"'-dichlorodiphenylacetyl)-(R)-N-[1-(4-hydroxyphenyl)ethyl]arginine amide;

(R)-N² -[(R,S)-2-(4-hydroxyphenyl)phenylacetyl]-(R)-N-[1-(4-hydroxyphenyl)ethyl]arginine amide;

(R)-N.sup.ω

-(ethyl)-N² -(diphenylacetyl)-(R)-N-[1-(4-methoxyphenyl)ethyl]arginine amide;

(R)-N.sup.ω

-(benzyl)-N² -(diphenylacetyl)-(R)-N-[1-(4-methoxyphenyl)ethyl]arginine amide;

(R)-N.sup.ω

-(1-(4-hydroxyphenyl)ethyl)-N² -(diphenylacetyl)-(R)-N-[1-(4-hydroxyphenyl)ethyl]arginine amide;

(R)-N² -(diphenylacetyl)-(R,S)-N-[1-(4-(aminocarbonylmethyl)phenyl)ethyl]arginine amide;

(R)-N² -(diphenylacetyl)-(R,S)-N-[1-(4-(aminocarbonylaminomethyl)phenyl)ethyl]arginine amide;

(R)-N² -(4,4'"'"'-dichlorodiphenylacetyl)-(R,S)-N-[1-(4-(aminocarbonylmethyl)phenyl)ethyl]arginine amide;

or

(R)-N² -(4,4'"'"'-dichlorodiphenylacetyl)-(R,S)-N-[1-(4-(aminocarbonylaminomethyl)phenyl)ethyl]arginine amide.

20. A compound as claimed in claim 1 which is:

(R)-N² -(diphenylacetyl)-(R)-N-[1-(4-methoxyphenyl)ethyl]arginine amide;

(R)-N² -(diphenylacetyl)-(R)-N-[1-(4-hydroxyphenyl)ethyl]arginineamide;

(R)-N² -[(R,S)-2-(4-chlorophenyl)phenylacetyl]-(R)-N-[1-(4-hydroxyphenyl)ethyl]arginine amide;

(R)-N² -(4,4'"'"'-dichlorodiphenylacetyl)-(R)-N-[1-(4-hydroxyphenyl)ethyl]arginine amide;

or

(R)-N² -[(R,S)-2-(4-hydroxyphenyl)phenylacetyl]-(R)-N-[1-(4-hydroxyphenyl)ethyl]arginine amide.

21. A pharmaceutical formulation including a compound as defined in claim 1, or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

22. A method of treatment of a cardiovascular disease, which method comprises administration of a therapeutically effective amount of a compound as defined in claim 1, or a pharmaceutically acceptable derivative thereof, to a person suffering from, or susceptible to, such a condition.

23. A method of treatment of a vasoconstriction, which method comprises administration of a therapeutically effective amount of a compound as defined in claim 1, or a pharmaceutically acceptable derivative thereof, to a person suffering from, or susceptible to, such a condition.

24. A process for the preparation of compounds of formula I which comprises:

(a) reaction of a compound of formula II, ##STR21## wherein Ar¹, R¹, R², R³, R⁵ and R⁶ are as defined in claim 1 with a compound of formula III,

space="preserve" listing-type="equation">R.sup.a SC(═

NR.sup.4)NH.sub.2 III

or a hydrogen sulphate salt thereof, wherein R^a represents C_1-4 alkyl and R⁴ is as defined in claim 1;

(b) for compounds of formula I in which R⁴ represents H, reaction of a compound of formula II as defined above with 1H-pyrazole-1-carboxamidine, or a hydrohalide salt thereof;

(c) reaction of a compound of formula II as defined above with a compound of formula IV,

space="preserve" listing-type="equation">R.sup.a OC(═

NR.sup.4)NH.sub.2 IV

or a hydrogen sulphate salt thereof, wherein R^a is as defined above and R⁴ is as defined in claim 1;

(d) for compounds of formula I in which R⁴ represents H, reaction of a compound of formula II as defined above with a compound of formula V, ##STR22## wherein m represents 2 or 3;

(e) reaction of a compound of formula VI, ##STR23## wherein R^b represents C_1-4 alkyl and Ar¹, R¹, R², R³, R⁵ and R⁶ are as defined in claim 1 with a compound of formula VII,

space="preserve" listing-type="equation">R.sup.4 NH.sub.2 VII

wherein R⁴ is as defined in claim 1;

(f) reaction of a compound of formula VIII, ##STR24## wherein Ar¹, R¹, R², R³ and R⁴ are as defined in claim 1 with a compound of formula IX, ##STR25## wherein R⁵ and R⁶ are as defined in claim 1;

(g) reaction of a compound of formula VIII, as defined above, with a compound of formula X, ##STR26## wherein R⁵ and R⁶ are as defined in claim 1;

or (h) reaction of a compound of formula VIII, as defined above, with a compound of formula XI, ##STR27## wherein R⁵ and R⁶ are as defined in claim 1.