Eli Lilly and Company

Lilly Industries, Inc.

Other

Jai P Singh

Colin W Smith

George J Cullinan

Dan L Wood

Shalley K Gupta

William F Heath, Jr

Lawrence E Stramm

Raymond Francis Kauffman

Colin P Dell

Samantha J Ambler

Peter Thaddeus Gallagher

William M Owton

Michael Brunavs

Todd R Wiernicki

Danny Lee Wood

The present invention is based of the discovery of two modified forms of human platelet factor-4, herein named MPF-4 and CPF-4, which were isolated from serum free culture medium of lipopolysaccharide-stimulated peripheral blood leukocytes. Amino acid sequence determination revealed that MPF-4 shares homology with platelet factor-4 beginning at N-terminal residue 17. CPF-4 consists of MPF-4 disulfide bonded to the 16 N-terminal residues of platelet factor-4. Both MPF-4 and CPF-4 are potent inhibitors of endothelial cell proliferation, approximately 10-100 fold more potent than native or recombinant platelet factor-4, making them useful in the treatment of angiogenic diseases.

Modified platelet factor-4

The current invention provides methods for increasing the concentration of nitric oxide (NO) in vascular endothelial cells, comprising administering a compound of formula I ##STR1## Wherein: R is hydrogen, --OH, --O(C.sub.1 -C.sub.4 alkyl), --OCO(C.sub.1 -C.sub.4 alkyl), or --OCOAr where Ar is a phenyl or optionally substituted phenyl;

Methods of increasing nitric oxide synthesis

This invention provides novel compounds and pharmaceutical methods comprising the administration of a compound of the Formula I: ##STR1## wherein n, m, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are variables.

Pharmaceutical compounds

Methods of inhibiting vascular smooth muscle cell migration comprising administering to a human or other mammal in need of treatment an effective amount of a compound having the formula ##STR1## wherein R.sub.1 and R.sub.3 are independently hydrogen, ##STR2## wherein Ar is optionally substituted phenyl; R.sub.2 is pyrrolidino, hexamethyleneimino, or piperidino; and pharmaceutically acceptable salts and solvates thereof.

Methods for inhibiting vascular smooth muscle cell migration

A method of inhibiting angiogenesis is disclosed comprising administering to a human in need thereof an effective amount of a compound having the formula ##STR1## wherein R.sup.1 and R.sup.3 are independently hydrogen, --CH.sub.3, ##STR2## wherein Ar is optionally substituted phenyl; R.sup.2 is selected from the group consisting of pyrrolidine and piperidino; or a pharmaceutically acceptable salt of solvate thereof.

Methods for inhibiting angiogenesis

Modified platelet factor-4 and cleaved platelet factor 4

Method for inhibiting angiogenesis with modified platelet factor-4 and

Methods of inhibiting vascular smooth muscle cell proliferation and vascular restinosis comprising administering to a human or other mammal in need of treatment an effective amount of a compound having the formula ##STR1## wherein R.sub.1 and R.sub.3 are independently hydrogen, ##STR2## wherein Ar is optionally substituted phenyl; R.sub.2 is ##STR3## R.sub.4 is hydrogen or --OR.sub.1, and pharmaceutically acceptable salts and solvates thereof.

Methods for inhibiting vascular smooth muscle cell proliferation and

Methods of inhibiting vascular smooth muscle cell proliferation and restinosis are disclosed comprising administering to a human or other mammal in need of treatment an effective amount of a compound having the formula ##STR1## wherein R.sub.1 and R.sub.3 are independently hydrogen, --CH.sub.3, ##STR2## wherein Ar is optionally substituted phenyl; R.sub.2 is ##STR3## and R.sub.4 is hydrogen or --OR.sub.1, and pharmaceutically acceptable salts and solvates thereof.

Methods of inhibiting vascular smooth muscle cell proliferation and vascular restinosis comprising administering to a human or other mammal in need of treatment an effective amount of a compound having the formula ##STR1## wherein R.sub.1 and R.sub.3 are independently hydrogen, --CH.sub.3, ##STR2## wherein Ar is optionally substituted phenyl; R.sub.2 is ##STR3## R.sub.4 is hydrogen or --OR.sub.1, and pharmaceutically acceptable salts and solvates thereof.

Methods of treating an immune disease, cell proliferation, restenosis and vascular smooth muscle cells using the pharmaceutical compounds of the formula ##STR1## in which R.sup.2 is phenyl, naphthyl or heteroaryl selected from thienyl, pyridyl, benzothienyl, quinolinyl, benzofuranyl or benzimidazolyl, said phenyl, naphthyl and heteroaryl groups being optionally substituted, or R.sup.2 is furanyl optionally substituted with C.sub.1-4 alkyl; and salts thereof.

Methods of using dihydropyrans

A method of inhibiting cell proliferation in mammals which comprises the local delivery of an inhibitory amount of dipyridamole. Inhibiting cell proliferation is useful for the treatment of proliferative diseases such as vascular restonesis, scleroderma, psoriasis, and rheumatoid arthritis. This method includes the local delivery of dipyridamole to the proliferative site by various techniques including local delivery catheters, site specific carriers, implants, direct injection, or direct application.

Local delivery of dipyridamole for the treatment of proliferative

A pharmaceutical compound of the formula ##STR1## in which n is 0, 1 or 2 and R.sup.1 is attached at any of the positions 5, 6, 7, 8, 9 or 10, and each R.sup.1 is halo, trifluoromethyl, C.sub.1-4 alkoxy, hydroxy, nitro, C.sub.1-4 alkyl, C.sub.1-4 alkylthio, hydroxy-C.sub.1-4 alkyl, hydroxy-C.sub.1-4 alkoxy, trifluoromethoxy, carboxy, --COOR.sup.5 where R.sup.5 is an ester group, --CONR.sup.6 R.sup.7 or --NR.sup.6 R.sup.7 where R.sup.6 and R.sup.7 are each hydrogen or C.sub.1-4 alkyl; R.sup.2 is phenyl, naphthyl or heteroaryl selected from thienyl, pyridyl, benzothienyl, quinolinyl, benzofuranyl or benzimidazolyl, said phenyl, naphthyl and heteroaryl groups being optionally substituted, or R.sup.2 is furanyl optionally substituted with C.sub.1-4 alkyl; R.sup.3 is nitrile, carboxy, --COOR.sup.8 where R.sup.8 is an ester group, --CONR.sup.9 R.sup.10 where R.sup.9 and R.sup.10 are each hydrogen or C.sub.1-4 alkyl, or R.sup.11 SO.sub.2 -- where R.sup.11 is C.sub.1-4 alkyl or optionally substituted phenyl; and R.sup.4 is --NR.sup.12 R.sup.13, --NHCOR.sup.12, --N(COR.sup.12).sub.2 or --N.dbd.CHOCH.sub.2 R.sup.12 where R.sup.12 and R.sup.13 are each hydrogen or C.sub.1-4 alkyl optionally substituted with carboxy, ##STR2## where X is C.sub.2-4 alkylene, or --NHSO.sub.2 R.sup.14 where R.sup.14 is C.sub.1-4 alkyl or optionally substituted phenyl; provided that when n is 0, R.sup.3 is nitrile and R.sup.4 is --NH.sub.2, R.sup.2 is not phenyl or phenyl substituted in the para-position with a single chloro, hydroxy or methoxy substituent; and salts thereof.

A method of inhibiting cell proliferation in mammals which comprises the local delivery of an inhibitory amount of dipyridamole. Inhibiting cell proliferation is useful for the treatment of proliferaive diseases such as vascular restonesis, scleroderma, psoriasis, and rheumatoid arthritis. This method includes the local delivery of dipyridamole to the proliferative site by various techniques including local delivery catheters, site specific carriers, implants, direct injection, or direct application.

Growing community of inventors

Carmel, IN, United States of America

Jai P Singh