Claims
- 1. A peptide comprising:
- (a) a cyclic moiety containing a sequence selected from:
- Xaa.sub.1 -Arg-Gly-Asp-Xaa.sub.2,
- and
- Xaa.sub.1 -Lys-Gly-Asp-Xaa.sub.2
- where;
- Xaa.sub.1 represents from 1 to 20 .alpha.-amino acids or .alpha.-amino acid analogues, and
- Xaa.sub.2 represents an .alpha.-amino acid or .alpha.-amino acid analogue bonded to Xaa.sub.1 through a bond selected from the group;
- amide,
- thioether,
- disulfide,
- ether,
- sulfoxide,
- sulfone, and
- (b) a positively charged nitrogen containing exocyclic moiety bonded to Xaa.sub.2 through a functional group of Xaa.sub.2.
- 2. The peptide of claim 1 wherein the positively charged exocyclic moiety is represented by the formula:
- --NH--(link)-q
- where;
- (link) represents a linking group selected from;
- C.sub.3 -C.sub.10 -alkyl, either branched, linear, or cyclic,
- C.sub.3 -C.sub.10 -alkenyl,
- C.sub.3 -C.sub.10 -alkynyl,
- C.sub.6 -C.sub.14 -aryl substituted with 2 or more C.sub.1 -C.sub.8 -alkyl groups,
- C.sub.1 -C.sub.13 -heterocycle, saturated or unsaturated, containing 1-4 heteroatoms selected from N, O and S,
- C.sub.1 -C.sub.6 -alkyl substituted C.sub.5 -C.sub.14 saturated or unsaturated heterocycle, containing from 1-4 heteroatoms selected from N, O and S, and
- optionally, (link) may be substituted with substituents selected from;
- COR,
- CONR'R'",
- halo (F,Cl,Br,I),
- nitro,
- C.sub.1 -C.sub.6 -alkyl,
- phenyl,
- benzyl, and
- C.sub.3 C.sub.6 -cycloalkyl,
- wherein R is selected from;
- hydroxy,
- C.sub.1 -C.sub.8 -alkoxy,
- C.sub.3 -C.sub.12 -alkenoxy,
- C.sub.6 -C.sub.12 -aryloxy,
- di-C.sub.1 -C.sub.8 -alkylamino-C.sub.1 -C.sub.8 -alkoxy,
- acylamino-C.sub.1 -C.sub.8 -alkoxy selected from the group;
- acetylaminoethoxy,
- nicotinoylaminoethoxy,
- succinamidoethoxy, and
- pivaloyloxyethoxy,
- C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.8 -alkoxy where the aryl group is unsubstituted or substituted with one or more of the groups;
- nitro,
- halo (F, Cl, Br, I),
- C.sub.1 -C.sub.4 -alkoxy, and
- amino,
- hydroxy-C.sub.2-C.sub.8 -alkoxy,
- dihydroxy-C.sub.3 -C.sub.8 -alkoxy, and
- wherein R' and R" are independently selected from;
- hydrogen,
- C.sub.1 -C.sub.10 -alkyl either branched, linear or cyclic,
- C.sub.3 -C.sub.10 -alkenyl provided the double bond is not adjacent any N,
- C.sub.6 -C.sub.14 -aryl,
- C.sub.1 -C.sub.6 -alkyl-C.sub.6 -C.sub.10 -aryl
- saturated or unsaturated heterocycle having from 5-14 atoms in the cycles and from 1-4 heteroatoms selected from N, O and S,
- optionally, R' and R" taken together may form
- trimethylene,
- tetramethylene,
- pentamethylene, and
- 3-oxopentamethylene,
- q represents a group selected from;
- amino,
- amidino, and
- guanido,
- wherein any hydrogen bonded to any nitrogen or carbon of the amino, amidino or guanido group is optionally substituted with a lower C.sub.1 -C.sub.6 -alkyl group.
- 3. The peptide of claim 2 wherein the positively charged exocyclic moiety is a positively charged amino acid residue selected from .alpha.-amino acids or .alpha.-amino acid analogues.
- 4. The peptide of claim 3 wherein the positively charged exocyclic moiety is a D or L .alpha.-amino acid selected from;
- His,
- Lys,
- Arg, and
- Orn,
- wherein the .alpha.-carboxyl group of the D or L .alpha.-amino acid is optionally derivitized with an amino or lower alkyl substituted amino group.
- 5. The peptide of claim 4 wherein Xaa.sub.2 is an amino acid residue selected from the group;
- .alpha.-aminoadipic,
- Cys,
- homo-Cys,
- Pen,
- Pmp,
- Pas,
- Asp,
- Glu,
- Orn,
- Lys,
- Ser,
- Thr, and
- Tyr.
- 6. The peptide of claim 5 where Xaa.sub.2 is selected from Cys and Pen.
- 7. The peptide of claim 6 wherein Xaa.sub.1 is one or more naturally occurring .alpha.-amino acids or the D steroisomers thereof.
- 8. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of claim 1.
- 9. A method for inhibiting platelet aggregation which method comprises administering a platelet aggregation inhibiting amount of the compound of claim 1.
- 10. A method for reducing platelet aggregation in a mammal, comprising administering a pharmaceutically effective amount of the composition of matter as defined by claim 1 to the mammal.
- 11. The method of claim 10, further comprising administering said composition of matter to the mammal in admixture with a pharmaceutically acceptable carrier.
- 12. A method for treating a mammal who has an increased propensity for thrombus formation, comprising administering a pharmaceutically effective amount of the composition of matter as defined by claim 1 to the mammal.
- 13. A method for treating a mammal who has an increased propensity for thrombus formation, comprising administering a pharmaceutically effective amount of the composition of matter as defined by claim 1 in combination with a thrombolytic agent.
- 14. A method for treating a mammal who has an increased propensity for thrombus formation, comprising administering a pharmaceutically effective amount of the composition of matter as defined by claim 1 in combination with an anticoagulant.
- 15. The cyclic peptide of claim 1 wherein the cycle contains 17 or 18 atoms in the ring.
- 16. A compound of the formula: ##STR100## wherein R.sub.1 is selected from;
- NHR.sub.15 Q, and
- NR.sub.15 R.sub.16 Q,
- wherein R.sub.15 and R.sub.16 are independently selected from;
- C.sub.3 -C.sub.10 -alkyl either linear, branched or cyclic,
- C.sub.3 -C.sub.10 -alkenyl,
- C.sub.3 -C.sub.10 -alkynyl,
- C.sub.6 -C.sub.14 -aryl,
- C.sub.1 -C.sub.6 -alkyl-C.sub.6 -C.sub.10 -aryl,
- saturated or unsaturated heterocycle or C.sub.1 -C.sub.6 -alkyl substituted heterocycle containing from 5 to 14 atoms in the cycle and from 1 to 4 heteroatoms selected from N, O and S,
- NR.sub.15 R.sub.16 taken together may form a heterocycle or C.sub.2 -C.sub.6 -alkyl substituted heterocycle wherein R.sub.15 and R.sub.16 taken together are trimethylene, tetramethylene, pentamethylene or 3-oxopentamethylene,
- and wherein each R.sub.15 or R.sub.16 may optionally be substituted with one or more substituents selected from;
- COR.sub.9,
- CONR'R",
- halo (F,Cl,Br,I),
- nitro,
- C.sub.1 -C.sub.6 -alkyl,
- phenyl,
- benzyl, and
- C.sub.3 -C.sub.6 -cycloalkyl, and
- Q is a group bonded to R.sub.15, R.sub.16 or substituents bonded thereto, Q being selected from;
- --NR'R"
- --NR'R"R'" ##STR101##
- --NR'--CR'.dbd.NR'
- --NR'--CR'.dbd.NR" ##STR102## wherein; R' and R" are independently selected from;
- hydrogen,
- C.sub.1 -C.sub.10 -alkyl either branched, linear or cyclic,
- C.sub.3 -C.sub.10 -alkenyl,
- C.sub.3 -C.sub.10 -alkynyl,
- C.sub.6 -C.sub.14 -aryl,
- C.sub.1 -C.sub.6 -alkyl-C.sub.6 -C.sub.10 -aryl
- saturated or unsaturated heterocycle having from 5-14 atoms in the cycles and from 1-4 heteroatoms selected from N, O and S,
- and wherein R' and R" taken together are
- trimethylene,
- tetramethylene,
- pentamethylene, and
- 3-oxopentamethylene,
- R"' is C.sub.1 -C.sub.10 -alkyl, phenyl and benzyl, and
- o+p is an integer selected form 0, 1, 2, 3, and 4;
- R.sub.2, R.sub.3, R.sub.5, R.sub.6, R.sub.7, R.sub.8 are the same or different and are selected from;
- hydrogen,
- C.sub.6 -C.sub.12 -aryl where the aryl group is unsubstituted or substituted by one or more of the groups; nitro, hydroxy, halo (F, Cl, Br, I), C.sub.1 -C.sub.8 -alkyl, halo-C.sub.1 -C.sub.8 -alkyl, C.sub.1 -C.sub.8 -alkoxy, amino, phenyloxy, phenyl, acetamido, benzamido, di-C.sub.1 -C.sub.8 -alkylamino, C.sub.1 -C.sub.8 -alkylamino, C.sub.6 -C.sub.12 -aroyl, C.sub.1 -C.sub.8 -alkanoyl and hydroxy-C.sub.1 -C.sub.8 -alkyl,
- C.sub.1 -C.sub.12 -alkyl either substituted or unsubstituted, branched or straight chain where the substituents are selected from;
- halo (F, Cl, Br, I),
- C.sub.1 -C.sub.8 -alkoxy,
- C.sub.6 -C.sub.12 -aryloxy where the aryl group is unsubstituted or substituted by one or more of the groups; nitro, hydroxy, halo (F, Cl, Br, I), C.sub.1 -C.sub.8 -alkyl, C.sub.1 -C.sub.8 -alkoxy, amino, phenyloxy, acetamido, benzamido, di-C.sub.1 -C.sub.8 -alkylamino, C.sub.1 -C.sub.8 -alkylamino, C.sub.6 -C.sub.12 aroyl and C.sub.1 -C.sub.8 -alkanoyl,
- isothioureido,
- C.sub.3 --C.sub.7 -cycloalkyl,
- ureido,
- amino,
- C.sub.1 -C.sub.8 -alkylamino,
- di-C.sub.1 -C.sub.8 -alkylamino,
- hydroxy,
- amino-C.sub.2 -C.sub.8 -alkylthio,
- amino-C.sub.2 -C.sub.8 -alkoxy,
- acetamido, and
- benzamido wherein the phenyl ring is unsubstituted or substituted by one or more of the groups; nitro, hydroxy, halo (F, Cl, Br, I), C.sub.1 -C.sub.8 -alkyl, C.sub.1 -C.sub.8 -alkoxy, amino, phenyloxy, acetamido, benzamido, di-C.sub.1 -C.sub.8 -alkylamino, C.sub.1 -C.sub.8 -alkylamino, C.sub.6 -C.sub.12 aroyl, and C.sub.1 -C.sub.8 -alkanoyl,
- C.sub.6 -C.sub.12 -arylamino wherein the aryl group is unsubstituted or substituted by one or more of the groups; nitro, hydroxy, halo, C.sub.1 -C.sub.8 -alkyl, C.sub.1 -C.sub.8 -alkoxy, amino, phenyloxy, acetamido, benzamido, di-C.sub.1 -C.sub.8 -alkylamino, C.sub.1 -C.sub.8 -alkylamino, C.sub.6 -C.sub.12 -aroyl, and C.sub.1 -C.sub.8 -alkanoyl,
- guanidino,
- phthalimido,
- mercapto,
- C.sub.1 -C.sub.8 -alkylthio,
- C.sub.6 -C.sub.12 -arylthio,
- carboxy,
- carboxamide,
- carbo-C.sub.1 -C.sub.8 -alkoxy, and
- C.sub.6 -C.sub.12 -aryl wherein the aryl group is unsubstituted or substituted by one or more of the groups nitro, hydroxy, halo, C.sub.1 -C.sub.8 -alkyl, C.sub.1 -C.sub.8 -alkoxy, amino, phenyloxy, acetamido, benzamido, di-C.sub.1 -C.sub.8 alkylamino, C.sub.1 -C.sub.8 -alkylamino, hydroxy-C.sub.1 -C.sub.8 -alkyl, C.sub.6 -C.sub.12 aroyl and C.sub.1 -C.sub.8 -alkanoyl, and
- aromatic heterocycle wherein the heterocycle contains 5-10 ring atoms and one or two O, N or S heteroatoms;
- R.sub.2 and R.sub.3, R.sub.5 and R.sub.6, or R.sub.7 and R.sub.8 may optionally and independently be joined together to form a carbocyclic or heterocyclic ring of from four to seven atoms where the heteroatoms are selected from O, S or NR.sub.12 where R.sub.12 is selected from;
- hydrogen,
- C.sub.1 -C.sub.8 -alkyl,
- C.sub.3 -C.sub.8 -alkenyl,
- C.sub.6 -C.sub.12 -aryl,
- C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.8 -alkyl,
- C.sub.1 -C.sub.8 -alkanoyl, and
- C.sub.6 -C.sub.12 -aroyl,
- R.sub.4 is selected from;
- hydrogen,
- C.sub.1 -C.sub.8 -alkyl,
- C.sub.3 -C.sub.10 -cycloalkyl,
- C.sub.6 -C.sub.12 -aryl, and
- C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.8 -alkyl;
- R.sub.2 or R.sub.3 may be optionally joined with R.sub.4 to form a piperidine, pyrrolidine or thiazolidine ring;
- R.sub.9 is selected from;
- hydroxy,
- C.sub.1 -C.sub.8 -alkoxy,
- C.sub.3 -C.sub.12 -alkenoxy,
- C.sub.6 -C.sub.12 -aryloxy,
- di-C.sub.1 -C.sub.8 -alkylamino-C.sub.1 -C.sub.8 -alkoxy,
- acylamino-C.sub.1 -C.sub.8 -alkoxy selected from the group acetylaminoethoxy, nicotinoylaminoethoxy and succinamidoethoxy,
- pivaloyloxyethoxy,
- C.sub.6 -C.sub.12 aryl-C.sub.1 -C.sub.8 -alkoxy where the aryl group is unsubstituted or substituted with one or more of the groups; nitro, halo (F, Cl, Br, I), C.sub.1 -C.sub.4 -alkoxy, and amino,
- hydroxy-C.sub.2 -C.sub.8 -alkoxy,
- dihydroxy-C.sub.3 -C.sub.8 -alkoxy, and
- NR.sub.10 R.sub.11 wherein R.sub.10 and R.sub.11 are the same or different and are hydrogen, C.sub.1 -C.sub.8 -alkyl, C.sub.3 -C.sub.8 -alkenyl, C.sub.6 -C.sub.12 -aryl where the aryl group is unsubstituted or substituted with one or more of the groups nitro, halo (F, Cl, Br, I), C.sub.1 -C.sub.4 -alkoxy, and amino, C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.8 -alkyl where the aryl group is unsubstituted or substituted by one or more of the groups nitro, halo (F, Cl, Br, I), C.sub.1 -C.sub.4 -alkoxy, and amino;
- R.sub.14 is selected from;
- hydrogen, C.sub.1 -C.sub.8 -alkyl, C.sub.3 -C.sub.8 -alkenyl, C.sub.6 -C.sub.12 -aryl and C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.8 -alkyl;
- R.sub.17 is selected from;
- hydrogen, and ##STR103## X is selected from; O or S,
- S bearing one or two O atoms,
- NR.sub.13 wherein R.sub.13 is;
- hydrogen,
- C.sub.1 -C.sub.8 -alkyl,
- C.sub.3 -C.sub.8 -alkenyl,
- C.sub.6 -C.sub.14 -aryl,
- C.sub.6 -C.sub.14 -aryl-C.sub.1 -C.sub.8 -alkyl,
- C.sub.1 -C.sub.8 -alkanoyl,
- C.sub.6 -C.sub.14 -aroyl,
- C.sub.6 -C.sub.14 -aryl-C.sub.1 -C.sub.8 -alkanoyl, and
- (CH.sub.2).sub.k where k is an integer from 0 to 5;
- n is an integer from 1 to 6;
- m is an integer from 0 to 4; and
- pharmaceutically acceptable salts thereof.
- 17. A method for treating a mammal who has an increased propensity for thrombus formation, comprising administering a pharmaceutically effective amount of the composition of matter as defined by claim 16.
CROSS REFERENCES
This application is a continuation of U.S. application Ser. No. 08/311,835 filed 23 Sep. 1994, U.S. Pat. No. 5,493,007 which application is a continuation of U.S. application Ser. No. 08/173,716 filed 23 Dec. 1993 (abandoned), which application is a continuation of U.S. application Ser. No. 08/045,566 filed 9 Apr. 1993 (abandoned), which application is a continuation of U.S. application Ser. No. 07/681,802 filed 5 Apr. 1991 (abandoned), which applications are incorporated herein by reference and to which applications priority is claimed under 35 USC .sctn.120.
US Referenced Citations (15)
Foreign Referenced Citations (4)
Number |
Date |
Country |
275748 |
Jul 1988 |
EPX |
317053 |
May 1989 |
EPX |
338634 |
Oct 1989 |
EPX |
341915 |
Nov 1989 |
EPX |
Continuations (4)
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311835 |
Sep 1994 |
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173716 |
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45566 |
Apr 1993 |
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681802 |
Apr 1991 |
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